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(Chest. 2001;119:874-883.)
© 2001 American College of Chest Physicians

Increased Endothelial Injury in Septic Patients With Coronary Artery Disease*

Hartmut Kern, MD; Ralph Wittich, MD; Ute Rohr, MD; Wolfgang J. Kox, MD, PhD and Claudia D. Spies, MD

* From the Department of Anesthesiology and Intensive Care, University Hospital Charité, Campus Mitte, Humboldt University of Berlin, Germany.

Correspondence to: Claudia Spies, MD, Department of Anesthesiology and Intensive Care, University Hospital Charité, Campus Mitte, Humboldt University of Berlin, Schumannstr. 20/21, 10098 Berlin, Germany; e-mail: claudia.spies{at}charite.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Recently, it was proposed that soluble intercellular adhesion molecule (sICAM)-1 plasma levels may allow subgroup identification of patients at risk for cardiovascular complications during sepsis. However, the impact of preexisting coronary artery disease (CAD) on these results has not yet been tested. The aim of this study was to investigate whether plasma levels of adhesion molecules, nitric oxide, and cytokines differ between septic patients with or without preexisting CAD.

Design: Prospective study.

Setting: Surgical ICU.

Patients: Forty-four septic patients, 24 of whom met the criteria of CAD.

Measurement: Hemodynamic measurements were performed and blood samples were taken within 12 h after onset of sepsis (early sepsis) and again 72 h thereafter (late sepsis). Soluble adhesion molecules and cytokines were determined using commercially available enzyme-linked immunosorbent assay kits, cyclic guanosinomonophosphate (cGMP) by competitive radioimmunoassay, and nitrite/nitrate photometrically by Griess reaction.

Results: In CAD patients, sICAM-1 (p < 0.02) was significantly elevated in early and late sepsis, whereas soluble endothelial-linked adhesion molecule (sE-selectin; p < 0.01) and cGMP (p < 0.03) were only increased in late sepsis. Oxygen consumption did not significantly differ between groups. Oxygen delivery and mixed venous oxygen saturation during early and late sepsis were significantly diminished and the oxygen extraction ratio significantly increased in the CAD group (p < 0.05).

Conclusions: Increased endothelial injury may be indicated by the elevated levels of sICAM-1, sE-selectin, and cGMP in septic patients with preexisting CAD. These parameters, however, failed to serve as predictors for unknown CAD or chances for survival in early sepsis.

Key Words: adhesion molecules • coronary artery disease • cytokines • nitric oxide • sepsis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The endothelium plays a major role in the pathogenesis of sepsis.1 In patients with systemic inflammatory response syndrome, sepsis, and multiple organ failure (MOF), elevated plasma levels of different adhesion molecules have been described.2 3 4 5 In addition, an age-dependent increase of soluble intercellular adhesion molecule (sICAM)-1, endothelial-linked adhesion molecule, and vascular adhesion molecule-1 have been demonstrated in critically ill intensive care patients.6 In animal models, the inhibition of adhesion molecules by antibodies seemed to prevent secondary organ failure in sepsis.7

Impaired endothelial function may contribute to increased organ dysfunction and in the end possibly to an increased mortality. The release of cytokines and soluble adhesion molecules into the circulation has been shown to correlate well with the degree of endothelial trauma in an experimental setting.8 At the same time, both groups of mediators were clearly related to the development of multiple organ dysfunction in trauma patients.

Recently, it was proposed that sICAM-1 plasma level may have clinical significance as a marker of endothelial injury and may allow identification of a subgroup of patients at a greater risk for cardiovascular complications during sepsis.9 10 This hypothesis is supported by the fact that a significant correlation between increasing concentrations of sICAM-1 and the risk for myocardial infarction has been found.11 In a previous study we were able to demonstrate an increased mortality rate in septic patients with elevated sICAM-1 plasma levels.10 The aim of this study was to investigate, firstly, whether the plasma levels of soluble endothelial-linked adhesion molecule (sE-selectin), sICAM-1, and soluble vascular adhesion molecule (sVCAM)-1 differed in septic patients with or without preexisting coronary artery disease (CAD) [primary outcome measure]. Secondly, the usefulness of these markers in predicting the existence of unknown CAD and chances for survival was tested (secondary outcome measure).


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
After approval by the local ethics committee, we obtained written informed consent from the patients’ next of kin. Forty-four consecutive septic patients (according to the criteria of the American College of Chest Physicians Consensus Conference 199212 ) in the ICU were included in this study.

The criteria for CAD by Mangano13 were slightly modified as follows:

1. Patients with proven or suspected CAD who had at least one of the following: (A) previous coronary artery bypass graft, (B) abnormal findings on coronary angiography, (C) previous myocardial infarction, (D) typical signs of angina pectoris.

2. Patients with chest pain and at least one of the following: (A) positive treadmill test, (B) wall motion abnormalities on echocardiography, (C) positive thallium scan.

3. Patients with peripheral vascular disease who had at least one of the following: (A) scheduled for major vascular surgery, (B) history of previous major vascular surgery, (C) intermittent claudication, (D) positive angiography, (E) amputation not due to trauma or carcinoma.

4. Patients who had any two of the following: (A) diabetes mellitus, (B) treated arterial hypertension, (C) cigarette smoking, (D) age > 70 years, (E) cholesterol levels of > 240 mg/dL.

Patients < 18 years old, pregnant women, and patients receiving continuous hemodialysis or hemofiltration were excluded from the study.

Monitoring and Management
A fiberoptic, pulmonary artery thermodilution catheter (Swan-Ganz Oximetry/TD-Catheter model 93A-741 h-7,5F; Baxter Edwards Laboratories; Irvine, CA) and a radial artery catheter were inserted as part of the routine cardiovascular monitoring. Proximal positioning of the catheter tip in the pulmonary artery was confirmed by continuous recording of the pulmonary artery pressure waveform, and the requirement of at least 1-mL inflation of the catheter balloon to achieve occlusion.

All patients were studied within the first 12 h following the diagnosis of sepsis. The patients were receiving analgesics, sedation, mechanical ventilation, and were conventionally resuscitated. Fluids were administered to achieve an optimal left atrial filling pressure established by plotting left ventricular stroke work index against pulmonary artery occlusion pressure. The optimal filling pressure was taken as the plateau value for left ventricular stroke work. In case of a cardiac index (CI) < 2.5 L/min/m2, dobutamine up to a maximum of 20 µg/kg/min was titrated to achieve a CI between 3.0 L/min/m and 3.5 L/min/m2. In patients with a mean arterial pressure (MAP) < 70 mm Hg, norepinephrine was titrated to maintain a MAP between 70 mm Hg and 80 mm Hg.

Protocol and Measurements
APACHE (acute physiology and chronic health evaluation) III14 and MOF15 scores were recorded daily. Blood was collected and hemodynamic measurements were performed within 12 h after diagnosis of sepsis (early sepsis) and again 72 h later (late sepsis).

Each hemodynamic measurement included heart rate and cardiovascular pressures with reference to the mid-axillary line. Cardiac output measurements were performed in triplicate with the results expressed as mean value (thermodilution method, 10-mL iced 0.9% saline solution as injectate using a cardiac computer [SAT-2 Oximeter/Cardiac Output Computer; Baxter Edwards Laboratories]). The coefficient of variation calculated for each determination was < 10%; the mean coefficient of variation for cardiac output measurements was 4.8 ± 2.0%. The blood samples were simultaneously drawn slowly and continuously over a period of 30 s. Each sample was immediately analyzed for PaO2, mixed venous oxygen tension, and PCO2 (ABL Radiometer 300; Radiometer; Copenhagen, Denmark) in addition to arterial oxygen saturation and mixed venous oxygen saturation (SvO2) [Hemoximeter OSM3; Radiometer]. The latter two instruments were calibrated before the start of each measurement. Additional evidence against contamination of mixed venous blood by "arterialized" blood was obtained by comparison of mixed venous and arterial values of pH and PCO2.

Laboratory Parameters
Blood samples were spun at 3,000 rpm for 10 min, and serum was stored at - 80°C. The soluble adhesion molecules and cytokines were measured using commercially available enzyme-linked immunosorbent assay kits (sE-selectin, BBE 2B; s-ICAM-1, BBE 1B; s-VCAM-1, BBE 3; tumor necrosis factor [TNF]-{alpha}, DTA 50; interleukin [IL]-1ß, DLB 50; IL-6, D6050; IL-8, D8000; IL-10, PerSeptive Diagnostic 8–6610; DPC Bierman; Bad Nauheim, Germany, licensed from R&D Systems Europe Ltd; Abington, UK). Median (range) adhesion molecule levels of normal volunteers according to each ELISA were for sE-selectin, 46 ng/mL (29 to 63 ng/mL); sICAM-1, 210 ng/mL (115 to 306 ng/mL); and sVCAM-1, 553 ng/mL (395 to 714 ng/mL). Cyclic guanosinomonophosphate (cGMP) was measured by competitive radioimmunoassay (Dianova-Immunotech GmbH; Hamburg, Germany). Nitrite/nitrate were measured using the Griess reaction.16

Calculations
CI, arterial oxygen content (CaO2), mixed venous oxygen content (CvO2), oxygen delivery (DO2), and oxygen consumption (O2) were calculated using standard equations:





where CO = cardiac output; BSA = body surface area; PvO2 = mixed venous oxygen tension; and SaO2 = arterial oxygen saturation.

Statistical Analysis
For statistical analysis, commercially available software (SPSS version 8.0; SPSS; Chicago, IL) was used. All data were expressed as median and range. Comparisons between groups were performed using the Mann-Whitney U test. Differences within groups were analyzed by the Wilcoxon signed rank sum test. For comparison of dichotomous variables within groups, the {chi}2 test for dichotomous variables was used. Correlation of two variables was tested according to Pearson. Receiver operator characteristics curves were plotted to validate the usefulness of these variables in predicting the existence of unknown CAD in early sepsis.17 A multivariate logistic regression was performed to identify independent variables that correlated with outcome.18 A p value < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients
Twenty-three patients met the criteria for CAD, and 20 patients were in the non-CAD group. One patient was assigned to the CAD group retrospectively because of proven coronary artery sclerosis on postmortem examination. None of our patients suffered from an acute myocardial infarction in either group, according to clinical, ECG, and laboratory results.

Clinical Data
Patient characteristics on ICU admission did not significantly differ between groups (Table 1 ), with the exception of the MOF score, which was significantly lower in the CAD group. There seemed to be a tendency for an increased length of stay in ICU (CAD, 16 days [2 to 38 days]; non-CAD, 22 days [4 to 50 days]; p = 0.07) in non-CAD patients as well as a lower mortality (CAD, 18 of 24 [75%]; non-CAD, 10 of 20 [50%]; p = 0.09). Using an {alpha}-error of 0.05 and a ß-error of 0.2, a study population of 62 patients would have been necessary to show a significant difference in mortality between groups.


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  		Table 1.. Basic Patient Characteristics*

 
No significant differences could be found by routine laboratory testing and APACHE III and MOF scores in early sepsis between the two groups (Table 2 ). In late sepsis, however, C-reactive protein (CRP) was significantly higher in the CAD group as compared with the non-CAD group. APACHE III scores and creatinine levels were significantly raised in the CAD group from early to late sepsis. Lactate and CRP levels did not show any differences in the CAD group, whereas in the non-CAD group there was a significant decrease (Table 2) . CAD and non-CAD patients did not differ significantly in the prevalence of septic shock,19 number of positive blood cultures, types of microbiological organisms, possible source of sepsis, and survival at 72 h (Table 1) .


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  		Table 2.. Laboratory Testing and Scoring During Early and Late Sepsis*

 
Hemodynamics and Oxygen Transport
CI was significantly lower during early and late sepsis in the CAD in comparison with the non-CAD group. Heart rate, MAP, central venous pressure, and pulmonary capillary wedge pressure did not differ significantly between the two groups (Table 3 ). DO2 during early and late sepsis was significantly lower in the CAD group, in comparison with the non-CAD patients, subsequently diminishing the SvO2 and increasing the oxygen extraction ratio (Table 3) . No significant differences in PaO2/fraction of inspired oxygen ratio (Table 2) and hemoglobin (data not shown) were found, excluding further impact of these variables on DO2. O2 also did not significantly differ during early and late sepsis between groups.


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  		Table 3.. Hemodynamics, Oxygen Transport-Related Variables, and Catecholamines

 
Median dobutamine dose in early sepsis was significantly elevated in the CAD in comparison with the non-CAD group, without a significant difference in the number of patients depending on dobutamine (10 of 24 patients in the CAD group vs 5 of 20 subjects in the non-CAD group; p = 0.25). In late sepsis, no significant difference in dobutamine administration was detected. In early sepsis, norepinephrine was administered in 79% (19 of 24) of the patients in the CAD group and in 95% (19 of 20) of the patients in the non-CAD group (p = 0.45). Median norepinephrine dose did not significantly differ between groups, although there was a significant increase in the norepinephrine administration in the CAD group from early to late sepsis.

Laboratory Results
sICAM-1 plasma levels were significantly higher in CAD patients during early and late sepsis in comparison with the non-CAD group (Fig 1 ). sE-selectin did not differ between groups in early sepsis (Fig 2 ). From early to late sepsis, sE-selectin showed a nonsignificant tendency to decrease in both groups, reaching statistical significance during late sepsis between groups (p < 0.01). TNF-{alpha} was also not significantly elevated in CAD patients. It decreased significantly, however, from early to late sepsis in the CAD group, whereas it remained almost unchanged in the non-CAD group (Table 4 ). IL-6 showed the same pattern as TNF-{alpha} without reaching statistical significance between groups (Table 4) . In early sepsis, the elevated nitrite plasma levels just failed significance in CAD patients. There was a tendency toward decreased nitrate levels without this being statistically significant. In contrast, cGMP did not differ in early sepsis but was significantly increased in CAD patients compared with non-CAD patients during late sepsis (Fig 3 ).



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  		Figure 1.. sICAM-1 in patients with CAD (open triangles = survivors; filled triangles = nonsurvivors) and without CAD (non-CAD; open squares = survivors; filled squares = nonsurvivors). Presented are each measurement and median (lines). ns = not significant.

 


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  		Figure 2.. sE-selectin in patients with CAD (open triangles = survivors; filled triangles = nonsurvivors) and without CAD (non-CAD; open squares = survivors; filled squares = nonsurvivors). Presented are each measurement and median (lines). See Figure 1 legend for abbreviation.

 

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  		Table 4.. Cytokines, Adhesion Molecules, cGMP, and Nitrite/Nitrate

 


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  		Figure 3.. cGMP in patients with CAD (open triangles = survivors; filled triangles = nonsurvivors) and without CAD (non-CAD; open squares = survivors; filled squares = nonsurvivors). Presented are each measurement and median (lines). See Figure 1 legend for abbreviation.

 
Correlations
The anthropometric data including APACHE III scoring characterizing patients at study admittance did not correlate significantly with adhesion molecule or cytokine levels. There was only a weak, but significant, positive correlation between sE-selectin and MOF score in the CAD patients (r = 0.56; p < 0.05) and in the non-CAD group (r = 0.63; p < 0.05). In early sepsis, TNF-{alpha} correlated negatively with CI (r = -0.82; p < 0.001) and DO2 (r = -0.86; p < 0.001). In late sepsis, TNF-{alpha} levels declined in the presented patients and CI did not increase. Therefore, a significant negative correlation between CI and TNF-{alpha} was no longer observed. Other hemodynamic parameters such as heart rate, MAP, central venous pressure, or pulmonary capillary wedge pressure did not correlate significantly with laboratory measurements. Only a slightly positive correlation of TNF-{alpha} with plasma nitrite levels in the CAD patients was detected (r = 0.64; p < 0.05) during late sepsis. Other proinflammatory parameters such as IL-6 and CRP neither correlated with hemodynamics nor with adhesion molecule levels. Correlating proinflammatory parameters with each other demonstrated a positive correlation in late sepsis between IL-6 and CRP (r = 0.71; p < 0.01) in CAD patients. The main result was that sICAM-1 (CAD, r = 0.60, p < 0.05; non-CAD, r = 0.74, p < 0.005) and cGMP (CAD, r = 0.69, p < 0.005; non-CAD, r = 0.77, p < 0.05) correlated positively with IV administered norepinephrine dosages in late sepsis. A positive correlation was detected between sVCAM-1 and IV administered norepinephrine dosages during the whole study period (early sepsis, r = 0.76, p < 0,001; late sepsis, r = 0.72, p < 0,01) only in CAD patients.

Predictive Capacity
The predictive capacity was tested only in ICAM-1, since solely this parameter demonstrated a significant difference between groups in early sepsis. However, the use of a receiver operating characteristics curve did not show a sufficient predicting capacity of sICAM-1 in early sepsis for the occurrence of unknown CAD (area under the curve, 0.28; sensitivity, 30%; specificity, 32%). In addition, a multivariate logistic regression was performed to identify independent variables that correlated with outcome.18 However, the overall prediction for survival and for nonsurvival in the study population for ICAM-1 was not statistically significant (p values of multivariate logistic regression: CAD, 0.78; non-CAD, 0.32; CAD + non-CAD, 0.92).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The most important result of this study was that altered endothelial function in patients with CAD may influence expression and shedding of endothelial adhesion molecules during sepsis since circulating levels of sICAM-1 and sE-selectin were significantly elevated in septic patients with CAD in comparison with septic patients without CAD. Since we did not find any significant differences in cytokine levels between the two groups, the demonstrated differences of adhesion molecule levels are thought to be due to septic injury of predamaged endothelial cells rather than the result of cytokine-related activation alone.

The highest levels of circulating sE-selectin, sICAM-1, and sVCAM-1 were clearly related to the development of MOF in patients suffering from systemic inflammatory response syndrome2 and to the development of sepsis in MOF patients.20 The release of soluble adhesion molecules into the circulation seemed to correlate well with the degree of trauma (elective surgery vs multiple trauma) depending on the associated ischemia/reperfusion injury.8 Elevated levels of adhesion molecules have been suggested to correspond with the intensity of sepsis and severity of shock, as well as with subsequent organ failure and outcome.3 5 However, it is possible that the age-dependent increase of sICAM-1, sE-selectin, and sVCAM-1 in critically ill intensive care patients6 may be due to the age-related increased occurrence of atherosclerosis.21

The presented data suggest sICAM-1 as an indicator of atherosclerotic endothelial cell activation during early and late sepsis in patients with CAD. Elevated serum concentrations of sICAM-1 have been detected in various pathologies, such as patients with proven atherosclerosis,22 following coronary angioplasty,23 and after acute myocardial infarction.23 24 25 The frequent ischemia/reperfusion syndromes in atherosclerotic regions and subsequent leukocyte-endothelial interactions might be responsible for the increased release of this molecule. This may result in impaired microcirculation and subsequently, a reduced immune response. The persistent inflammation may be indicated by the significantly increased CRP levels in CAD patients during late sepsis, which is in accordance with previous studies in cardiovascular patients.26 In contrast to previously published data9 indicating sICAM-1 as a predictor for the development of cardiovascular complications during sepsis, the plasma levels of this adhesion molecule demonstrated an insufficient usefulness in predicting chances of survival in the present study. Survival was tested as a secondary outcome measure since cardiac complications defined as impaired biventricular compliance27 are common in septic patients with preexisting CAD and do not influence outcome per se. Furthermore, Bouza et al9 did not distinguish between patients with or without preexisting CAD. On the other hand, since the expression of the endothelial-specific sICAM-1 is induced by interferon-{gamma}, TNF-{alpha}, and IL-1 within 24 h,28 the peak plasma level might have been missed in the present study due to the blood sampling period within the first 12 h after onset of sepsis.

In the present study, only a significantly increased cGMP level in CAD patients during late sepsis was seen, whereas during early sepsis the cGMP level did not differ between groups. There are several possible reasons for the isolated increase of cGMP in CAD patients without significant changes of nitrite and nitrate themselves:

1. Due to renal elimination, impaired renal function might result in accumulation of cGMP29 ; however, this might not be relevant as the difference between groups was not significant.

2. Increased secretion by platelets as described in septic coagulopathy30 might be unlikely, since platelet count did not differ significantly between the two groups.

3. Increased cGMP activation through a nitric oxide independent pathway31 via IL-1 cannot be ruled out despite the fact that the difference in IL-1 was not significant between the two groups.

4. It is possible that cGMP derives not only from endothelium but also from smooth muscle cells. Persistent endothelial leakage in septic CAD patients may result in smooth muscle cell damage resulting in elevated cGMP plasma levels.

5. The reduction of nitrate levels in CAD patients during early sepsis may represent the impaired endothelial function in atherosclerosis.32

Nossuli et al33 demonstrated that maximally achievable concentrations of peroxynitrite exert significant cardioprotective effects in myocardial ischemia and reperfusion injury. The markedly but insignificantly increased levels of nitrite in CAD patients during early and late sepsis might have been induced by a potential shift of balance between nitrate and nitrite toward the cardioprotective derivates of nitric oxide.

In early sepsis, CAD patients were treated with significantly higher doses of dobutamine. Norepinephrine dosages significantly increased in CAD patients during the course of sepsis, whereas they remained unchanged in the non-CAD group. sICAM-1, sVCAM-1, and cGMP significantly correlated with the norepinephrine dosage, probably indicating selective impairment of endothelium-derived relaxation in CAD patients.34 Potential interactions between the increased use of {alpha}-adrenergic and ß-adrenergic drugs in CAD patients and cytokine production have to be taken into account, since receptor manipulation of the sympathetic nervous system has been reported to modify the immunologic response to septic insult.35 This might explain the correlation between the proinflammatory cytokine IL-6 and CRP in CAD patients during late sepsis. Furthermore, the reported increase of TNF-{alpha} and IL-6 in CAD patients treated with higher amounts of norepinephrine may be due to an impaired negative feedback mechanism between endogenous norepinephrine release and cytokine production as described by van der Poll et al.36 TNF-{alpha} negatively correlated with cardiac function, probably resulting in increased dosages of catecholamines and decreased DO2. This is in accordance with the findings of Müller-Werdan et al,37 that endotoxin and TNF-{alpha} were the main cardiodepressing mediators in septic cardiomyopathy.

The preoperative enhancement of DO2 to the tissues, guided by data obtained with pulmonary artery catheters, has been shown to improve outcome of patients considered to be at high risk in the event of elective major surgery.38 39 A significant improvement in mortality with the use of supranormal hemodynamic targets, however, was reported neither in studies that included patients with sepsis and/or ARDS40 41 nor in studies of unselected critically ill patients.42 43 The present data support the results of Raper and Sibbald27 in the presence of sepsis and CAD. This was associated with a significant reduction in cardiac output and systemic DO2 and subsequently increased the oxygen extraction ratio despite the requirement for significantly larger doses of inotropic support. In contrast, O2 did not differ significantly between the two groups and increased during the course of sepsis. Therefore, the trend toward an enhanced mortality in CAD patients seemed not to be created by a "hidden oxygen debt," since O2 was not observed to be dependent on oxygen supply. The use of the reverse Fick method to measure O2 resulting in the possibility of mathematical coupling of measurement errors shared in common variables44 demonstrated no correlation between DO2 and O2 in the two groups.

In conclusion, an additional effect of increased endothelial injury in septic patients with CAD may be indicated by the elevated levels of sICAM-1 and sE-selectin. It remains speculative that persistent endothelial damage in CAD patients may result in persistent endothelial leakage, impaired microcirculation, and subsequently reduced immune response, development of multiple organ dysfunction, and enhanced mortality in particular because these parameters failed to serve as predictors of unknown CAD or chances for survival in early sepsis.


   Acknowledgements
 
We thank H. Redlich, PhD (Center for Information and Communication, University of Potsdam) for statistical help, Dr. M. Martin (native American English speaker from our department), and Mrs. A. Todd (native American English-speaking copy editor) for linguistic advice.


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; CAD = coronary artery disease; CaO2 = arterial oxygen content; cGMP = cyclic-guanosinomonophosphate; CI = cardiac index; CRP = C-reactive protein; CvO2 = mixed venous oxygen content; DO2 = oxygen delivery; IL = interleukin; MAP = mean arterial pressure; MOF = multiple organ failure; sE-selectin = soluble endothelial-linked adhesion molecule; sICAM = soluble intercellular adhesion molecule; sVCAM = soluble vascular adhesion molecule; SvO2 = mixed venous oxygen saturation; TNF = tumor necrosis factor; O2 = oxygen consumption

Received for publication December 22, 1999. Accepted for publication August 1, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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