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The immune response of the host against invading pathogens is clinically manifested as sepsis. Sepsis is a complicated process characterized by distinct phases that usually occur in a sequential manner. The initial hyper-inflammation helps in elimination of the pathogen, but potentially may lead to excessive tissue injury. Hypo-inflammation helps in restoring immune homeostasis, but may lead to significant immune suppression and death from secondary infections if not appropriately controlled. Immune-modulating intervention in sepsis should be based on a balanced control of both the hyper and the hypo-inflammatory phase. © 2016. Journal of Thoracic Disease.

Purpose: The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe sepsis/septic shock. Methods: A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ, interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured. Results: Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 (P

Purpose: Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect "immunocompetent" seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. Methods: This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ, interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. Results: During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. Conclusions: Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome. © 2014 Elsevier Inc.

Background Reduced coronary velocity flow reserve (CFR) is associated with poor outcome in patients with cardiovascular disease. We investigated whether CFR is associated with tissue ischemia and acidosis, impaired myocardial deformation and adverse outcome in patients with septic shock. Methods In 70 mechanically-ventilated patients with septic shock, we examined: a) S′ and E′ mitral annular velocities using tissue Doppler imaging (TDI), b) CFR of the left anterior descending artery after adenosine infusion using transesophageal Doppler echocardiography and c) lactate, pyruvate and glycerol in tissue by means of a microdialysis (MD) catheter inserted into the subcutaneous adipose tissue as markers of tissue ischemia and acidosis. SOFA and APACHE II prognostic scores and mortality in the intensive care unit (ICU) were recorded. Results Reduced CFR, S′ and E′ as well as increased E/E′ correlated with increased SOFA, APACHE II and MD lactate to pyruvate ratio (p < 0.05 for all correlations). Impaired TDI markers also correlated with increased MD glycerol (p < 0.05). Reduced CFR correlated with decreased E′ (p < 0.05). CFR was 1.8 ± 0.42 in non-survivors (n = 34) versus 2.08 ± 0.44 in survivors (p = 0.007). A CFR < 1.90 predicted mortality with sensitivity of 70% and specificity of 69% (area under the curve 77%; p = 0.003). CFR had an additive value to APACHE (chi-square change: 4.358, p = 0.03) and SOFA (chi-square change: 3.692, p = 0.04) for the prediction of mortality. Conclusion Tissue ischemia and acidosis is a common pathophysiological link between decreased CFR and impaired LV myocardial deformation in septic shock. CFR is an additive predictor of ICU mortality to traditional risk scores in septic shock. © 2014 Elsevier Ireland Ltd.

Purpose: The purpose of this study is to assess lipid metabolism at the tissue level in critically ill subjects. Materials and methods: We studied 182 patients with systemic inflammatory response syndrome/severe sepsis or shock during the acute (day 1) and subacute phase of critical illness (day 6). All subjects had a tissue microdialysis (MD) catheter placed in femoral adipose tissue upon admission to the intensive care unit (ICU). Plasma cholesterol, high-density lipoprotein, low-density lipoprotein, free fatty acids (FFAs), triglyceride, and MD glycerol (GLYC) were measured on days 1 and 6 in the ICU. Results: On admission, 56% of the patients had increased levels (> 200 μmol/L) of MD GLYC. Patients with shock displayed more pronounced subcutaneous tissue lipolysis and more profound derangements of circulating lipids vs patients without shock (but no appreciable differences in FFA levels). Furthermore, in patients with shock during the acute period, there were positive, albeit weak, correlations of subcutaneous tissue lipolysis (MD GLYC), plasma FFAs (r = 0.260; P = .01), and norepinephrine's dose (r = 0.230; P = .01), whereas during the subacute phase, MD GLY levels were higher in patients receiving glucocorticoids (344.7 ± 276.0 μmol/L vs 252.2 ± 158.4 μmol/L; P = .03). Conclusions: Subcutaneous tissue lipolysis is only one of the many determinants of plasma FFAs. Routinely applied therapeutic modalities in the ICU interfere with adipose tissue metabolism. © 2014 Elsevier Inc.

Context: Adrenal dysfunction remains a controversial issue in critical care. The long-stay intensive care unit (ICU) population may be at increased risk of adrenal insufficiency. Objective: We aimed to determine whether adrenal dysfunction develops during the course of sepsis. Design: This is a prospective observational longitudinal study. Setting: The study was conducted in the ICU of a secondary/tertiary care hospital Patients: We studied 51 consecutive mechanically ventilated patients with sepsis. Intervention: We measured cortisol, ACTH, cortisol-binding globulin, cytokines, and cortisol 30 minutes after 1 μg ACTH(1-24), upon sepsis diagnosis and every 3 to 4 days, until Day 30 or until recovery or death. Main Outcome Measures: We looked for changes in baseline and stimulated cortisol levels and its relationship to ACTH levels, sepsis severity or survival. Results: Base line and stimulated cortisol levels did not vary significantly. Septic patients with shockhad higher baseline (20 ± 6 vs 17 ± 5 μg/dL, P = .03) and stimulated cortisol levels (26 ± 5 vs 23 ± 6 μg/dL, P = .04), compared with those without shock. On Day 1, ACTH levels could not predict cortisol levels (R2 = 0.06, P = .08). ACTH levels increased significantly after Day 10 and, at this time point, they related to cortisol levels (R2 = 0.35, P < .001). Development of septic shock, or resolution from it, was not associated with changes in baseline, stimulated cortisol levels, or the cortisol increment. There was much inpatient variability in the diagnosis of adrenal dysfunction at different time points. Conclusions: Total cortisol levels relate both to the severity and outcome of sepsis and remain fairly unchanged during the course of illness. Initially, cortisol levels are largely ACTH independent, whereas ACTH increases and correlates with cortisol levels later on. Adrenal dysfunction does not seem to be a major problem during the prolonged phase of sepsis. Although not significant, the variation in cortisol levels may be such that classification of patients varies, questioning the utility of arbitrary cut-offs to define adrenal dysfunction in septic patients. Copyright © 2014 by the Endocrine Society.

Purpose: The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels. Materials and Methods: An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls. Results: The patients had higher adiponectin (10.9 ± 6.1 μg/mL vs 6.0 ± 2.9 μg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted. Conclusions: Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis. © 2012 Elsevier Inc.

Introduction: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.Methods: A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden.Results: Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥17 and suPAR ≥12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II

Purpose: The aim of the study was to study the interrelationship between blood and tissue lactate in critically ill patients with or without shock admitted in a general intensive care unit. Materials and Methods: We studied 162 mechanically ventilated patients: 106 with shock (septic shock, 97; cardiogenic shock, 9) and 56 without shock (severe sepsis, 38; systemic inflammatory response syndrome, 18). A microdialysis catheter was inserted in the subcutaneous adipose tissue of the upper thigh, and interstitial fluid was collected every 4 hours for a maximum of 6 days. We assessed the relationship between tissue and blood lactate using cross-approximate entropy and cross-correlation analysis. Results: Patients with shock had higher area under the curve for blood (261 vs 175 mmol/L*hours, P < .0001) and tissue lactate (386 vs 281 mmol/L*hours, P < .0001) compared with patients without shock. The interrelationship of tissue-blood lactate, as assessed with cross-approximate entropy, was more regular in patients with shock compared with patients without shock. Cross-correlation of tissue vs blood lactate yielded higher correlation coefficients in patients with shock compared with those without shock, being higher when tissue lactate preceded blood lactate by 4 hours compared with tissue vs blood lactate with no lag time. Conclusions: In critical illness, the detailed dynamics between blood and tissue lactate are affected by the presence of shock. In patients with shock, microdialysis-assessed tissue lactate is higher compared with those without shock and may detect metabolic disturbances before these become evident in the systemic circulation. © 2012 Elsevier Inc.

Purpose: To define early kinetics of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and of TREM-1 monocyte gene expression in critically ill patients with sepsis. Methods: Blood was sampled at regular time intervals from 105 patients with sepsis. Concentrations of tumour necrosis factor α (TNF α), interleukin (IL)-6, IL-8 and IL-10 and IL-12p70 and sTREM-1 were measured by an enzyme immunoassay. Blood mononuclear cells were isolated on day 0 from 20 patients and 10 healthy volunteers; RNA was extracted and gene expression of TREM-1 and TNF α were assessed by reverse transcriptase polymerase chain reaction. Results: Early serum concentrations of sTREM-1 were greater among patients with severe sepsis/shock than among patients with sepsis; those of TNF α, IL-6, IL-8 and IL-10 were pronounced among patients with septic shock. Gene transcripts of TNF α were lower among patients with severe sepsis/shock than among patients with sepsis; that was not the case for TREM-1. Early serum levels of sTREM-1 greater than 180 pg/mL were predictors of shorter duration of mechanical ventilation. Conclusions: Although serum levels of sTREM-1 are increased early upon advent of severe sepsis/shock, gene expression of TREM-1 on monocytes in severe sepsis/shock is not increased. These findings add considerably to our knowledge on the pathophysiology of sepsis. © 2012 Elsevier Inc.

Background: In critically ill patients independent studies have shown contradictory findings regarding the prognostic significance of the D/D genotype of the I/D angiotensin converting enzyme (ACE) polymorphism. The study aim was to evaluate the effect of both ACE I/D polymorphism and ACE serum levels on the clinical outcomes of critically ill septic patients. Methods: This study recruited 186 Caucasian patients with sepsis, severe sepsis or septic shock. Epidemiological, clinical data, co-morbidities and severity scores were recorded. Measurements of serum ACE activity and genotyping for ACE I/D polymorphism were carried out. Primary outcomes were the 28-and the 90-day mortality; secondary outcomes included the number of days without renal or cardiovascular failure and ventilation-free days over the 28-day period following study enrolment. Results: Neither 28-nor 90-day mortality were associated with ACE I/D polymorphism (p=0.59 and 0.34, respectively) or circulating ACE levels (p=0.17 and 0.25, respectively). Similarly, ACE polymorphism and levels were not related to ventilation-free days (p=0.14 and 0.25, respectively), days without cardiovascular failure (p=0.14 and 0.81, respectively) and days without renal failure (p=0.64 and 0.27, respectively). Conclusions: Neither ACE I/D polymorphism nor serum ACE levels seem to be significant prognostic factors of clinical outcomes in septic, critically ill patients. © 2012 by Walter de Gruyter Berlin Boston.

Purpose: More than a disorder of macrocirculation, sepsis is a disease affecting the microcirculation and the tissue metabolism. In vivo microdialysis (MD) is a bedside technique that can monitor tissue metabolic changes. We conducted this study aiming (1) to assess whether patients at different sepsis stages present with different MD-assessed tissue metabolic profiles and (2) to determine if different underlying types of infections and implicated pathogens are associated with dissimilar metabolic alterations. Methods: We studied 90 mechanically ventilated patients, 65 with septic shock and 25 with severe sepsis. An MD catheter was inserted in the subcutaneous adipose tissue of the upper thigh and interstitial fluid samples were collected along with arterial blood samples every 4 h for a maximum of 6 days. Lactate, pyruvate, glycerol, and glucose concentrations were measured. Results: During the study period, patients with septic shock had higher MD-assessed glycerol (P = 0.009), glycerol gradient (P = 0.016), and glucose (P = 0.004) than patients with severe sepsis, whereas tissue lactate, lactate gradient, and pyruvate dropped significantly with time (P = 0.007

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P = 0.01) and glycerol (340 vs. 169 μmol/L, P = 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P = 0.008), glycerol (P = 0.004), and pyruvate (P = 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio [OR], 1.075; 95% confidence interval [CI], 1.004-1.150; P = 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043-2.312; P = 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001-1.012; P = 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor. Copyright © 2011 by the Shock Society.

The mechanisms of the N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) release in intensive care unit (ICU) patients with preserved ejection fraction (EF) are unclear. We investigated whether left ventricular (LV) dysfunction, as assessed by tissue Doppler imaging (TDI), is related to NT-pro-BNP levels in ICU patients with preserved EF and has a complementary value to NT-pro-BNP in the determination of in-hospital mortality. We examined 58 mechanically ventilated patients with no history of heart failure (age, 60 ± 18 years; EF, 63% ± 7%). The systolic (S) and early diastolic (E′) velocity of the mitral annulus by TDI and the E/E′ as well as NT-pro-BNP, troponin, lactate acid, blood oxygen (PO2/FiO2), sepsis, and ICU mortality were assessed. Systolic, E′, and E/E′ correlated with age, PO 2/FiO2, lactate acid, NT-pro-BNP, troponin, history of arterial hypertension, and diabetes (P < 0.05). By multivariate analysis, the determinants of NT-pro-BNP were S (P = 0.024), E/E′ (P = 0.017), and sepsis (P = 0.015). An NT-pro-BNP greater than 941 pg/mL was a reliable predictor of LV diastolic dysfunction defined as a composite of E′ less than or equal to 8 cm/s and/or mean E/E greater than or equal to 13 (area under the curve, 75%; P = 0.03). Patients with combined NT-pro-BNP greater than 941 pg/mL and abnormal TDI markers had increased creatinine levels and a lower MAP, PO2/FiO2, and survival rate than those with abnormal TDI or NT-pro-BNP alone or patients with normal TDI markers and NT-pro-BNP (25%, 60%, 70%, and 84%, respectively; P < 0.05). The addition of abnormal TDI in a model including NT-pro-BNP and sepsis increased the model's value for in-hospital mortality (P for change = 0.01). In ICU patients with preserved EF, LV diastolic dysfunction and sepsis determine NT-pro-BNP levels. Tissue Doppler imaging markers and NT-pro-BNP have a complementary value for in-hospital mortality. © 2010 by the Shock Society.

Background: Controversial findings of former clinical trials on the effect of low dose hydrocortisone in patients with septic shock led to investigate the effect of corticosteroids on the production of cytokines from endotoxin (LPS)-stimulated whole blood. Methods: Whole blood from 33 septic patients was sampled within 24 h alter diagnosis. Hydrocortisone was not administered during follow-up. Whole blood was stimulated with 30 ng/ml of LPS in the presence of 0.01, 0.1, 1 and 10 μM of dexamethasone. Concentrations of cytokines and of sTREM-1 were estimated in supernatants after six hours of incubation. Results: Dexamethasone inhibited LPS-stimulated release of ΤΝFα, of IL-6, of IL-8 and of IL-10 in dose-dependent manner. A dual effect on the kinetics of release of IL-1β and of sTREM-1 was shown. Release of IL-1β was either decreased, what was connected with unfavorable outcome, or it was unaffected what was connected with a favorable outcome. Release of sTREM-1 was either increased, what was connected with unfavorable outcome, or it was decreased what was connected with a favorable outcome. Conclusions: Part of the beneficiary effect of corticosteroids in sepsis may be due to an effect on the release of IL-1β and of sTREM-1. This effect does not seem to be homogeneous for all septic patients. © 2009 Elsevier Ltd. All rights reserved.

Clostridium difficile infection is an emerging and often difficult-to-treat iatrogenic complication. Recent data suggest that tigecycline, a novel antibiotic with broad-spectrum antibacterial activity, can be used successfully to treat patients with severe Clostridium difficile infection. We report a 70-year-old man who developed severe Clostridium difficile infection, was admitted to the intensive care unit and eventually succumbed to complications of his illness despite receiving tigecycline for approximately three weeks in combination with vancomycin, metronidazole and intravenous immunoglobulin. Additionally, we discuss the unique challenges that emerged during tigecycline treatment, such as the development of Proteus mirabilis bacteraemia and of colonisation with Acinetobacter baumannii resistant to tigecycline. Finally, we review data on other cases reported in the medical literature. Even though tigecycline looks promising for the treatment of Clostridium difficile infection, we urge caution against its indiscriminate use for off label indications.

Genetic variants of hemostatic factors leading to prothrombotic phenotypes of hypercoagulability and hypofibrinolysis might affect prognosis of septic critically ill patients. Our aim was to evaluate the effect of four hemostatic genetic variants, namely fibrinogen-β-455G/A, factor XIII (FXIII) V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms and factor V Leiden (FVL) mutation on survival of critically ill patients with severe sepsis or septic shock. A prospective, observational study in an 18-bed general ICU included 73 patients with severe sepsis or septic shock. Epidemiological, laboratory data and comorbidities along with severity scores were recorded. Genotyping for fibrinogen-β-455G/A, FXIII V34L and PAI-1 4G/5G polymorphism and FVL mutation was carried out in all patients. The primary outcomes were the 28-day and the 90-day survival. Age, septic shock, severity indexes, prior steroid use and arterial pH were identified as predictors of the 28-day and 90-day survival in both the univariate and the multivariate models. On the contrary, none of the examined polymorphisms was found to significantly affect either the 28-day or the 90-day survival. Our data suggest that the importance of these hemostatic polymorphisms as predictors of the prognosis of sepsis in critically ill patients is probably very small. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular- Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.Methods: Inhaled APC (12.5 μg drotrecogin-α × 4 doses) or saline was given to tracheotomized C57/Bl6 mice starting 20 min prior to initiation of injurious mechanical ventilation with tidal volume 25 mL/Kg for 4 hours and then hourly thereafter; control groups receiving inhaled saline were ventilated with 8 mL/Kg for 30 min or 4 hr. We measured lung function (respiratory system elastance H), arterial blood gases, surrogates of vascular leak (broncho-alveolar lavage (BAL) total protein and angiotensin-converting enzyme (ACE)-activity), and parameters of inflammation (BAL neutrophils and lung tissue myeloperoxidase (MPO) activity). Morphological alterations induced by mechanical ventilation were examined in hematoxylin-eosin lung tissue sections. The activation status of ERK was probed in lung tissue homogenates by immunoblotting and in paraffin sections by immunohistochemistry. The effect of APC on ERK signaling downstream of the thrombin receptor was tested on A549 human lung epithelial cells by immunoblotting. Statistical analyses were performed using ANOVA with appropriate post-hoc testing.Results: In mice subjected to VILI without APC, we observed hypoxemia, increased respiratory system elastance and inflammation, assessed by BAL neutrophil counts and tissue MPO activity. BAL total protein levels and ACE activity were also elevated by VILI, indicating compromise of the alveolo-capillary barrier. In addition to preserving lung function, inhaled APC prevented endothelial barrier disruption and attenuated hypoxemia and the inflammatory response. Mechanistically, we found a strong activation of ERK in lung tissues by VILI, which was prevented by APC, suggestive of pathogenetic involvement of the Mitogen-Activated Kinase pathway. In cultured human lung epithelial cells challenged by thrombin, APC abrogated the activation of ERK and its downstream effector, cytosolic Phospholipase A2.Conclusions: Topical application of APC by inhalation may effectively reduce lung injury induced by mechanical ventilation in mice. © 2010 Maniatis et al.; licensee BioMed Central Ltd.

Objectives: To describe the concentrations of sTREM-1 in patients with sepsis and to explore the effects of their serum on the expression of TREM-1 on U937 monocytes. Methods: Blood was sampled at regular time intervals in 56 patients with sepsis. Concentrations of tumour necrosis factor-alpha (TNFα), interleukin-1beta (IL-1α), IL-6, IL-8, IL-10 and IL-12p70 and sTREM-1 were measured. U937 monocytes were incubated in the presence of serum at sepsis onset. Results: Median sTREM-1 concentration on day 1 for patients with septic shock was 915 pg/ml and 228.5 pg/ml for those without shock (p = 0.002). TNFα, IL-1α, IL-6, IL-8 and IL-10 did not differ between them. A positive correlation was found between changes of sTREM-1 and SOFA scores from day 1 to 7. Sera of patients with septic shock evoked a significant increase of the expression of TREM-1. The concentrations of TNFα and IL-8 in supernatants increased only after stimulating with sera of patients without shock, but not after stimulating with sera of patients with shock. Conclusions: Levels of sTREM-1 correlated with sepsis severity. sTREM-1 is considerably higher in patients with shock compared to patients without shock. The serum of shocked patients could stimulate the expression of TREM-1 on U937 monocytes. © 2008 Birkhäuser Verlag.

The present study aimed to determine whether amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicts intensive care unit (ICU) mortality in a cohort of general, noncardiac, critically ill patients. To this end, a total of 233 consecutive mechanically ventilated patients (109 men) having a median age of 60 years and a wide range in admitting diagnoses, including medical (n = 118), surgical (n = 83), and multiple trauma (n = 32) cases were prospectively studied. Median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores on ICU admission were 16 and 9, respectively. The study end point was ICU outcome. Blood samples were drawn on admission in the ICU and on postadmission days 1 and 2 to determine NT-pro-BNP levels. In a subgroup (n = 77), admission proinflammatory and anti-inflammatory cytokine levels, including TNF-α, IL-6, and IL-10, were also measured. Nonsurvivors (n = 98) had significantly higher NT-pro-BNP levels than survivors (n = 135) on admission in the ICU (2,074 vs. 283 pg/mL; P < 0.001), on day 1 (2,197 vs. 221 pg/mL; P < 0.001), and on day 2 (2,726 vs. 139 pg/mL; P< 0.001). Median values for TNF-α, IL-6, and IL-10 were 3.70, 131.57, and 111.88 pg/mL, respectively. Receiver operating characteristic analysis showed that the area under the receiver operating characteristic curve in predicting ICU mortality was 0.70 for APACHE II and 0.77 for admission NT-pro-BNP (P = 0.08). The cutoff in admission NT-pro-BNP that best predicted outcome was 941 pg/mL. Multiple logistic regression analysis revealed that APACHE II score (odds ratio, 1.06; P = 0.007) and the best cutoff point in admission NT-pro-BNP (odds ratio, 7.74; P < 0.001) independently predicted ICU mortality, even if cytokines were entered in the analysis. In conclusion, plasma NT-pro-BNP is frequently raised in noncardiac, mixed, critically ill patients, and nonsurvivors have consistently higher levels than survivors. Elevated admission NT-pro-BNP represents an independent predictor for poor ICU outcome in the presence of clinical severity scores. Copyright © 2009 by the Shock Society.

We aimed to investigate if angiopoietin-2 (Ang-2) participates in the septic process and what may be the role of monocytes as a site of release of Ang-2 in sepsis. Concentrations of Ang-2 were estimated in sera and in supernatants of monocytes derived form one already described cohort of 90 patients with septic syndrome due to ventilator-associated pneumonia (VAP). Mononuclear cells of 17 healthy volunteers were stimulated by serum of patients in the presence or absence of various intracellular pathway inhibitors. Ang-2 gene expression after stimulation was also tested. Ang-2 was higher in patients with septic shock compared to patients with sepsis, severe sepsis and controls. Ang-2 was significantly increased in non-survivors compared with survivors. Serum levels greater than 9700 pg/ml were accompanied by a 3.254 odds ratio for death (p: 0.033). Ang-2 release from monocytes of septic patients was slightly decreased after stimulation with lipopolysaccharide (LPS) of Escherichia coli O55:B5. Release of Ang-2 from healthy mononuclear cells was stimulated by serum of patients with shock but not by serum of non-shocked patients (p: 0.016). Release was decreased by LPS; increased in the presence of a TLR4 antagonist; and decreased by anti-TNF antibody. RNA transcripts of PBMCs after stimulation with serum of patients with septic shock were higher than those after LPS stimulation. It is concluded that Ang-2 is increased in serum in the event of septic shock and that its increase is related to unfavorable outcome. It seems that a circulating factor may exist in the serum of patients with septic shock that stimulates gene expression and subsequent release of Ang-2 from monocytes. TLR4 and TNFα modulate release of Ang-2. © 2009 Elsevier B.V. All rights reserved.

Background: Procalcitonin (PCT) has been proposed as a diagnostic and prognostic sepsis marker, but has never been validated in febrile patients with prolonged ICU stay.Methods: Patients were included in the study provided they were hospitalised in the ICU for > 10 days, were free of infection and presented a new episode of SIRS, with fever >38°C being obligatory. Fifty patients fulfilled the above criteria. PCT was measured daily during the ICU stay. The primary outcome was proven infection.Results: Twenty-seven out of 50 patients were diagnosed with infection. Median PCT on the day of fever was 1.18 and 0.17 ng/ml for patients with and without proven infections (p < 0.001). The area under the curve for PCT was 0.85 (95% CI; 0.71-0.93), for CRP 0.65 (0.46-0.78) and for WBC 0.68 (0.49-0.81). A PCT level of 1 ng/mL yielded a negative predictive value of 72% for the presence of infection, while a PCT of 1.16 had a specificity of 100%. A two-fold increase of PCT between fever onset and the previous day was associated with proven infection (p 0.001) (OR = 8.55; 2.4-31.1), whereas a four-fold increase of PCT of any of the 6 preceding days was associated with a positive predictive value exceeding 69.65%. A PCT value less than 0.5 ng/ml on the third day after the advent of fever was associated with favorable survival (p 0.01).Conclusion: The reported data support that serial serum PCT may be a valuable diagnostic and prognostic marker in febrile chronic critically ill patients. © 2009 Tsangaris et al; licensee BioMed Central Ltd.

Background: Several reports have shown that homocysteine promotes thrombosis by disturbing the procoagulant-anticoagulant balance, whereas alterations in coagulation and fibrinolysis have been suggested as important pathogenetic and prognostic determinants of mortality in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The objective of the study was to evaluate the effect of plasma homocysteine levels on the outcomes of patients with ALI/ARDS. Methods: Sixty-nine consecutive ventilated patients with ALI/ARDS were studied. Blood samples were drawn within 3 days of clinical recognition of ARDS. Measurement of plasma homocysteine, vitamin B12, folate, creatinine, protein C and plasminogen-activator inhibitor-1 antigen levels, and genotyping of the methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms were carried out. The primary outcomes were 28- and 90-day mortality, whereas secondary outcomes included nonpulmonary organ failure-free days, liberation from mechanical ventilation up to day 28, and ventilator-free days during the 28 days after enrollment. Results: In the multivariable analysis, plasma homocysteine concentration adjusted for age, Acute Physiology and Chronic Health Evaluation II score, methylenetetrahydrofolate reductase C677T and A1298C polymorphisms, and levels of plasminogen-activator inhibitor-1 antigen, protein C, creatinine, vitamin B12, and folate was not found to affect significantly mortality at 28 and 90 days (P = 0.39 and P = 0.83, respectively), days without organ failure besides lungs (P = 0.38), the probability of being free from mechanical ventilation at day 28 (P = 0.63), and days without ventilation assistance (P = 0.73). CONCLUSION:: Our data suggest that increased plasma homocysteine levels, either alone or in synergy with other thrombophilic risk factors, do not seem to adversely affect the prognosis in patients with ALI/ARDS. © 2009 Lippincott Williams & Wilkins.

Background. The performance of separate Intensive Care Unit (ICU) status scoring systems vis-à-vis prediction of outcome is not satisfactory. Computer-based predictive modeling techniques may yield good results but their performance has seldom been extensively compared to that of other mature or emerging predictive models. The objective of the present study was twofold: to propose a prototype meta-level predicting approach concerning Intensive Care Unit (ICU) survival and to evaluate the effectiveness of typical mining models in this context. Methods. Data on 158 men and 46 women, were used retrospectively (75% of the patients survived). We used Glasgow Coma Scale (GCS), Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Injury Severity Score (ISS) values to structure a decision tree (DTM), a neural network (NNM) and a logistic regression (LRM) model and we evaluated the assessment indicators implementing Receiver Operating Characteristics (ROC) plot analysis. Results. Our findings indicate that regarding the assessment of indicators' capacity there are specific discrete limits that should be taken into account. The Az score ± SE was 0.8773± 0.0376 for the DTM, 0.8061± 0.0427 for the NNM and 0.8204± 0.0376 for the LRM, suggesting that the proposed DTM achieved a near optimal Az score. Conclusion. The predicting processes of ICU survival may go "one step forward", by using classic composite assessment indicators as variables. © 2008 Gortzis et al; licensee BioMed Central Ltd.

Objectives: Modern clinicians use scalable data mining models to evaluate their hypotheses. The purpose of this paper is to present the lessons learned in solving prognostic problems in Intensive Care Unit (ICU) by using data mining models developed with standardized algorithms as an alternative solution to clinical assessment tools. Methods: The study included data from 201 ICU patients (156 male and 45 female) that were assessed by means of the APACHE II, the SOFA and the ISS as well as free thyroxin fT4, total triiodothyronine (TT3) T3, thyrotropin (TSH), corticotropin (ACTH), prolactin, cortisol and dehydroepiandrosterone sulphate (DHEAS) and the Synacthen test. We formulated three data mining models - a decision tree (DTM), a neural network (NNM), and a linear regression (LRM)- using the standardized algorithms of Microsoft™ SQL Server 2005 Data Mining Platform. The outcomes were compared against those of ICU clinical assessment tools and hormone measurements. Results: From the ROC plot analysis the APACHE II score was only marginally better than the SOFA or ISS score in predicting ICU survival. Moreover, the standardized data mining models applied on endocrine parameters were not outperformed by the APACHE II, SOFA or ISS scores alone in predicting ICU survival. Conclusions: From negative results, useful information can always be deduced. Our results point to the need to use custom algorithms to support particular ICU mining needs in lieu of standardized algorithms. © 2008 IOS Press. All rights reserved.

OBJECTIVE:: To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients. PARTICIPANTS:: A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate. DESIGN/METHODS:: The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence. RESULTS:: The task force coined the term critical illness-related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness-related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness-related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of

Objective: To assess whether adrenal cortex hormones predict ICU mortality in acute, mixed, critically ill patients. Design and setting: Prospective study in consecutive intensive care patients in the general ICU of a teaching hospital. Patients: 203 severely ill patients with multiple trauma (n = 93), medical (n = 57), or surgical (n = 53) critical states. Measurements and results: Within 24 h of admission in the ICU a morning blood sample was obtained to measure baseline cortisol, corticotropin (ACTH), and dehydropiandrosterone sulfate (DHEAS). Subsequently a low-dose (1 μg) ACTH test was performed to determine stimulated cortisol. The incremental rise in cortisol was defined as stimulated minus baseline cortisol. Overall, 149 patients survived and 54 died. Nonsurvivors were older and in a more severe critical state, as reflected by higher SOFA and APACHE II scores. Nonsurvivors had a lower incremental rise in cortisol (5.0 vs. 8.3 μg/dl and lower DHEAS (1065 vs. 1642 ng/ml) than survivors. The two groups had similar baseline and stimulated cortisol. Multivariate logistic regression analysis revealed that age (odds ratio 1.02), SOFA score (1.36), and the incremental rise in cortisol (0.88) were independent predictors for poor outcome. Conclusions: In general ICU patients a blunted cortisol response to ACTH within 24 h of admission is an independent predictor for poor outcome. In contrast, baseline cortisol or adrenal androgens are not of prognostic significance. © 2007 Springer-Verlag.

Background: The course of serum cytokine levels in patients with postoperative systemic inflammatory response syndrome (SIRS) after major abdominal surgery remains currently unclear. Methods: Blood was sampled pre- and post-operatively and on days 1 and 2 in 40 patients undergoing major abdominal surgery. Concentrations of tumour necrosis factor-alpha (TNFα), interleukin (IL) -6, IL-8, and IL-10 were measured by the LINCOplex assay; those of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by an enzyme immunoassay. Results: Compared to their pre-operative values, sTREM-1 was elevated on day 2; TNFα on day 1; IL-6 and IL-10 post-operatively and on days 1 and 2; and IL-8 post-operatively and on day 1. The duration of operation correlated with TNFα and IL-10 at all sampling times, and with IL-6 post-operatively. There were no differences in cytokine concentrations between patients who exhibited post-operative complications and those who did not. IL-10/TNFα below 30 was found in all patients with complications (100%) and in 20 patients without complications (64.5%, p: 0.043). Conclusions: SIRS following major surgery is characterised by complex alterations in cytokine concentrations. The balance between TNFα and IL-10 seems to determine the occurrence of post-operative complications. © 2007 Elsevier Ltd. All rights reserved.

Background: The pulmonary side-effects induced by novel antineoplastic agents have not been well characterized. Methods: To further investigate this topic, relevant English and non-English language studies were identified through Medline. For our search we used the generic names of novel cytotoxic or non-cytotoxic antineoplastic agents and the key phrases pulmonary/lung toxicity, dyspnea, pneumonitis, acute lung injury, acute respiratory distress syndrome and alveolar damage. The references from the articles identified were reviewed for additional sources. Abstracts from International Meetings were also included. Furthermore, information was obtained from the Pneumotox((R)) website, which provides updated knowledge on drug-induced respiratory disease as well as from pharmaceutical websites. Results: Most novel antineoplastic drugs may induce pulmonary toxicity, which involves mainly the parenchyma, and less frequently the airways, pleura or the pulmonary circulation. Furthermore, a subset of these agents impairs pulmonary function tests. The exact incidence of lung toxicity remains unclear. The most common patterns consist of dyspnea without further details and infiltrative lung disease (ILD), denoting changes in the interstitium or alveoli. The diagnosis is one of exclusion. ILD is usually benign and responds to appropriate treatment; however, fatalities have been reported. Conclusions: Clinicians should be aware of the potential of most novel antineoplastic agents to cause lung toxicity. A high index of suspicion is required if these are combined with other cytotoxic drugs or radiation.

Background: A significant number of studies have shown that critically ill patients with brain injury (BI) frequently exhibit abnormal pituitary hormonal responses during the immediate postinjury period. Discussion: The elucidation of endocrine alterations depends on the criteria used, the diagnostic tests applied, and the timing of testing in relation to BI. The pattern of the detected hormonal abnormalities shows considerable variability. Altered endocrine responses are due mostly to hypothalamic changes rather than to pituitary dysfunction. Several studies have examined the correlation between hormonal alterations and BI severity, but the results are inconsistent. Furthermore, it remains currently unclear whether and how pituitary abnormalities adversely affect the clinical course of BI patients during the period of critical illness. On the basis of current knowledge, with the exception of clinically significant relative adrenal deficiency and diabetes insipidus, the other endocrine alterations do not seem to require any therapeutic intervention in severely ill BI patients. It is also uncertain whether hormonal abnormalities detected in the early post-BI period persist for the rest of these patients’ lives. Conclusions: In view of current evidence indicating a high incidence of pituitary dysfunction even years following BI it is recommended that repetition of endocrine evaluation should be performed during the rehabilitation phase in all patients.

Introduction: Endocrine abnormalities in critically ill patients with stroke during the early recovery period have not been well characterized. Methods: To investigate this issue, 33 consecutive mechanically ventilated patients (27 men) with hemorrhagic (n = 21) or ischemic (n = 12) stroke having a mean age of 57 +/- 12 years were studied. Glasgow Coma Scale score on admission in the hospital was 8 +/- 3. The following basal hormones were measured within 72 hours postextubation: cortisol, corticotropin (ACTH), free thyroxine, tri-iodothyronine, thyroid-stimulating hormone, testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, growth hormone, and insulin-like growth factor (IGF)-1. Subsequently, a low-dose (1 mu g) ACTH stimulation test was performed. Results: Twenty-six (79%) patients showed endocrine alterations. The most common change was low IGF-1 levels compatible with growth hormone deficiency (45%), followed by hypogonadism (39%), thyroid dysfunction (36%), and cortisol hyporesponsiveness (33%). Conclusion: Neuroendocrine changes occur with high frequency in critically ill patients with stroke during the early recovery period. It remains to be determined whether these changes have implications for functional and/or clinical outcome.

Objective: To evaluate health-related quality of life and disability in multiple-trauma patients requiring intensive care unit management. Design: A total of 87 survivors of multiple trauma, with a median age of 31 yrs and a median Injury Severity Score of 22, were enrolled in the present study. The Nottingham Health Profile, Glasgow Outcome Scale, and Rosser Disability Scale were used to assess the functional consequences of trauma 1 yr after intensive care unit discharge. Results: A total of 64 of 87 patients had a problem in at least one of the six domains related to subjective health status. The most prevalent complaint was related to somatic subdimensions, but emotional functioning was also affected. Nottingham Health Profile part 2 showed that 63 of the survivors experienced problems in at least one of the daily activities. Of particular importance, inability to work was reported by 47% of the patients. Fifty-nine percent experienced moderate-to-severe disability as evaluated by Glasgow Outcome Scale and Rosser Disability Scale. High aggregate injury severity score along with severe head trauma were independent predictors of poor health-related quality of life and disability. Conclusions: The majority of survivors of major trauma exhibit considerable levels of disability and impairment in health-related quality of life. Global injury severity score and degree of brain trauma determine functional limitations. This information may help in organizing long-term rehabilitation of multiple-trauma patients.

OBJECTIVE: To evaluate health-related quality of life and disability in multiple-trauma patients requiring intensive care unit management. DESIGN: A total of 87 survivors of multiple trauma, with a median age of 31 yrs and a median Injury Severity Score of 22, were enrolled in the present study. The Nottingham Health Profile, Glasgow Outcome Scale, and Rosser Disability Scale were used to assess the functional consequences of trauma 1 yr after intensive care unit discharge. RESULTS: A total of 64 of 87 patients had a problem in at least one of the six domains related to subjective health status. The most prevalent complaint was related to somatic subdimensions, but emotional functioning was also affected. Nottingham Health Profile part 2 showed that 63 of the survivors experienced problems in at least one of the daily activities. Of particular importance, inability to work was reported by 47% of the patients. Fifty-nine percent experienced moderate-to-severe disability as evaluated by Glasgow Outcome Scale and Rosser Disability Scale. High aggregate injury severity score along with severe head trauma were independent predictors of poor health-related quality of life and disability. CONCLUSIONS: The majority of survivors of major trauma exhibit considerable levels of disability and impairment in health-related quality of life. Global injury severity score and degree of brain trauma determine functional limitations. This information may help in organizing long-term rehabilitation of multiple-trauma patients. Am J Phys Med Rehabil

Objective. To investigate adrenal responses to the low-dose corticotropin (ACTH) stimulation test in acute traumatic or non-traumatic brain injury (BI) and to assess its value in predicting outcome. Design. Prospective study. Setting. Intensive care unit (ICU) in a university hospital. Patients and participants. Seventy-five patients with acute BI, with a median age of 45 years were investigated. BI was due to trauma (n=51), ischemic stroke (n=17), subarachnoid hemorrhage (n=4) or intracerebral hemorrhage (n=3). Interventions. Blood was taken on day 16 (median) after admission to the ICU to determine baseline cortisol and ACTH. Thereafter, a low-dose stimulation test (LDST) was performed: 1 mug of tetracosactrin was injected and 30 min later a second blood specimen was obtained to measure stimulated cortisol. Patients having a stimulated cortisol below 500 nmol/l were defined as non-responders to the LDST. Measurements and results. Median baseline and stimulated cortisol were 491 nmol/l and 690 nmol/l, respectively. The median increment in cortisol was 154 nmol/l (range 5-579 nmol/l). Mean ACTH was 46+/-21 pg/ml. Ten (13%) patients were non-responders to the LDST; these had a higher mortality rate compared to patients with adequate cortisol production (70 vs 32%, p=0.034). Logistic regression analysis revealed that APACHE II (p

Background: Small series and retrospective studies have suggested that treatment with gemcitabine may be associated with pulmonary toxicity. However, a prospective evaluation of cancer patients treated with gemcitabine-based chemotherapy without neoplastic involvement of the thorax and without administration of radiotherapy has not been performed. Patients and methods: To investigate this issue, 41 consecutive patients receiving gemcitabine and carboplatin underwent prospective evaluation of lung function, which included pulmonary symptoms, pulmonary function tests, arterial blood gases and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with a substantial decline in diffusion capacity for carbon monoxide (DLCO), defined as a drop of greater than or equal to20%, were reassessed 2 months later. Results: After chemotherapy, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, alveolar volume or total lung capacity. In contrast, there was a significant decline in DLCO (73 +/- 22 versus 67 +/- 24% predicted; P = 0.017) and in carbon monoxide transfer coefficient (KCO) (89 +/- 24 versus 80 +/- 24% predicted; P = 0.004). Arterial blood gases did not change following treatment. Ten of the 41 patients (24%) exhibited a substantial decline in DLCO, which, however, recovered within 2 months (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84 14, 58 16 and 77 +/- 17% predicted, respectively; P0.05). Four of the 41 patients (10%) experienced dyspnea, which was self-limiting, with the exception of one patient who developed interstitial lung fibrosis. Among the various risk factors examined, older age, female gender and lower baseline DLCO were associated with more profound changes in DLCO post-treatment. Conclusions: This prospective analysis showed that the combination of gemcitabine and carboplatin induces a significant, but reversible, decrease in diffusion capacity, which is mostly asymptomatic. Thus, this regimen is safe as regards clinically significant lung toxicity.

Background and Purpose - To investigate the incidence, pattern, and magnitude of neuroendocrine changes in long-term survivors of aneurysmal subarachnoid hemorrhage (SAH). Methods - Thirty patients (16 women) with a mean age of 50±13 years underwent endocrine assessment between 12 and 24 months after aneurysmal SAH. SAH severity was graded clinically by the Hunt & Hess scale (median, II) and radiologically by the Fisher classification (median, II). Patients underwent measurement of basal hormone levels and dynamic assessment by the low-dose (1 μg) corticotropin stimulation test. Functional outcome was examined concurrently with endocrine testing by the modified Rankin Scale and the Barthel Index. Results - Of the 30 patients tested, 14 patients (47%) showed isolated or combined endocrine abnormalities. These included low insulin-like growth factor 1 levels compatible with growth hormone deficiency in 37%, hypogonadism in 13%, and cortisol hyporesponsiveness to the low-dose corticotropin stimulation test in 10%; thyroid dysfunction in the form of subclinical hypothyroidism was observed in 7% of patients. Median modified Rankin Scale and Barthel Index at the time of endocrine testing were 1 and 100, respectively. There was no correlation between the presence of endocrine dysfunction and SAH severity indices or functional outcome scores. Conclusions - Long-term survivors of aneurysmal SAH frequently exhibit endocrine changes, with growth hormone and gonadal deficiencies predominating. Thus, screening of pituitary function is recommended in patients surviving SAH. The relationship between late hormonal alterations and functional outcome in patients with SAH warrants further study.

Objective. To assess thyroid function abnormalities in survivors of severe head trauma and to examine their relationship with indices of brain injury severity. Design. Prospective study. Setting. General intensive care unit (ICU) in a university hospital. Patients and participants. Twenty-two (21 men) head-injured patients, with a median age of 25.5 years at the time of injury, were investigated. Severity of brain trauma was assessed by Glasgow Coma Scale (GCS) score, Marshall Computerized Tomographic Classification, intracranial pressure levels and serum S-100b concentrations measured over a 6-day period. Interventions. Thyroid function testing was performed 1 year after ICU discharge and included the measurement of free thyroxine, triiodothyronine and thyrotropin. Measurements and results. On admission to the ICU, GCS ranged from 3 to 8. Peak S-100b was 1.49 mug/l (range: 0.37-5.26 mug/l). Median triiodothyronine and thyrotropin were 123 ng/dl and 1.60 muIU/ml, respectively. Free thyroxine was 1.08+/-0.22 ng/dl (range: 0.7-1.5 ng/dl). Overall, 7 of the 22 patients (32%) had thyroid dysfunction. Four patients had central hypothyroidism and three patients had subclinical hypothyroidism. Peak S-100b correlated negatively with free thyroxine (r=-0.47, p=0.02). There were no correlations between other brain injury severity indices and thyroid hormone levels. Conclusions. A significant subset of brain injury patients presents with changes in thyroid function 1 year after ICU discharge; these depend upon biochemical serum markers of head trauma severity.

Objective. To investigate the incidence and type of endocrine abnormalities in critical care patients with traumatic brain injury (TBI) and to examine their relationships to possible predisposing factors. Design. Prospective study. Setting. General intensive care unit in a university hospital. Patients and participants. Thirty-four TBI patients (27 men, 7 women), having a mean age of 37+/-16 years, were studied after weaning from mechanical ventilation. Interventions. Baseline endocrine assessment was carried out by measuring cortisol, corticotropin, dehydroepiandrosterone sulfate, free thyroxine, thyrotropin (TSH), testosterone, oestradiol, follicle stimulating hormone (FSH), luteinizing hormone, prolactin, growth hormone and insulin-like growth factor I. Dynamic evaluation was performed by human corticotropin releasing hormone and growth hormone releasing hormone in all patients. Male patients underwent additional investigation with gonadotropin-releasing hormone. Severity of neurological derangement was graded according to Glasgow Coma Scale (GCS), Marshall Computerized Tomographic Classification and intracranial pressure (ICP) levels. Measurements and results. Eighteen of the 34 patients (53%) had an abnormal result in at least one hormonal axis tested, with cortisol hyporesponsiveness and gonadal dysfunction being equally common, affecting 24% of patients. Endocrine abnormalities were associated with a higher brain CT-scan classification score (p=0.02). The GCS on admission correlated positively with baseline FSH (r=0.37, p=0.03), peak FSH (r=0.41, p=0.03), testosterone (r=0.44, p=0.02) and TSH (r=0.39, p=0.03). There were no relations between ICPmax and any baseline or dynamic hormone measurements. Conclusions. Patients with TBI receiving critical care show changes in their neuroendocrine responses, which depend upon clinical and radiological measures of head injury severity. Most common abnormalities include cortisol hyporesponsiveness and hypogonadism.

Objective. To identify predictors of prolonged (>7 days) mechanical ventilation (MV) in patients with blunt thoracic trauma. Design. Prospective analysis of consecutive patients. Setting. Adult intensive care unit (ICU) in a teaching, tertiary-care hospital. Patients and participants. Sixty-nine patients (53 men, 16 women) with thoracic trauma having a median age of 35 (range 17-85) years and a median injury severity score (ISS) of 29 (range 14-41) were enrolled in the present study. Associated injuries included head-neck (77%), extremities (72%), external (67%), abdomen-pelvis (67%), and face (55%). Interventions. Patient surveillance and data collection. Measurements and results. Thirty-three (48%) of the 69 patients required prolonged ventilatory support, ranging in duration from 8 to 38 (median 18) days. Logistic regression analysis revealed that advancing age (odds ratio=1.04, p=0.04), severity of head injury (odds ratio=1.92, p=0.008), and bilateral thoracic injuries (odds ratio=12.80, p

Objective: To analyze the time course of serum protein S-100b in patients with traumatic brain injury deteriorating to brain death and to investigate the predictive value of initial S-100b levels in relation to clinical and radiologic measures of injury severity with regard to brain death. Methods: Forty-seven patients who sustained severe head injury were studied. Blood samples for measurement of S-100b were drawn on admission in the intensive care unit and every 24 hours thereafter for a maximum of 6 consecutive days or until brain death occurred. Variables related to outcome were recorded, including age, sex, Glasgow Coma Scale (GCS), and brain CT findings on admission. Outcome was defined as deterioration to brain death or not. Results: Of the 47 patients studied, 17 deteriorated to brain death and 30 did not. On admission, patients who became brain dead had higher median serum S-100b levels compared with those who did not (2.32 mug/L vs 1.04 mug/L, p = 0.0028). Logistic regression analysis showed that initial S-100b was an independent predictor of brain death (p = 0.041), in the presence of advanced age (p = 0.043) and low GCS score (p = 0.013). The odds ratio of 2.09 (95% CI, 1.03 to 4.25) indicates a more than doubling of the probability of deteriorating to brain death per 1-mug/L increase in S-100b on admission. At clinical brain death, median S-100b was higher in patients with brain death compared with the peak S-100b value obtained over a 6-day period in those who did not become brain dead (6.58 mug/L vs 1.49 mug/L, p < 0.0001). Conclusions: Prediction of brain death after severe head injury can be improved by combining clinical and S-100b data; thus, serum S-100b determination deserves to be included in the neuromonitoring of patients with severe traumatic brain injury.

Objective: To investigate the adrenocortical function in brain-dead patients, potential organ donors. Design: Prospective study. Setting: Intensive care units in two teaching hospitals. Patients: A total of 37 patients (28 men, nine women) with severe brain injury, having a mean age of 42+/-18 yrs, were included in the study. Group A consisted of 20 brain-injured patients who did not deteriorate to brain death. Group B included 17 brain-injured patients who were brain dead; of these, ten patients developed brain death during ICU stay and seven patients were admitted to the ICU after clinical brain death. Interventions: In all patients (group A and group B), a morning blood sample was obtained at admission to the ICU to determine baseline plasma cortisol. Subsequently, 1 mug of corticotropin (adrenocorticotropic hormone, Synacthen) was administered intravenously, and a blood sample was taken 30 mins after the injection. In group B patients who became brain dead while being treated in the ICU (n=10), the same procedure was repeated the morning after the confirmation of brain death. Patients having a cortisol level of at least 18 mug/dL after the administration of adrenocorticotropic hormone were defined as responders. Measurements and Main Results: After the occurrence. of brain death, group B patients had significantly lower values for baseline (8.5+/-6.2 vs. 17.0+/-6.6 mug/dL, p

BACKGROUND. Adverse effects of paclitaxel and carboplatin have been well described: however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. METHODS. To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary, function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patient. Patients with substantial declines in PFTs, defined as a decline greater than or equal to20 percent in forced expiratory volume in 1 second (FEV1) total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. RESULTS. After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111% +/- 21% of the predicted value before chemotherapy vs. 111 +/- 20% of the predicted value after chemotherapy), FEV1 (108% +/- 24% of the predicted value before chemotherapy vs, 107% +/- 22% of the predicted value after chemotherapy), FEV1/FVC ratio (79% +/- 8% before chemotherapy vs. 78% +/- 6% after chemotherapy), alveolar volume (VA; 95% +/- 14% of the predicted value before chemotherapy vs. 96% +/- 14% of the predicted value after chemotherapy), or TLC (96% +/- 14% of the predicted value before chemotherapy vs, 97% +/- 13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101% +/- 20% of the predicted value before chemotherapy vs. 96 +/- 21% of the predicted value after chemotherapy; P < 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by greater than or equal to 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (greater than or equal to 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 month after the completion of chemotherapy, respectively: 99% +/- 36% of the predicted value vs, 75% +/- 28% of the predicted value vs. 74% +/- 31% of the predicted value; P < 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1, levels were associated with changes in DLCO post-treatment, CONCLUSIONS. This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment. (C) 2002 American Cancer society.

To investigate thyroid function in chronic obstructive pulmonary disease (COPD), 46 consecutive patients (35 men) with stable, mild-to-severe disease, having a mean (SD) age of 67 +/-7 years were studied. All subjects underwent pulmonary function tests (PFTs), arterial blood gas determination, and measurement of serum total thyroxine (TT4), total triiodothyronine (TT3), resin T3 uptake (RT3U), reverse triiodothyronine (rT3), and thyroid-stimulating hormone (TSH) levels. The free thyroxine and free triiodothyronine indexes (FT4l = RT3U/30TT4 and FT3l = RT3U/30TT3, respectively) along with the TT3/TT4 ratio were calculated; the latter was used as a marker of peripheral conversion of thyroxine into triiodothyronine. Interleukin (IL)-6 was also measured to evaluate its potential associations with thyroidal hormone levels. On the basis of forced expiratory volume in 1 second (FEV1), patients were divided in 2 groups: group 1, (FEV1 greater than or equal to 50% of predicted, n=26), with mild-to-moderate COPD and group 2 (FEV1 < 50% of predicted, n=20) having severe disease. All subjects had normal serum thyroid hormone levels; for the entire COPD population, mean values were 7.801.60 mug/dL for TT4, 1.12 +/-0.20 ng/mL for TT3, 29.0 +/-1.88 for RT3U, 7.54 +/-1.34 for FT4l,1.07 +/-0.16for FT3l,18.71 +/-5.89 ng/dL for rT3, and 1.15 +/-0.6 muU/mL for TSH. Mean TT3/TT4 ratio was 0.14 +/-0.03. In group 1, TT3, TT4, and TT3/TT4 ratio did not correlate with age, FEV1, PaO2, or inhaled corticosteroids. Similarly, in group 2, TT3 and TT4 were unrelated to the above-mentioned variables; however, there was a strong positive correlation between TT3/TT4 ratio and PaO2 (r =.61, P=.004). IL-6 was within normal limits in all subjects, and it did not correlate with any thyroid hormone either in group 1 or in group 2. It is concluded that in stable COPD, severity of disease through hypoxemia is important in determining the peripheral metabolism of thyroid hormones. Whether this constitutes an adaptation is not known. Copyright (C) 2001 by W.B. Saunders Company.