James V. Quinn

Hemodynamic Effects Of Carbon Dioxide Pneumoperitoneum During Mechanical Ventilation And Positive End-expiratory Pressure

Laparoscopy is frequently used for diagnosis and treatment of critically ill trauma patients. Its effects on cardiopulmonary performance in the intensive care unit patient population, however, are not well-defined. This study evaluated the effects of positive end-expiratory pressure (PEEP) and carbon dioxide (CO2) pneumoperitoneum on hemodynamic function during mechanical ventilation. Five anesthetized, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at 0, 5, 10, 15, and 20 cm H2O PEEP without, and then with 15 mm Hg CO2 pneumoperitoneum. A hemodynamic profile, analyses of arterial and mixed venous blood gases and mixed venous hemoglobin oxygen saturation values were obtained at each data point. Compared with the non-insufflated group, CO2 pneumoperitoneum significantly increased central venous pressure, mean arterial pressure, mean pulmonary artery pressure, pulmonary vascular resistance index, and stroke index for the range of PEEP levels. With PEEP of 10 cm H2O, hemodynamic changes in non-insufflated animals were not statistically significant, but with CO2 pneumoperitoneum, stroke index and left ventricular stroke work index were decreased at 5 cm H2O PEEP, as was cardiac index at 10 cm PEEP. Pulmonary gas exchange was not affected by CO2 pneumoperitoneum. The results indicate that, in this paradigm, CO2 pneumoperitoneum for laparoscopy increases ventricular afterload and exacerbates the adverse effects of PEEP. These findings could be clinically significant in critically ill patients.

Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock.

OBJECTIVE Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF). The purpose of this investigation was to a) examine temporal patterns of TNF and arachidonic acid metabolite release in a porcine model of bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and leukotrienes to determine the relationships among these inflammatory response mediators and the alterations in cardiorespiratory dysfunction for which they are required. DESIGN Prospective, nonrandomized, controlled trial. SETTING Laboratory at a university medical center. SUBJECTS Thirty-four female Yorkshire swine. INTERVENTIONS Animals were divided into six experimental groups: five septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr, gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6; prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no mediator inhibitor and served as a septic control, and one anesthesia control group (n = 6) received no intervention. MEASUREMENTS AND MAIN RESULTS PAF receptor blockade significantly increased systemic hypotension and mixed venous oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene inhibition increased mean arterial pressure, pulmonary and systemic vascular resistance indices, and arterial and mixed venous oxygen saturation and reduced pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption, and all measured mediators. Thromboxane receptor blockade lowered TNF and leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and significantly increased arterial and tissue oxygenation compared with septic controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations, arterial hypoxemia, and oxygen consumption during sepsis and increased circulating leukotriene B4. CONCLUSIONS Elevations in plasma TNF predictably precede peak levels of eicosanoids in this model. PAF, leukotrienes, and thromboxane A2 are necessary for pulmonary hypertension during bacteremia. Systemic hypotension and increased vascular permeability are mediated by both leukotrienes and PAF. There are complex interactions among mediators during sepsis and further studies are required to define these relationships.

Multivariate regression modeling for the prediction of inflammation, systemic pressure, and end-organ function in severe sepsis.

The purpose of this study was to evaluate the feasibility of developing multivariate equations that predicted blood pressure and measured levels of end-organ function indicators quantitatively up to 72 h in advance in critically ill patients with severe sepsis. Data collected prospectively from 59 patients entered into two sequential placebo-controlled clinical trials of recombinant interleukin-1 receptor antagonist in severe sepsis and septic shock was analyzed retrospectively. A series of multivariate equations were developed to predict systemic pressure, coagulation, and vital organ function indicators quantitatively at 24, 48, and 72 h after the onset of severe sepsis. These equations used physiologic and clinical laboratory measurements, plus circulating levels of eicosanoids and cytokines obtained when severe sepsis criteria first were met, and end-organ function indicators measured 24, 48, and 72 h later. Multivariate predictive equations were developed for temperature, white blood cell count, mean arterial pressure (MAP), Pao2/Fio2 ratio, the Murray acute lung injury score, alanine and aspartate aminotransferases, prothrombin time, partial thromboplastin time, platelet count, serum creatinine, and Glasgow Coma Scale. The percentage of data variation explained by the equations ranged from 11.4% (MAP at 48 h) to 85.1 % (platelet count at 24 h). Linear regression analysis of predicted values, obtained by entering baseline data from individual patients into the multivariate equations, versus observed results at 24, 48, and 72 h yielded regression coefficients ranging from .371 (MAP at 48 h) to .924 (platelet count at 24 h). Among patients without end-organ dysfunction at baseline, sensitivities for predicting values consistent with the onset of organ failure were ≥88% in 21/27 (78%) of the predictive equations. Resolution of organ failure indicators present at baseline was predicted successfully in individual patients, with 20/27 (74%) specificities ≥76%. In critically ill patients with severe sepsis, multivariate analysis of interactions among clinical observations, standard laboratory tests, and inflammatory response mediators produced equations that predicted systemic blood pressure and inflammatory and end-organ function indicators quantitatively up to 72 h in advance. Whether or not this methodology might be developed further to predict subclinically the onset and resolution of acute organ failure and shock in critically ill patients, and if it can be validated in a prospective trial will require further studies.

Differences in eicosanoid and cytokine production between injury/hemorrhage and bacteremic shock in the pig.

Plasma concentrations of the eicosanoids leukotriene (LT)B4, LTC4D4E4, thromboxane (TX)A2 and prostaglandin (PG)I2, and tumor necrosis factor (TNF) were measured during acute bacteremic shock and injury/hemorrhage in two porcine models. As TXA2 and PGI2 are rapidly metabolized, we measured their stable metabolites TXB2 and 6-keto-PGF1α. Bacteremic shock was induced by a graded infusion of Aeromonas hydrophila over 4 h. Injury/hemorrhage was produced by a 30 min, 30% total blood volume hemorrhage followed by a 30 min shock period and then reinfusion of shed blood. Nociceptive afferent nerve stimulation was applied to the brachial plexi to mimic the cardiovascular responses to tissue injury. There was no increase in eicosanoid or TNF levels in the injury/hemorrhage model. In sepsis there was an early peak in TNF (at 60 min) followed by peaks in LTB4 and LTC4D4E4 at 180 min. Both TXB2 and 6-keto-PGF1α showed large increases at the end of the study but there was no evidence that they had reached a peak. These results suggest that the very early inflammatory response in bacteremic shock and injury/hemorrhagic shock may be quite different. This may have implications for any therapies aimed at reducing the incidence of multiple organ failure after either of these physiological insults.

Interleukin-1 mediates increased plasma levels of eicosanoids and cytokines in patients with sepsis syndrome.

The purpose of this was to study evaluate the effects of interleukin-1 (IL-1) inhibition by human recombinant IL-1 receptor antagonist (IL-1ra) on plasma prostaglandin, leukotriene, and cytokine levels in sepsis syndrome. As part of a multisite, prospective, randomized, double-blind, placebo-controlled clinical trial, 19 septic patients received IL-1ra in a 100 mg bolus followed by 2.0 mg/kg/h i.v. for 72 h (n = 10) or placebo (n = 9). Plasma thromboxane B2 (TXB2), prostaglandin 6-keto-F1 alpha (PGI), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF) were measured by ELISA before study drug infusion (baseline) and at 24, 48, 72, and 96 h after the beginning of the study drug infusion. Differences between placebo and IL-1-ra for plasma LTB4 and TNF were not significant. Plasma TXB2, PGI, LTC4D4E4, and IL-6, expressed as % baseline, were significantly lower in patients receiving IL-1ra than in the placebo group (p < .05), while plasma IL-1 was increased significantly. IL-1 may be a necessary mediator of increased circulating PGI, TXB2, LTC4D4E4, and IL-6 levels in patients with sepsis syndrome. Plasma IL-1 is increased with infusion of IL-1ra. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis.

OBJECTIVE The purpose of the study was to identify the changes in plasma prostaglandin, leukotriene, and cytokine levels during clinical severe sepsis for which interleukin-1 was necessary. SUMMARY BACKGROUND DATA Circulating prostaglandins, leukotrienes, and cytokines have been implicated as causative agents of systemic inflammation due to sepsis. However, interactions between interleukin-1 and the other cytokine and eicosanoid mediators of severe sepsis are not well-defined. METHODS As part of two sequential multisite, prospective, randomized, double-blind, placebo-controlled clinical trials, 37 patients with severe sepsis received interleukin-1 receptor antagonist (IL-1ra) 100-mg bolus followed by 2 mg/kg per hour intravenously for 72 hours (n = 20) or placebo (n = 17). Plasma thromboxane B2 (TxB2), prostaglandin 6-keto-F1alpha (PGI), leukotriene B4 (LTB4), leukotriene C4D4E4 (LTC4D4E4), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay before study drug infusion (baseline) and at 24, 48, and 72 hours after the beginning of the study drug infusion. RESULTS Differences between placebo and IL-1ra for plasma LTB4 were not significant, but only IL-1ra LTB4 increased from baseline. Plasma TxB2, PGI, LTC4D4E4, TNF, and IL-6, expressed as % baseline, decreased significantly in patients receiving IL-1ra compared with the placebo group (p < 0.05), whereas plasma IL-1 increased significantly. CONCLUSIONS Interleukin-1 may be a necessary mediator of increased circulating PGI, TxB2, LTC4D4E4, TNF, and IL-6 levels in patients with severe sepsis. Plasma IL-1 and LTB4 are increased with infusion of IL-1 receptor antagonist. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

Evaluation of enzyme-linked immunosorbent assays for quantitation of eicosanoid mediators of sepsis syndrome.

ABSTRACT Thromboxane, prostacyclin, and the leukotrienes are eicosanoids that have been implicated as mediators of the host inflammatory response to infection and injury. Commercial enzyme-linked immunosorbent assays (ELISA) are being increasingly utilized to quantitate plasma eicosanoid concentrations in both clinical and experimental systemic inflammatory conditions. The objectives of this study were to 1) critically examine the performance characteristics of commercial ELISA kits for thromboxane B2, 6 keto-prostaglandin F1±, leukotriene B4, and leukotrienes C4, D4, and E4; 2) apply the four ELISA kits in obtaining actual eicosanoid plasma values under both baseline and septic conditions; and 3) recommend quality control measures for general use. Although averages of multiple standard curves from individual assays were variable, there was a strong linear regression relationship between the backfit dose and nominal dose for each level of standard. Precision profiles constructed for each assay type defined a working range where the intra-assay coefficient of variation is less than 10%. Backfit doses deviated most from nominal doses at both extremes of the standard curves and this variation is reflected in the higher percentage errors in these regions. Recovery of each eicosanoid analyte was 96–103%. Calculated sensitivities were somewhat higher than the manufacturers specifications. When applied to actual measurements in human and porcine plasma, the assays yielded values that fell within the working ranges of the standard curves with the exception of leukotriene B4. Thus, the ELISAs examined were reproducible, precise, and accurate within a specific working range for each assay type. However, internal controls were lacking in the commercial kits examined, which made assessment of intra- and inter-assay variation difficult.

THROMBOXANE INTERACTION WITH CARDIOPULMONARY DYSFUNCTION IN GRADED BACTERIAL SEPSIS

The relationship between plasma levels of thromboxane A2, radioimmunoassayed as thromboxane B2 (TxB), and cardiopulmonary dysfunction in graded bacterial sepsis was investigated. Five adult female pigs under anesthesia were intubated and allowed to breathe room air spontaneously. Femoral arterial, venous, and pulmonary artery catheters were inserted. After a 60-minute control period Aeromonas hydrophila (1.0 X 10(9)/ml) was infused intravenously at 0.2 ml/kg/hr, gradually increasing to 4.0 ml/kg/hr over 4 hours. Arterial and mixed venous blood gases, hemodynamic measurements, and TxB plasma concentrations were obtained during the control period, at 10, 20, 30, 45, and 60 minutes and at 30-minute intervals thereafter. Cardiac index increased significantly from control at 20 minutes, remained above control levels for 1 hour, and then declined to significantly low values at 150 minutes. TxB was increased from control at 20 minutes, rising to four times control at 120 minutes. Mean arterial pressure, pulmonary capillary wedge pressure, left ventricular stroke work, paO2, and pvO2 decreased significantly during the experiment. Pulmonary artery pressure and pulmonary vascular resistance increased significantly. Changes in TxB were significantly cross-correlated with changes in cardiac index, pulmonary vascular resistance, stroke volume, left ventricular stroke work, and paO2. TxB elevations led the cross-correlated variables by 0 to 60 minutes. Pulmonary vascular resistance cross-correlated with mean arterial pressure and cardiac index. TxB is increased early in graded bacterial sepsis. Changes in TxB appear to precede impaired cardiopulmonary function. The data suggest that TxB is involved in the detrimental hemodynamic effects of early septicemia.

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, Dunnetts t test, and Students 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.

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

ObjectiveThis 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. DesignExperimental. SettingLaboratory. SubjectsTwenty-three anesthetized adult swine. IntervensionsSwine 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. ConclusionsProstacyclin 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.