Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis

The vascular growth factor angiopoietin 2 (Ang-2) is known to promote inflammation and endothelial dysfunction, but its prognostic capacity and relationship to outcomes in human sepsis are unknown. This is a prospective observational cohort study of 66 patients newly admitted to a tertiary care medical intensive care unit (ICU), which included ICU patients with no sepsis (n = 20) as well as those with sepsis (n = 10), severe sepsis (n = 12), and septic shock (n = 24). Clinical data were collected until hospital discharge, and Ang-2 and IL-6 levels were determined on specimens obtained after ICU admission. Serum Ang-2 correlated with IL-6 and severity-of-illness scores. In the septic cohort, circulating Ang-2 levels were significantly higher (P = 0.01) in those who died (24.9 ng/mL; interquartile range, 21.5-38.0 ng/mL) compared with those who survived (13.5 ng/mL; interquartile range, 8.1-21.6 ng/mL). Elevated circulating serum Ang-2 levels are associated with increased hospital mortality in patients with sepsis.     

Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome

OBJECTIVES: To investigate the concentrations of mononuclear cell-associated ceramide and serum tumor necrosis factor-alpha (TNF-alpha) in patients with sepsis and to assess their predictive value for the development of multiple organ dysfunction syndrome (MODS). DESIGN: Prospective, cohort study. SETTING: Intensive care unit and two research laboratories at a university hospital. PATIENTS: Twenty-three adult patients admitted to an intensive care unit meeting the criteria for diagnosis of sepsis. INTERVENTIONS: Blood samples were collected at the time when diagnosis of sepsis was made. MEASUREMENTS AND MAIN RESULTS: Mononuclear cell-associated ceramide and serum TNF-alpha were significantly elevated in the samples from the septic patients compared with the control individuals (318.01+/-270.15 pmol/10(6) cells vs. 99.90+/-52.75 pmol/10(6) cells; p<.001, and 28.52+/-18.77 pg/mL vs. 10.43+/-3.37 pg/mL; p<.0001, respectively), and a direct correlation linked ceramide and TNF-alpha concentrations (r2 = .90, p<.00001). In the septic patients who went on to develop MODS, ceramide and TNF-alpha were significantly higher compared with the no MODS patients (489.22+/-264.93 pmol/10(6) cells vs. 131.23+/-99.02 pmol/10(6) cells; p<.0001, and 40.96+/-18 pg/mL vs. 14.95+/-5.60 pg/mL; p<.001, respectively). The receiver operating characteristic curves demonstrated that both TNF-alpha and ceramide were prognostic of MODS, but ceramide concentrations were more efficient predictors. CONCLUSIONS: These observations suggest that mononuclear cells of peripheral blood from patients with sepsis are committed to undergo apoptosis, because there is evidence that ceramide acts as an endogenous mediator of apoptosis. The strong correlation we found between cell-associated ceramide and serum TNF-alpha supports the hypothesis that this cytokine plays an important role in activating the sphingomyelin pathway and ceramide generation in patients with sepsis. In addition, this study provides evidence that consistent concentrations of mononuclear cell-associated ceramide may predict progression toward MODS in septic patients. KEY WORDS: ceramide; tumor necrosis factor; outcome; apoptosis; multiple organ dysfunction syndrome; critical illness; mononuclear cells; intensive care unit (ICU); sphingomyelin pathway     

Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock

OBJECTIVE: To investigate the changes in B-type natriuretic peptide concentrations in patients with severe sepsis and septic shock and to investigate the value of B-type natriuretic peptide in predicting intensive care unit outcomes. DESIGN: Prospective observational study. SETTING: General intensive care unit. PATIENTS: Forty patients with severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: B-type natriuretic peptide measurements and echocardiography were carried out daily for 10 consecutive days. In-hospital mortality and length of stay were recorded. The admission B-type natriuretic peptide concentrations were generally increased (747 +/- 860 pg/mL). B-type natriuretic peptide levels were elevated in patients with normal left ventricular systolic function (568 +/- 811 pg/mL), with sepsis-related reversible cardiac dysfunction (630 +/- 726 pg/mL), and with chronic cardiac dysfunction (1311 +/- 1097 pg/mL). There were no significance changes in B-type natriuretic peptide levels over the 10-day period. The daily B-type natriuretic peptide concentrations for the first 3 days neither predicted in-hospital mortality nor correlated with length of intensive care unit or hospital stay. CONCLUSION: B-type natriuretic peptide concentrations were increased in patients with severe sepsis or septic shock regardless of the presence or absence of cardiac dysfunction. Neither the B-type natriuretic peptide levels for the first 3 days nor the daily changes in B-type natriuretic peptide provided prognostic value for in-hospital mortality and length of stay in this mixed group of patients, which included patients with chronic cardiac dysfunction.     

Soluble selectins and the systemic inflammatory response syndrome after successful cardiopulmonary resuscitation

OBJECTIVE: Elevated cytokine levels have been reported after ischemia/reperfusion injury and might cause a systemic inflammatory response syndrome (SIRS) after successful cardiopulmonary resuscitation (CPR). It is unknown whether patients with SIRS after CPR exhibit higher levels of soluble adhesion molecules than patients without SIRS and whether SIRS or elevation of adhesion molecules is associated with outcome after CPR. We analyzed the relationships among various CPR-related variables, plasma levels of E- and P-selectin, the occurrence of SIRS after CPR, and the development of sepsis and outcome. DESIGN: Prospective, controlled study. SETTING: Intensive care unit at a university hospital. PATIENTS: A total of 25 patients on the second day after successful CPR and 7 non-critically ill control patients. INTERVENTIONS: Blood sampling for determination of plasma levels of soluble (s) E- and P-selectin. MEASUREMENTS AND MAIN RESULTS: SIRS was a frequent finding after CPR (66% of all patients) unrelated to time until return of spontaneous circulation (SIRS, 17+/-13 mins; no SIRS, 19+/-16 mins; p = .761), epinephrine dose (SIRS, 4+/-5 mg; no SIRS, 5+/-6 mg; p = .906), or serum lactate level after CPR (SIRS, 8.6+/-2.6 mmol/L; no SIRS, 8.7+/-4.0 mmol/L; p = .174). sP-selectin levels were higher in patients with SIRS (291.7+/-227.4 ng/mL) compared with patients without SIRS (113.4+/-88.4 ng/mL; p = .018) or with non-critically ill patients (116.9+/-33.4 ng/mL; p = .031). Compared with non-critically ill control patients (42.8+/-19.4 ng/mL), sE-selectin levels were higher in patients with (96.2+/-47.3 ng/mL; p = .023) and without SIRS (99.5+/-65.7 ng/mL; p = .030). sP-selectin was higher in patients developing sepsis within 1 wk after CPR (n = 9) than in patients without sepsis (350.2+/-233.4 ng/mL vs. 158.5+/-157.8 ng/mL; p = .022) and sE-selectin levels were higher in nonsurvivors (n = 5) than in survivors (144.2+/-62.4 ng/mL vs. 85.7+/-45.3 ng/mL; p = .025) whereas SIRS was unrelated to the development of sepsis (p = .4) and unrelated to survival (p = .4). CONCLUSIONS: SIRS is an unspecific finding after CPR with only minor impact on outcome. Determination of sP- and sE-selectin early after CPR might help to identify patients at a high risk for sepsis or for an adverse outcome, respectively.     

Diagnostic and prognostic value of procalcitonin in patients with septic shock

OBJECTIVE: To determine whether procalcitonin is a reliable diagnostic and prognostic marker in septic shock compared with nonseptic shock. DESIGN: Prospective controlled trial. SETTING: Intensive care unit of the Avicenne Teaching Hospital, Bobigny, France. PATIENTS: All patients admitted to our intensive care unit over a 12-month period with clinical evidence of shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Echocardiography or pulmonary artery flotation catheter measurements were used to assess hemodynamics, and multiple specimens were obtained for microbiological studies. Standard criteria were used to diagnose septic shock. Serum concentrations of procalcitonin, C-reactive protein, and lactate were determined on the day of shock onset (day 1) and on days 3, 7, and 10. Seventy-five patients were included, 62 in the septic shock group and 13 in the cardiogenic shock group. Serum procalcitonin on day 1 was significantly higher in patients with than without septic shock (median, 14 [0.3-767] ng/mL vs. 1 [0.5-36] ng/mL, p < .01). A cutoff value of 1 ng/mL had 95% sensitivity and 54% specificity for separating patients with and without sepsis. C-reactive protein failed to discriminate between these two groups. Among patients with sepsis, procalcitonin concentrations were significantly higher in those who died than in the survivors, at all four measurement time points (median, 16 [0.15-767] ng/mL vs. 6 [0.2-123] ng/mL, p = .045 on day 1; 6.5 [0.3-135] ng/mL vs. 1.05 [0.11-53] ng/mL, p = .02 on day 10). A cutoff value of 6 ng/mL on day 1 separated patients who died from those who survived with 87.5% sensitivity and 45% specificity. C-reactive protein was not helpful for predicting mortality. Serum lactate was a nonspecific prognostic marker. CONCLUSIONS: These data indicate that procalcitonin may be a valuable early diagnostic and prognostic marker in patients with septic shock.     

Evidence for intestinal and liver epithelial cell injury in the early phase of sepsis

The development of sepsis and multiple organ failure are important determinants of the outcome in critically ill patients. Hepatosplanchnic hypoperfusion and resulting intestinal and hepatic cell damage have been implicated as central events in the development of sepsis and multiple organ failure. Our aim was to study (1) the relation between intramucosal perfusion and intestinal and hepatic cell damage in an early phase of sepsis and (2) the correlation of these parameters with mortality. Two groups of patients were consecutively selected after intensive care unit admission: patients with postoperative abdominal sepsis (n = 19) and patients with pneumonia-induced sepsis (n = 9). Intramucosal perfusion was assessed by gastric tonometry (Pr-aCO2 gap, Pico2). Circulating levels of intestinal fatty acid binding protein (I-FABP) and liver (L)-FABP were used as markers for intestinal and hepatic cellular damage, respectively. Outcome was determined on day 28. Pr-aCO2 gap correlated with I-FABP (Pearson r = 0.56; P < 0.001) in all patients, and gastric mucosal Pico2 correlated significantly with I-FABP (r = 0.57; P = 0.001) in patients with abdominal sepsis. At intensive care unit admission, nonsurvivors had significantly higher I-FABP and L-FABP values than survivors (I-FABP: 325 vs. 76 pg/mL, P < 0.04; L-FABP: 104 vs. 31 ng/mL, P < 0.04). Patients with abdominal sepsis was especially responsible for high-admission I-FABP and L-FABP levels in nonsurvivors (I-FABP: 405 vs. 85 pg/mL, P < 0.04; L-FABP: 121 vs. 59 ng/mL, P < 0.04). This study shows that splanchnic hypoperfusion correlates with intestinal mucosal damage, and that elevated plasma levels of I-FABP and L-FABP are associated with a poor outcome in critically ill patients with abdominal sepsis.     

Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6

OBJECTIVE: To evaluate whether plasma concentrations of procalcitonin (PCT), interleukin-6 (IL-6), protein complement 3a (C3a), leukocyte elastase (elastase), and the C-reactive protein (CRP) determined directly after the clinical onset of sepsis or systemic inflammatory response syndrome (SIRS) discriminate between patients suffering from sepsis or SIRS and predict the outcome of these patients. DESIGN: Prospective study. SETTING: Medical intensive care unit at a university hospital. PATIENTS: Twenty-two patients with sepsis and 11 patients with SIRS. MEASUREMENTS AND MAIN RESULTS: The plasma concentrations of PCT, C3a, and IL-6 obtained < or =8 hrs after clinical onset of sepsis or SIRS but not those of elastase or CRP were significantly higher in septic patients (PCT: median, 16.8 ng/mL, range, 0.9-351.2 ng/mL, p = .003; C3a: median, 807 ng/mL, range, 422-4788 ng/mL, p < .001; IL-6: median, 382 pg/mL, range, 5-1004 pg/mL, p = .009, all Mann-Whitney rank sum test) compared with patients suffering from SIRS (PCT: median, 3.0 ng/mL, range, 0.7-29.5 ng/mL; C3a: median, 409 ng/mL, range, 279566 ng/mL; IL-6: median, 98 pg/mL, range, 23-586 pg/mL). The power of PCT, C3a, and IL-6 to discriminate between septic and SIRS patients was determined in a receiver operating characteristic analysis. C3a was the best variable to differentiate between both populations with a maximal sensitivity of 86% and a specificity of 80%. An even better discrimination (i.e., a maximal sensitivity of 91% and a specificity of 80%) was achieved when PCT and C3a were combined in a "sepsis score." C3a concentrations also helped to predict the outcome of patients. Based on the sepsis score, a logistic regression model was developed that allows a convenient and reliable determination of the probability of an individual patient to suffer from sepsis or SIRS. CONCLUSIONS: Our data show that the determination of PCT, IL-6, and C3a is more reliable to differentiate between septic and SIRS patients than the variables CRP and elastase, routinely used at the intensive care unit. The determination of PCT and C3a plasma concentrations appears to be helpful for an early assessment of septic and SIRS patients in intensive care.     

Time course of hemoglobin concentrations in nonbleeding intensive care unit patients

OBJECTIVES: To evaluate the time course of hemoglobin concentrations in nonbleeding intensive care unit patients. DESIGN: Prospective, observational study. SETTING: Multidisciplinary (medicosurgical) department of intensive care. PATIENTS: Ninety-one patients with no evidence of recent or active blood loss, no history of hematologic disease or chronic renal failure, and no need for extracorporeal epuration techniques. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data collection included primary diagnoses, Acute Physiology and Chronic Health Evaluation II and sepsis-related organ failure assessment scores, signs of sepsis, 24-hr fluid balance, and hemoglobin concentrations. For the entire intensive care unit stay, the fall in hemoglobin concentrations (calculated from the mean of individual slopes of hemoglobin concentrations over time) averaged 0.52 +/- 0.69 g/dL/day. For the 33 patients who stayed in the intensive care unit for >3 days, this decline was larger for the first 3 days than for subsequent days (0.66 +/- 0.84 g/dL/day vs. 0.12 +/- 0.29 g/dL/day; p<.01). After the third intensive care unit day, the change in hemoglobin concentrations was inversely related to the severity of the disease, as reflected by the Acute Physiology and Chronic Health Evaluation II and the sepsis-related organ failure assessment scores. Hemoglobin concentrations decreased by 0.44 +/- 0.70 g/dL/day in the nonseptic and 0.68 +/- 0.66 g/dL/day in the septic patients (p =.13). After the third intensive care unit day, hemoglobin concentrations continued to decrease in the septic patients but not in the nonseptic patients (-0.29 +/- 0.19 vs. 0.006 +/- 0.3 g/dL/day; p=.0016). The fall in hemoglobin concentrations was not significantly related to the fluid balance. The volume of blood drawn daily for laboratory studies was 40.3 +/- 15.4 mL: 49.0 +/- 11.3 mL in the septic patients and 36.7 +/- 14.9 mL in the nonseptic patients (p =.04). CONCLUSIONS: Hemoglobin concentrations typically decline by >0.5 g/dL/day during the first days of intensive care unit stay in nonbleeding patients. Beyond the third day, hemoglobin concentrations can remain relatively constant in nonseptic patients but continue to decrease in septic patients, as well as patients with high sepsis-related organ failure assessment or Acute Physiology and Chronic Health Evaluation II scores. These observations may help in the interpretation of hemoglobin concentrations in critically ill patients.     

Procalcitonin: a valuable indicator of infection in a medical ICU?

OBJECTIVE: To assess the use of procalcitonin (PCT) for the diagnosis of infection in a medical ICU. DESIGN: Prospective, observational study. PATIENTS: Seventy-seven infected patients and 24 patients with systemic inflammatory response syndrome (SIRS) due to other causes. Seventy-five patients could be classified into sepsis (n = 24), severe sepsis (n = 27) and septic shock (n = 24), and 20 SIRS patients remained free from infection during the study. Plasma PCT and C-reactive protein (CRP) levels were evaluated within 48 h of admission (day 0), at day 2 and day 4. RESULTS: As compared with SIRS, PCT and CRP levels at day 0 were higher in infected patients, regardless of the severity of sepsis (25.2 +/- 54.2 ng/ml vs 4.8 +/- 8.7 ng/ml; 159 +/- 92 mg/l vs 71 +/- 58 mg/l, respectively). At cut-off values of 2 ng/ml (PCT) and 100 mg/l (CRP), sensitivity and specificity were 65% and 70% (PCT), 74% and 74% (CRP). PCT and CRP levels were significantly more elevated in septic shock (38.5 +/- 59.1 ng/ml and 173 +/- 98 mg/l) than in SIRS (3.8 +/- 6.9 ng/ml and 70 +/- 48 mg/l), sepsis (1.3 +/- 2.7 ng/ml and 98 +/- 76 mg/l) and severe sepsis (9.1 +/- 18. 2 ng/ml and 145 +/- 70 mg/l) (all p = 0.005). CRP, but not PCT, levels were more elevated in severe sepsis than in SIRS (p<0.0001). Higher PCT levels in the patients with four dysfunctional organs and higher PCT and CRP levels in nonsurvivors may only reflect the marked inflammatory response to septic shock. CONCLUSION: In this study, PCT and CRP had poor sensitivity and specificity for the diagnosis of infection. PCT did not clearly discriminate SIRS from sepsis or severe sepsis.     

Usefulness of procalcitonin for diagnosis of infection in cardiac surgical patients

OBJECTIVE: To determine the value of procalcitonin (PCT) as a marker of postoperative infection after cardiac surgery. DESIGN: A prospective single institution three phase study. SETTING: University cardiac surgical intensive care unit (31 beds). PATIENTS: Phase 1: To determine the normal perioperative kinetics of PCT, 20 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass were included. Phase 2: To determine whether PCT may be useful for diagnosis of postoperative infection, 97 consecutive patients with suspected infection were included. Phase 3: To determine the ability of PCT to differentiate patients with septic shock from those with cardiogenic shock, 26 patients with postoperative circulatory failure were compared. MEASUREMENTS AND MAIN RESULTS: Phase 1: Serum samples were drawn for PCT determination after induction of anesthesia (baseline), at the end of surgery, and daily until postoperative day (POD) 8. Baseline serum PCT concentration was 0.17 +/- 0.08 ng/mL (mean +/- SD). Serum PCT increased after cardiac surgery with a peak on POD 1 (1.08 +/- 1.36). Serum PCT returned to normal range on POD 3 and remained stable thereafter. Phase 2: In patients with suspected infection, serum PCT was measured at the same time of C-reactive protein (CRP) and bacteriologic samples. Among the 97 included patients, 54 were infected with pneumonia (n = 17), bacteremia (n = 16), mediastinitis (n = 9), or septic shock (n = 12). In the 43 remaining patients, infection was excluded by microbiological examinations. In noninfected patients, serum PCT concentration was 0.41 +/- 0.36 ng/mL (range, 0.08-1.67 ng/mL). Serum PCT concentration was markedly higher in patients with septic shock (96.98 +/- 119.61 ng/mL). Moderate increase in serum PCT concentration occurred during pneumonia (4.85 +/-3.31 ng/mL) and bacteremia (3.57 +/- 2.98 ng/mL). Serum PCT concentration remained low during mediastinitis (0.80 +/- 0.58 ng/mL). Five patients with mediastinitis, two patients with bacteremia, and one patient with pneumonia had serum PCT concentrations of <1 ng/mL. These eight patients were administered antibiotics previously and serum PCT was measured during a therapeutic antibiotic window. For prediction of infection by PCT, the best cutoff value was 1 ng/mL, with sensitivity 85%, specificity 95%, positive predictive value 96%, and negative predictive value 84%. Serum CRP was high in all patients without intergroup difference. For prediction of infection by CRP, a value of 50 mg/L was sensitive (84%) but poorly specific (40%). Comparing the area under the receiver operating characteristic curves, PCT was better than CRP for diagnosis of postoperative sepsis (0.82 for PCT vs. 0.68 for CRP). Phase 3: Serum PCT concentration was significantly higher in patients with septic shock than in those with cardiogenic shock (96.98 +/- 119.61 ng/mL vs. 11.30 +/- 12.3 ng/mL). For discrimination between septic and cardiogenic shock, the best cutoff value was 10 ng/mL, with sensitivity of 100% and specificity of 62%. CONCLUSION: Cardiac surgery with cardiopulmonary bypass influences serum PCT concentration with a peak on POD 1. In the presence of fever, PCT is a reliable marker for diagnosis of infection after cardiac surgery, except in patients who previously received antibiotics. PCT was more relevant than CRP for diagnosis of postoperative infection. During a postoperative circulatory failure, a serum PCT concentration >10 ng/mL is highly indicative of a septic shock.     

Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma

Glycosaminoglycans (GAGs) are structurally heterogeneous negatively charged polysaccharides. Endothelial GAGs, also known as glycocalyx, are involved in capillary permeability. In rat venules stimulated with proinflammatory substances ex vivo, the GAG-containing proteoglycan, syndecan-1, is shed from the endothelium. We wanted to investigate if we could trace the same response during septic shock as reflected in the circulating GAG levels. Arterial plasma samples were collected from 18 consecutive septic shock patients admitted to our intensive care unit. Plasma GAGs were measured with an Alcian blue slot binding assay, and syndecan-1 levels were measured with enzyme-linked immunosorbent assay. Effects of GAGs on the antibacterial activity of plasma were assessed by a radial diffusion assay. The median plasma GAG level was significantly higher in the septic shock patients than in matched controls (median [interquartile range], 2.7 microg/mL [1.9 - 4.8 microg/mL] vs. 1.8 microg/mL [1.7 - 2.0 microg/mL]). Furthermore, the GAG levels were significantly higher in nonsurvivors (4.6 microg/mL [3.1 - 8.8 microg/mL], n = 8) than survivors (1.8 microg/mL [1.6 - 2.6 microg/mL], n = 10). The syndecan-1 levels were also increased in the patients compared with controls (246 ng/mL [180 - 496 ng/mL] vs. 26 ng/mL [23 - 31 ng/mL]) and correlated to the cardiovascular Sequential Organ Failure Assessment (SOFA) score. The GAGs inhibited the endogenous antibacterial activity of plasma as well as isolated antimicrobial peptides. The concentrations required were in the same range as the GAG levels measured in the patients. These results show that the GAG levels are increased in septic shock patients, possibly reflecting peripheral endothelial cell damage. We also found that GAGs in relevant concentrations neutralize antimicrobial peptides in plasma.     

High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock

OBJECTIVE: Sepsis and septic shock are a common cause of mortality in critically ill patients. Many substances have been implicated in the pathophysiology of these syndromes. We postulated that adenosine may be implicated in the sepsis- or septic shock-induced blood pressure failure. Indeed, this nucleoside is a strong endogenous vasodilating agent released by endothelial cells and myocytes under circumstances of metabolic stress, such as during critical illness. DESIGN: A prospective, comparative observational study. SETTING: The adult intensive care unit of a tertiary care university hospital. PATIENTS: We measured adenosine plasma concentration (APC) in patients with severe sepsis (n = 11), in patients with septic shock (n = 14), in patients with hemorrhagic traumatic shock (n = 14), and in 12 healthy volunteers. APC was evaluated every 12 hrs over 3 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At study entry, we found that APC was higher in patients with septic shock (mean +/- so = 8.4 +/-3.5 micromol/L) than in patients with hemorrhagic traumatic shock (1.1 +/- 0.6 micromol/L) and controls (0.8 +/- 0.3 micromol/L). Intermediate values (3.9 +/- 1.9 micromol/L) were found in patients with severe sepsis. APC in patients with traumatic shock did not differ from controls. In the course of the hospitalization, for both sepsis and septic shock patients, APC decreased significantly but remained higher than controls 72 hrs after entry into the study. In the septic shock group, APC was significantly higher in the nonsurvivor group (n = 6) than in the survivor group (n = 8), whatever the time of sample collection and assay. CONCLUSIONS: High adenosine plasma concentrations are found in patients with septic shock but not during traumatic shock, or in healthy volunteers. Intermediate values of circulating adenosine are found in patients with severe sepsis. APC may be a prognostic index for outcome in septic patients, with much higher values being found in nonsurvivors.     

Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia

OBJECTIVES: To document changes in serum secretory leukocyte protease inhibitor (SLPI) in human sepsis and in experimental endotoxemia in vivo. To compare changes in serum SLPI in human sepsis with changes in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. To determine whether or not changes in SLPI correlate with the severity of multiple organ dysfunction syndrome as measured by the maximal multiple organ dysfunction score. Finally, because neutrophils have been implicated in tissue injury associated with organ dysfunction, to determine whether recombinant human SLPI blocks activation of isolated human neutrophils. DESIGN: Case-control study and ex-vivo cellular assay. SETTING: Surgical intensive care unit and clinical research center of university hospitals; laboratory of a medical school. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There was a significant dose-dependent elevation (50.2+/-4.0 ng/mL, p = .01) in plasma SLPI 12 hrs after administration of lipopolysaccharide to seven healthy adults (36.4+/-2.3 ng/mL). Further, serum concentrations of SLPI (132+/-15 ng/mL) were elevated in septic surgical patients compared with healthy controls (43+/-2 ng/mL, p < .01) and nonseptic surgical controls (69+/-10 ng/mL, p = .01). Serum SLPI concentrations correlated (r2 = .71, p < .01) better with organ dysfunction as measured by maximal multiple organ dysfunction score than did serum IL-6 (r2 = .49, p < .01), IL-10 (r2 = .05, p = .22), or TNF-alpha (r2 = .02, p = .44). We found that recombinant human SLPI in vitro inhibits TNF-alpha-induced hydrogen peroxide production by human neutrophils (ID50 = 1-2 microg/mL). CONCLUSIONS: Serum SLPI is elevated in human sepsis and experimental endotoxemia. Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis. Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.     

Linear and nonlinear analysis of hemodynamic signals during sepsis and septic shock

OBJECTIVE: Neuroautonomic modulation of heart rate (HR) and blood pressure were assessed in sepsis or septic shock. We hypothesized that these metrics would be diminished in pediatric patients with sepsis and septic shock, indicating uncoupling of the autonomic and cardiovascular systems. DESIGN: Prospective case series. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Thirty pediatric patients with sepsis or septic shock. INTERVENTIONS: None. MEASURES AND MAIN RESULTS: Metrics used included power spectral analysis, a linear frequency domain measure, and detrended fluctuation analysis, a nonlinear technique that assesses the degree of long-range correlation in HR or blood pressure. We found decreased low-frequency (2.68 +/- 0.24 vs. 3.37 +/- 0.17 [SEM] bpm2; p = .03) and high-frequency HR power (2.18 +/- 0.14 vs. 2.79 +/- 0.23 bpm2; p = .04) and increased detrended fluctuation analysis scaling exponent (1.22 +/- 0.06 vs. 1.00 +/- 0.07 bpm2; p = .02) in sepsis vs. shock patients, respectively. Compared with sepsis or shock, recovery was associated with increases in low-frequency (3.61 +/- 0.15 vs. 3.05 +/- 0.19 bpm2; p < .0001) and high-frequency HR power (3.11 +/- 0.15 vs. 2.50 +/- 0.22 bpm2; p < .0001). CONCLUSIONS: We conclude that uncoupling of the autonomic and cardiovascular systems occurs over both short- and long-range time scales during sepsis, and the degree of uncoupling may help differentiate between sepsis, septic shock, and recovery states.     

Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis

OBJECTIVE: To describe the course of plasma sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin (PCT), and C-reactive protein (CRP) concentrations during sepsis and their clinical informative value in predicting outcome. DESIGN: Prospective, noninterventional study. SETTING: Medical adult intensive care unit at a university hospital in France. PATIENTS: Sixty-three critically ill patients with sepsis, severe sepsis, or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Soluble TREM-1 concentrations were significantly lower at admission in nonsurvivors (n = 21) than in survivors (n = 42) (94 [30-258] vs. 154 [52-435] pg/mL, p = .02), whereas PCT levels were higher among nonsurvivors (19.2 [0.3-179] vs. 2.4 (0-254) pg/mL, p = .001). CRP levels did not differ between the two groups of patients. Plasma PCT and CRP decreased during the 14-day period of study in both survivors and nonsurvivors. Conversely, sTREM-1 plasma concentrations remained stable or even increased in nonsurviving patients and decreased in survivors. An elevated baseline sTREM-1 level was found to be an independent protective factor with an odds of dying of 0.1 (95% confidence interval, 0.1-0.8). CONCLUSION: A progressive decline of plasma sTREM-1 concentration indicates a favorable clinical evolution during the recovery phase of sepsis. In addition, baseline sTREM-1 level may prove useful in predicting outcome of septic patients.     

Impaired ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor production may identify "septic" intensive care unit patients

Currently, there is no reliable diagnostic test to identify septic intensive care unit (ICU) patients. We initiated studies to test the hypothesis that in sepsis, the in vivo exposure to endotoxin is detectable by the ex vivo analysis of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production. We obtained heparinized whole blood (WB) from 58 ICU patients and 14 healthy controls. The samples were incubated +/-10 ng/mL of LPS at 37 degrees C for 3 h. Plasma TNF levels were measured using enzyme-linked immunoassay (mean +/- standard error of the mean). Clinical data, including ICU length of stay (LOS), ventilator days (VentD), WBC, and positive cultures (Clt+), were obtained retrospectively. A wide range of LPS-stimulated WB TNF production (pg/mL) was observed in ICU patients (4481+/-469) and controls (6706+/-715). Patients were stratified into quartiles (I-IV) on the basis of the distribution of plotted LPS-stimulated TNF values (pg/mL). Patients in quartile I (N = 14) had significantly lower TNF production (< 2000 pg/mL, P < 0.05) and required increased VentD (16 vs. 10 days, P < 0.05) compared to quartiles II-IV (N = 44). Patients in quartile I also had a higher incidence of infection (79 vs. 50%) and longer LOS (18 vs. 13 d) compared to quartiles II-IV. Impaired TNF release may be a manifestation of monocyte endotoxin tolerance and may be useful to diagnose sepsis.     

N-terminal pro-B-type natriuretic peptide is an independent predictor of outcome in an unselected cohort of critically ill patients

OBJECTIVES: Natriuretic peptides emerged during recent years as potent prognostic markers in patients with heart failure and acute myocardial infarction. In addition, natriuretic peptides show strong predictive value in patients with pulmonary embolism, sepsis, renal failure, and shock. The present study tests the prognostic information of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in an unselected cohort of critically ill patients. DESIGN: Prospective, observational study. SETTING: A tertiary intensive care unit in a university hospital. PATIENTS: A total of 289 consecutive patients admitted to the intensive care unit during a 16-month period with the following data: age 64 +/- 14 yrs, male n = 191, Simplified Acute Physiology Score II of 52 +/- 24, mechanical ventilation n = 180 (62%), vasopressors n = 179 (62%), renal failure n = 24 (8%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma NT-pro-BNP samples (Roche Diagnostics) were obtained on intensive care unit admission. Data are given as median [range]. Intensive care unit survivors had significantly lower NT-pro-BNP values compared with intensive care unit nonsurvivors (3394 [24-35,000] vs. 6776 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). Hospital survivors were characterized by significantly lower NT-pro-BNP values (2656 [24-35,000] vs. 8390 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). NT-pro-BNP levels were not significantly different in patients with primary cardiac diagnosis compared with those with a noncardiac admission diagnosis (4794 [26-35,000], n = 202 vs. 3349 [24-35,000], n = 87, cardiac vs. noncardiac, respectively, p = .28). In a logistic regression model, Simplified Acute Physiology Score II and NT-pro-BNP were independently associated with hospital survival (chi = 35.6, p = .0001 and chi = 11.3, p = .0008, Simplified Acute Physiology Score II and NT-pro-BNP, respectively). Areas under the receiver operating characteristic curves of NT-pro-BNP and Simplified Acute Physiology Score II were not statistically significant different regarding the prediction of outcome. CONCLUSIONS: NT-pro-BNP on admission is an independent prognostic marker of outcome in an unselected cohort of critically ill patients. A single measurement of NT-pro-BNP might facilitate triage of emergency and intensive care unit patients.     

Levels of protein C activity and clinical factors in early phase of pediatric septic shock may be associated with the risk of death

Severe sepsis and septic shock are major causes of morbidity and mortality among children in pediatric intensive care units (PICUs) worldwide. Activated protein C (PC) is a critical endogenous regulator of coagulation and inflammation in patients with sepsis. However, the role of PC in pediatric sepsis is still obscure. We prospectively recruited infants and children aged between 1 month and 15 years old who were admitted to PICU with a clinical diagnosis of systemic inflammatory response syndrome, sepsis, or septic shock. Clinical data were recorded and blood samples kept for further analysis. We then measured the levels of PC activity. Of the approximately 1,100 pediatric patients admitted to PICU from January 1, 2004 to December 31, 2005, 75 were diagnosed with septic shock (6.8%), and 67 samples were available for analysis. Out of these, 41 (61%) were survivors, and 26 (39%) were nonsurvivors. The average plasma PC activity (%) was at 37.8 +/- 4.4. Plasma PC activity (%) was significantly lower in the nonsurvivors compared with the survivors at 23.6 +/- 4.3 and 46.8 +/- 6.3 (P = 0.002), respectively. D-Dimer levels were not significantly different between the survivors (1,461 +/- 266 ng/mL) and the nonsurvivors (1,989 +/- 489 ng/mL) (P = 0.68). Also, there was no correlation between plasma PC activity and D-dimer levels (r = -0.07; P = 0.6). Importantly, the odds of dying were significantly higher in patients whose level of PC activity was less than 25% (odds ratio = 5.6; P = 0.02). Pediatric patients with septic shock demonstrate very low levels of PC activity, and this may be associated with an increased risk of death.     

Coagulation system and platelets are fully activated in uncomplicated sepsis

OBJECTIVE: To test the hypothesis that the coagulation system and platelets are activated in sepsis, the uncomplicated and usually earliest stage of the septic process, and to compare the findings detected in sepsis with those found in severe sepsis and septic shock. DESIGN: Prospective study comparing patients with sepsis, severe sepsis, and septic shock, and healthy volunteers. SETTING: General intensive care unit in a tertiary university hospital. PATIENTS: Seventy-four consecutive septic patients (45 with sepsis, 15 with severe sepsis, and 14 with septic shock). Fourteen healthy volunteers served as control subjects. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: After blood sampling, molecular activation markers of coagulation (prothrombin fragments 1 and 2, fibrinopeptide A, thrombin-antithrombin complexes, and monomers of fibrin) and of platelets (beta-thromboglobulin and platelet factor 4), several coagulation factors, global tests of coagulation (prothrombin time and activated partial thromboplastin time), and platelet count (PTL) were measured. In sepsis, prothrombin fragments 1 and 2, fibrinopeptide A, thrombin-antithrombin complexes, and monomers of fibrin were increased to 2.52+/-0.21 nmol/L, 20.88+/-2.52 ng/mL, 33.8+/-2.9 microg/L, and 69% positive, respectively, compared with control subjects (0.86+/-063 nmol/L, 1.14+/-0.15 ng/mL, 16.07+/-1.01 microg/L, and 0%, respectively). Beta-Thromboglobulin and the beta-thromboglobulin-to-platelet factor 4 ratio were also increased to 107.87+/-11.87 IU/mL and 8.86+/-1.06, compared with controls (18.36 +/-2.99 IU/mL and 2.67+/-0.52, respectively). With the exception of a decrease in factor XII and an increase in fibrinogen, coagulation factors, global coagulation tests, and PTL were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation factors were markedly decreased, global coagulation tests were prolonged, and PTL was reduced. All changes were independent of the causative infectious pathogen. CONCLUSION: Coagulation system and platelets are strongly activated in sepsis. In this stage, only factor XII is decreased. In contrast, in severe sepsis and mainly in septic shock, most of the coagulation factors are depleted, PTL is decreased, and global coagulation tests are prolonged, indicating exhaustion of hemostasis. Finally, Gram-positive, Gram-negative, and other microorganisms produce identical impairment of coagulation.     

Increased circulating endothelial progenitor cells in septic patients: correlation with survival

OBJECTIVE: Endothelial damage and detachment of endothelial cells are known to occur in septic patients. Thus, recruitment of circulating endothelial progenitor cells (cEPCs) to these lesions might have a beneficial effect on the clinical course in septic patients. Therefore, we were interested in whether EPCs, detected by flow cytometry, are increasingly mobilized during sepsis and if this mobilization is associated with clinical outcome. DESIGN: Prospective, nonrandomized study. SETTING: Intensive care unit of a university hospital. PATIENTS: Patients with (n = 32) and without (n = 15) sepsis and healthy volunteers (n = 15). INTERVENTIONS: Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, and cEPCs were characterized by three-color fluorescence flow cytometry using antibodies against CD133, CD34, and vascular endothelial growth factor receptor-2. Serum concentrations of vascular endothelial growth factor, granulocyte macrophage-colony stimulating factor, and erythropoietin were determined by enzyme-linked immunosorbent assay. Severity of sepsis was assessed according to Acute Physiology and Chronic Health Evaluation II scoring. MEASUREMENTS AND MAIN RESULTS: In septic patients, the number of cEPCs was significantly higher than in nonseptic intensive care unit patients (p < .05) and healthy controls (p < .02). Nonsurvivors (n = 8), defined as death within 28 days after onset of sepsis, had significantly lower numbers of cEPCs than survivors (n = 24) (p < .0001). The number of cEPCs was correlated with survival in septic patients. Serum vascular endothelial growth factor concentrations were significantly higher in septic patients compared with nonseptic intensive care unit patients and healthy controls (p < .01) and correlated with the cEPC numbers (p < .0001). Similar findings were observed for granulocyte macrophage-colony stimulating factor and erythropoietin. CONCLUSIONS: Our data suggest that cEPC enumeration in peripheral blood of septic patients might be a valuable marker to assess the clinical outcome in these patients.