Prostacyclin is neither sufficient alone nor necessary to cause pulmonary dysfunction: results from infusions of prostacyclin and antiprostacyclin antibody in porcine septic shock.

OBJECTIVE: This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock. DESIGN: Experimental. SETTING: Laboratory. SUBJECTS: Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion. MEASUREMENTS AND MAIN RESULTS: Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups. CONCLUSIONS: Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

The cardiovascular hemodynamics and leukotriene kinetics during prostacyclin and anti-prostacyclin antibody infusions in septic shock.

This study evaluated whether or not prostacyclin (PGI2) was necessary or sufficient by itself in a pathophysiologic concentration to mediate the cardiovascular dysfunction of septic shock. Anesthetized adult swine received anesthesia only (ANESTHESIA CONTROL, n = 6); graded Aeromonas hydrophila, 10(10)/mL, infusion at 0.2 mL/kg/h that increased to 4.0 mL/kg/h over 3 h (SEPTIC SHOCK CONTROL, n = 6); pathophysiologic prostacyclin infusion to match septic shock control plasma levels without bacteremia (PGI2 INFUSION, n = 6), or graded Aeromonas hydrophila plus anti-prostacyclin antibody infusion (ANTI-PGI2-Ab INFUSION, n = 5). This graded porcine bacteremia model was 100% lethal after 4 h. Cardiovascular hemodynamics, arterial blood gases, and plasma levels of arachidonate metabolites were measured at baseline and hourly over a 4-h period. The results showed that PGI2 was not a necessary mediator of impaired cardiovascular hemodynamics in graded bacteremia, as anti-PGI2 antibody infusion did not improve the cardiac index, systemic vascular resistance, or peripheral oxygen balance in septic animals. Also, PGI2 was not sufficient alone to cause the cardiovascular dysfunction of sepsis, as pathophysiologic infusion of PGI2 did not reproduce such changes in normal animals. PGI2 blockade during bacteremia significantly increased LTC4D4E4, and LTB4 whereas PGI2 infusion suppressed LTC4D4E4 concentration, suggesting that endogenous PGI2 may blunt leukotriene release during septic shock. These results indicate a complex dynamic equilibrium among prostacyclin and leukotrienes in septic shock.

Interleukin-1 mediates hemodynamic dysfunction and release of eicosanoids and tumor necrosis factor during graded bacteremia.

The pathophysiologic events of sepsis mediated by interleukin-1 (IL-1) remain ill-defined. The purpose of this study was to identify the circulatory derangements of which IL-1 was a necessary mediator and evaluate its interactions with tumor necrosis factor (TNF) and the eicosanoids during graded bacteremia. Eleven adult female swine were anesthetized, mechanically ventilated, and monitored with pulmonary artery catheters and arterial lines; they received intravenously either saline vehicle (septic control, n = 6) or human recombinant IL-1 receptor antagonist (IL-1ra, n = 5). The animals were then infused with Aeromonas hydrophila (10(9)/mL) for 4 h at rates gradually increased from .2 mL/kg/h to 4 mL/kg/h over 3 h, then sacrificed after 4 h. Mean arterial pressure (MAP), left ventricular stroke work index (LVSWI), and systemic vascular resistance index (SVRI) were recorded at baseline and hourly thereafter, and plasma 6-keto-PGF1alpha (6-KETO), tumor necrosis factor-alpha (TNF) and leukotrienes B4(LTB4) and C4D4E4 (LTCDE), pg/mL, were measured by ELISA. MAP, LVSWI, arterial P(O2) all decreased in the septic control group to levels significantly below those of the IL-1 antagonist animals. Circulating 6-KETO, LTCDE, and TNF increased significantly in all septic animals. Plasma LTB, and TNF were reduced by IL-1 blockade, compared with septic controls. TxB2 was not affected by IL-1 inhibition. There were no intergroup differences in platelet aggregation, but the in vitro aggregation response decreased from baseline in septic controls to 54+/-27% (p < .05). IL-1 is necessary to the development of systemic hypotension impaired LVSWI, and increased intravascular platelet aggregation during graded bacteremia. Conversely, IL-1 helps to maintain stroke volume and low SVRI in graded bacteremia, possibly through increased prostacyclin release. It may contribute to impaired pulmonary gas exchange and increased tissue oxygen demands. TNF release is stimulated in the presence of unopposed IL-1 and may be synergistic with it in the adverse hemodynamic effects of endogenous IL-1. IL-1 is required for increased leukotriene and prostacyclin levels in this model, but it is not involved in thromboxane release. Whether the lack of survival benefit from IL-1ra in human sepsis is due to these mixed cardiopulmonary and mediator effects, to species differences, or to timing of IL-1ra administration is not clear from the data.

Platelet activating factor mediates cardiopulmonary dysfunction during graded bacteremic shock.

OBJECTIVE: To determine whether or not platelet activating factor (PAF) is a necessary mediator of cardiovascular dysfunction during graded bacteremia, and to identify PAF interactions with eicosanoids and tumor necrosis factor-alpha (TNF-alpha). METHODS: Seventeen anesthetized, hemodynamically monitored adult swine were studied for 4 hours in three groups. Group 1 (ANES, n = 5) were anesthesia controls; group 2 (septic control, SC, n = 6) received intravenous Aeromonas hydrophila (109/mL) at rates incrementally increased from 0.2 to 4.0 mL/ kg/h; group 3 (WEB, n = 6) received the PAF receptor antagonist WEB 2086, 3.0 mg/kg intravenously, then A. hydrophila. Cardiopulmonary parameters and plasma thromboxane B2 (TXB2), prostaglandin 6-keto F1 alpha (PGI2), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), and TNF-alpha were measured hourly. Statistical analysis was carried out using two-way analysis of variance (ANOVA) for repeated measurements, Dunnett's t test, and Student's t test, where appropriate. Statistical significance was determined at the 95% confidence interval. Values are presented as the mean +/- SEM. RESULTS: Pulmonary arterial pressure, pulmonary capillary wedge pressure, central venous pressure heart rate, VO2 and O2ER decreased significantly after WEB 2086 infusion, compared with SC, and mean arterial pressure, systemic vascular resistance index, stroke volume index, and left ventricular stroke work index increased. Arterial pH decreased significantly in SC animals, but was maintained at normal levels during bacteremia in the WEB group. Differences between WEB and SC for cardiac index, pulmonary vascular resistance index, right ventricular stroke work index, PaO2, SaO2, and PcO2, were not significant. The addition of WEB 2086 significantly decreased plasma levels of TXB2, PGI2, LTB4, and TNF-alpha compared with the SC group. LTC4D4E4 was decreased in WEB compared with SC animals, in which LTC4D4E4 increased during graded bacteremia. CONCLUSIONS: PAF is necessary to the development of systemic vasodilation and hypotension, pulmonary hypertension, decreased stroke volume, metabolic acidosis, and increased oxygen uptake during graded bacteremia. PAF-induced eicosanoid and cytokine release may be involved.

Aortocaval fistula treated by aortic exclusion.

Aortocaval fistulas are a rare complication of spontaneous rupture of an abdominal aortic aneurysm, representing an incidence of 2% and 4%. A review of the literature revealed 159 reported cases of aortocaval fistulas. We recently had a patient admitted to our institution with an abdominal aortic aneurysm that ruptured into the vena cava. The presence of the fistula was only recognized during operation. Primary closure of the fistula was not possible, and the aneurysmal segment was excluded. To our knowledge, this is the first report of aortic exclusion being used as the surgical treatment of an aortocaval fistula.

Comparison of the hemodynamic effects of gasless abdominal distention and CO2 pneumoperitoneum during incremental positive end-expiratory pressure.

Laparoscopy is used increasingly in managing critically ill patients. Carbon dioxide (CO2) pneumoperitoneum is used during these procedures. The increased intra-abdominal pressure of CO2 pneumoperitoneum, however, can affect cardiopulmonary performance adversely. Recently, gasless abdominal wall distention has been introduced as an alternative to CO2 pneumoperitoneum. The purpose of this study was to compare the hemodynamic effects of gasless abdominal distention (GAD) with those of CO2 pneumoperitoneum during mechanical ventilation with positive end-expiratory pressure (PEEP). Six anesthetized, paralyzed, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at incremental values of PEEP (0-20 cm H2O, by 5, Control) and then allowed to return to baseline hemodynamic status at 0 cm H2O PEEP. The animals were then randomly assigned to receive either CO2 pneumoperitoneum at 15 mm Hg intra-abdominal pressure (PNEUMO) or GAD (equal to anterior abdominal wall displacement of CO2) and PEEP was reapplied. The animals were allowed to return to hemodynamic baseline and PEEP was reapplied with the alternate method of abdominal wall distention. A complete hemodynamic profile and arterial/mixed venous blood gas measurements were monitored at each value of PEEP. With GAD, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and PaCO2 were significantly reduced, compared to PNEUMO, and PaO2 was increased. Cardiac index was higher in GAD versus PNEUMO at baseline, but was lower for GAD at PEEP levels above 10 cm H2O. These results indicate that in its net effect, GAD does not exacerbate the adverse hemodynamic effects of PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)