Sepsis in critically ill patients with injury bears a high morbidity and mortality. Extensive phenotypic monitoring of leucocyte subsets in critically ill patients at ICU admission and during sepsis development is still scarce. The main objective of this study was to identify early changes in leukocyte phenotype which would correlate with later development of sepsis.

Patients who were admitted in a tertiary ICU for organ support after severe injury (elective cardiac surgery, trauma, necessity of prolonged ventilation or stroke) were sampled on admission (T1) and 48-72 h later (T2) for phenotyping of leukocyte subsets by flow cytometry and cytokines measurements. Those who developed secondary sepsis or septic shock were sampled again on the day of sepsis diagnosis (Tx).

Ninety-nine patients were included in the final analysis. Nineteen (19.2%) patients developed secondary sepsis or septic shock. They presented significantly higher absolute monocyte counts and CRP at T1 compared to non-septic patients (1030/µl versus 550/µl, p = 0.013 and 5.1 mg/ml versus 2.5 mg/ml, p = 0.046, respectively). They also presented elevated levels of monocytes with low expression of L-selectin (CD62Lneg monocytes) (OR[95%CI] 4.5 (1.4-14.5), p = 0.01) and higher SOFA score (p < 0.0001) at T1 and low mHLA-DR at T2 (OR[95%CI] 0.003 (0.00-0.17), p = 0.049). Stepwise logistic regression analysis showed that both monocyte markers and high SOFA score (> 8) were independently associated with nosocomial sepsis occurrence. No other leucocyte count or surface marker nor any cytokine measurement correlated with sepsis occurrence.

Monocyte counts and change of phenotype are associated with secondary sepsis occurrence in critically ill patients with injury.

Potential physiological correlates of stress and the role of stress neuropeptides, other than those of the hypothalamic-pituitary-adrenal axis, in critical illness have not been addressed. We investigated: (a) serum levels of stress neuropeptides (ACTH, substance P (SP), neuropeptide Y (NPY), cortisol, prolactin) in critically ill individuals compared to matched controls, (b) associations with lymphocyte counts, (c) associations among stress neuropeptide levels, and (d) associations with perceived intensity of stress, critical illness severity and survival.

Correlational design with repeated measures. Thirty-six critically ill patients were followed up for 14 days compared to 36 healthy matched controls. Stress was assessed by the ICUESS scale. Correlations, cross-sectional comparisons and multiple regression models were pursued.

For the first time, we report lower SP (Difference of means (DM) = 2928-3286 ng/ml, p < 0.001) and NPY (DM = 0.77-0.83 ng/ml, p < 0.0001) levels in critically ill individuals compared to controls. Cortisol levels were higher (DM = 140-173 ng/ml, p<0.0001) and lymphocyte population counts (p < 0.002) were lower in patients throughout the study. NPY levels associated with lymphocyte (r = 0.411-0.664, p < 0.04), T-lymphocyte (r = 0.403-0.781, p< 0.05), T-helper (r = 0.492-0.690, p < 0.03) and T-cytotoxic cell populations (r = 0.39-0.740, p < 0.03). On day 1, cortisol levels exhibited associations with lymphocyte (r = -0.452, p = 0.01), T-cell (r = -0.446, p = 0.02), T-helper (r = -0.428, p = 0.026) and T-cytotoxic cells ( r = -0.426, p = 0.027). ACTH levels associated with NK cell counts (r = 0.326-0.441, p < 0.05). Associations among stress neuropeptides levels were observed throughout (p < 0.05). ACTH levels associated with disease severity (r = 0.340-0.387, p < 0.005). A trend for an association between ACTH levels and intensity of stress was noted (r = 0.340, p = 0.057).

The significantly lowered NPY and SP levels and the associations with cortisol, ACTH and lymphocytes suggest that the role of these peptides in critical illness merit further investigation. Future studies need to address associations between these neuropeptides and functional immune cell responses and inflammatory markers in critical illness.

We previously demonstrated a negative effect of cardiopulmonary bypass (CPB) in a canine model of single-lung graft function and an improved effect with ultrafiltration during CPB.

To investigate the mechanism of these effects, focusing on cytokines and pulmonary surfactants using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).

Fifteen left-sided single-lung transplant procedures were performed in pairs of dogs. The animals were divided into 3 groups. In one group, transplantation was performed without CPB (non-CPB group); in a second group, transplantation was performed with CPB and CPB flow was decreased slowly and pulmonary artery pressure was controlled (CPB group; and in the third group, transplantation was performed with CPB and ultrafiltration (CPB+UF group). Grafted lung specimens were harvested for RT-PCR of cytokines (IL-6, IL-8, and IL-10) and surfactant proteins (SP-A, SP-B, and SP-C).

Real-time quantitative RT-PCR demonstrated increased IL-6 expression in the CPB group compared with the non-CPB group. IL-6 gene expression was suppressed and pulmonary surfactant restored using ultrafiltration. Gene expression of surfactant protein (SP)-A, SP-B, and SP-C was decreased in the CPB group compared with normal lung and ultrafiltration groups, which demonstrated sustained gene expression of SP-A and SP-B.

Cardiopulmonary bypass has negative effects on grafts; however, ultrafiltration attenuates acute lung dysfunction by decreasing the inflammatory response and increasing pulmonary surfactant.

Interleukin-8 (IL-8, also known as neutrophil-activating peptide 1, NAP1 and CXCL8, CXC chemokine ligand 8) is recognized as a potent effector of neutrophil functions. IL-8 is a major response factor following NfkB activation by cytokines or lipopolysaccharide and several different cell types T lymphocytes, monocytes, epithelial and endothelial cells secrete this polypeptide. IL-8 is not to be determined at significant concentrations in plasma due to its receptor binding but may play a major role in tissues. The prediction of sepsis is a major and current field of research in the treatment of surgical patients. The aim of this study was to compare the determination of IL-8 in whole blood cell lysates (whole blood IL-8) and in plasma for the prediction of sepsis in postoperative intensive care.

Whole blood IL-8, IL-8 in plasma, and CRP were measured in the daily routine monitoring of 84 patients in a surgical intensive care unit. Sepsis was defined by the criteria of the Society of Critical Care Medicine (SCCM). For comparison the APACHE II score (APACHE=Acute Physiology and Chronic Health Evaluation) was calculated. The diagnostic value of the three tests was compared by receiver operating characteristic (ROC) curves.

Whole blood IL-8 showed higher areas under the curve (AUC) than IL-8 in plasma and CRP. The ROC curves for the APACHE II scores gave similar results.

Sepsis is a complex disease and is induced by systemic infection of patients suffering from systemic inflammatory response syndromes (SIRS). Therefore, the identification of infection or the host response to infection is of crucial importance. The prediction of an individual marker or interleukin or its binding to surface proteins is not necessarily indicative for sepsis. In cases with unequivocally identified bacterial infections, the current results suggest that whole blood IL-8 may have a similar diagnostic accuracy as plasma levels. Of note, this technique needs less blood and is not being affected by hemolysis.

The pathogenic, diagnostic and therapeutic landscape of sepsis is no longer confined to the intensive care unit: many patients from other portals of entry to care, both outside and within the hospital, progress to severe disease. Approaches that have led to improved outcomes with other diseases (e.g., acute myocardial infarction, stroke and trauma) can now be similarly applied to sepsis. Improved understanding of the pathogenesis of severe sepsis and septic shock has led to the development of new therapies that place importance on early identification and aggressive management. This review emphasizes approaches to the early recognition, diagnosis and therapeutic management of sepsis, giving the clinician the most contemporary and practical approaches with which to treat these patients.

Brain injury as well as early inflammatory and endocrine responses were found to be indicators for infectious complications in patients with multiple injuries. In this context, brain-derived inflammatory response as well as centrally triggered neuroendocrine activation and systemic immunodepression seem to be of major importance. Therefore, we hypothesize that a circulating index of inflammatory or endocrine function measured soon after brain injury (in patients with admission Glasgow Coma Scale [GCS] score of 4-7) would discriminate severe from moderate injury as indexed by GCS status on postinjury day 7.

In a retrospective study, 25 patients with either acute traumatic brain injury or cerebral hemorrhage and an initial GCS score of 4 to 7 were examined. Blood samples were obtained at different time points, and different immune variables and neuroendocrine hormones were determined. According to the GCS score on day 7, patients were divided into two groups (GCS score > or = 8, moderate brain injury; and GCS score < 8, severe brain injury or patients who died within the first week) for comparison of variables. Concluding from the results of this retrospective analysis, in a prospective study patients (n = 26) were divided into two groups according to their interleukin (IL)-6 plasma concentrations on day 1 (IL-6 > or = 100 pg/mL and IL 6 < 100 pg/mL). After 7 days, the GCS score, the infection rate, and the mortality were compared between these two groups.

In the retrospective study, we could show that severe brain injury (as assessed by GCS score and mortality on day 7) was associated with high plasma levels of pro- and anti-inflammatory cytokines, acute phase proteins, and neuroendocrine hormones within 2 to 6 hours after the acute event. Among the investigated variables, elevated IL-6 plasma concentrations were stable up to 1 day after the acute event with a high predictive value with regard to the short-term prognosis and incidence of infectious complications within the first week. Because of this stability during the first 24 hours, we selected IL-6 for further studies. In the prospective study with a calculated cut-off IL-6 plasma concentration of 100 pg/mL on day 1, the predictive value of this parameter regarding the severity of the brain injury was fully confirmed (positive predictive value, 0.94; this value represents the observed pretest probability of 0.62). All patients who died (n = 5) or developed infectious complications within the first week (n = 8) showed plasma IL-6 levels > or = 100 pg/mL on day 1.

The IL-6 plasma level 1 day after the acute event with a cut-off of 100 pg/mL (Immulite) seems to be a predictor for short-term prognosis and infectious complications in brain-injured patients.

Today the basic principles of septic conditions are understood. Nevertheless, sepsis research has reached a critical point. To integrate our knowledge towards a consistent theory of the disease process and to derive effective therapies, new perspectives for future research that fit the complexity of the problem have to be found. We conducted a review of the literature concerning systemic inflammatory response syndrome (SIRS) and sepsis with particular reference to liver pathophysiology. And compared our findings with characteristic features of complex systems. The complexity of sepsis is broadly recognized. A review of the different aspects of liver inflammation during SIRS and sepsis, i.e. endotoxin challenge, cytokine induced dysfunction, the mechanisms of leukocyte transmigration, and hormonal and neuroendocrine regulatory mechanisms is given. Key aspects of complex systems, including parallelism, locality, emergence, and cross-scale interactions are introduced. We conclude that sepsis research needs new perspectives that allow us to handle the complex interactions occurring during the disease process. We propose to focus research on the interactions between the constituents of the system rather than only describing isolated aspects of the disease process. We also conclude that the ideas and techniques of non-linear systems theory are suitable tools for the analysis of complex and dynamic diseases like SIRS and sepsis.

The aim of this study is to assess the associations between the timing of secondary definitive fracture surgery on inflammatory changes and outcome in the patient with multiple injuries. The study population consists of a series of patients with multiple injuries who were managed using a strategy of primary temporary skeletal stabilization followed by delayed definitive fracture fixation.

In a prospective cohort study performed at a Level I trauma center, the patients' injuries and operative details as well as immune markers and clinical outcomes were studied. The patients were split into an early secondary surgery group (group ESS, surgery at days 2-4) and a late secondary surgery group (group LSS, surgery at days 5-8). During the posttraumatic course, inflammatory markers (interleukin [IL]-6, tumor necrosis factor-alpha) were determined on a daily basis. Perioperatively, these markers were additionally evaluated at 30 minutes, 7 hours, and 24 hours after initiation of surgery.

Secondary surgery on days 2 to 4 was associated with a higher incidence of postoperative organ dysfunction (n = 33 [46.5%]) than secondary surgery on days 5 to 8 (n = 9 [15.7%], p = 0.01). A significant association between the combination of initial IL-6 values > 500 pg/dL plus surgery on days 2 to 4 and the development of multiple organ failure (r = 0.96, p < 0.001) occurred. A correlation between the initial IL-6 values > 500 pg/dL and surgery on days 5 to 8 (r = 0.57, p < 0.07) could not be found. IL-6 also demonstrated a predictive value for the development of multiple organ failure: IL-6 > 500 pg/dL in group ESS, r = 0.96, p < 0.001; IL-6 > 500 pg/dL in group LSS, r = 0.57, p < 0.07.

According to our data, no distinct clinical advantage in carrying out secondary definitive fracture fixation early could be determined. In contrast, in patients who demonstrated initial IL-6 values above 500 pg/dL, it may be advantageous to delay the interval between primary temporary fracture stabilization and secondary definitive fracture fixation for more than 4 days. In patients with blunt multiple injuries undergoing primary temporary fixation of major fractures, the timing of secondary definitive surgery should be carefully selected, because it may act as a second hit phenomenon and cause a deterioration of the clinical status.

We sought to determine whether levels of the endogenous mediators tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, and nitric oxide (NO) measured in patients with presumed sepsis (systemic inflammatory response syndrome [SIRS] and infection) are different than levels in patients with presumed noninfectious SIRS, whether levels are associated with septic complications, and whether there are potential relationships between mediators.

A prospective, observational tricenter study of a convenience sample of adults presenting to the emergency department meeting Bone's criteria for SIRS (any combination of fever or hypothermia, tachycardia, tachypnea, or WBC count aberration) was performed. Mediator levels were determined and associated with deterioration to severe sepsis (hypotension, hypoperfusion, or organ dysfunction) and death in subjects admitted to the hospital with presumed sepsis.

One hundred eighty subjects with SIRS were enrolled and classified into 3 groups: group 1 (SIRS, presumed infection, admitted; n=108), group 2 (SIRS, presumed infection, discharged; n=27), and group 3 (SIRS, presumed noninfectious, admitted; n=45). Group 1 TNF-alpha and IL-6 levels were significantly higher than those found in the other groups. NO levels for groups 1 and 2 were significantly lower than those for group 3. TNF-alpha and IL-6 levels were higher in the group 1 subjects who had bacteremia or progressed to severe sepsis or death. NO levels were not associated with these outcomes.

ED patients admitted with presumed sepsis have elevated cytokine levels compared with patients with sepsis who are discharged and with those patients with presumed noninfectious SIRS. An association appears to exist between cytokines and subsequent septic complications in these patients. The importance of these measures as clinical predictors for the presence of infection and subsequent septic complications needs to be evaluated.

To define the pro- and anti-inflammatory cytokine response during acute severe pancreatitis and to evaluate its predictive value on hospital mortality.

Prospective, multicenter study.

Nine multidisciplinary intensive care units (ICUs).

Fifty patients with a diagnosis of acute pancreatitis who were admitted to the ICUs during a 14-month period were prospectively enrolled.

None.

Plasma concentrations of tumor necrosis factor (TNF)-alpha interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist (IL-1ra) were determined at the inclusion and during the ICU stay at Days 1, 3, 8, and 15. The patient population was analyzed by age, gender, previous health status, preexisting organ dysfunction, and type of acute pancreatitis. Physiologic variables were measured at inclusion and during ICU stay to calculate the new Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the number of organ system failures. Prognostic factors were determined by univariate methods and stepwise logistic regression analysis. Fifty patients were included, among whom 34 at the time of the ICU admission. Preinclusion symptom history was < or = 48 hrs in 78% of the patients. Eleven patients (22%) died during their hospital stay. At inclusion, 46 of 50 patients had elevated IL-6 serum levels (1512 +/- 635 pg/mL; normal value < 10 pg/mL), 36% of the patients had raised TNF-alpha concentrations, and all patients had an anti-inflammatory response (IL-10, 92 +/- 15 pg/mL [normal value < 10 pg/mL]; and/or IL-1ra, 7271 +/- 2530 pg/mL [normal value < 200 mg/mL]). During the follow-up period, pro- and anti-inflammatory cytokines remained elevated in at least 75% of the population. Positive correlations were found between inclusion pro- (IL-6) and anti-inflammatory cytokine concentrations at Day 1 (IL-10, IL-1ra; p < .0001) and between cytokines levels and the Simplified Acute Physiology Score II. While hospital mortality was linked to six factors in univariate analysis (age, cirrhosis, delay between hospitalization and ICU admission, severity of illness, and IL-10 and IL-6 plasma levels) when using stepwise logistic regression, only severity scoring indexes were predictive of death.

During acute severe pancreatitis, the pro- and anti-inflammatory cytokine response occurred early and persisted in the systemic circulation for several days. Although associated with the patient's severity at inclusion and outcome, cytokine plasma concentrations were unable to predict death accurately in individual patients. If confirmed, these results should be taken into consideration when selecting patients who are apt to benefit from new therapies aimed at modifying the immune inflammatory response.