Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

Circulating eNampt and resistin as a proinflammatory duet predicting independently mortality in critically ill patients with sepsis: A prospective observational study.

BACKGROUND: The adipocytokines eNampt and resistin are involved in the regulation of inflammation exerting pro-inflammatory actions. Our aim was to jointly investigate whether circulating eNampt and resistin, and their kinetics predict 28-day mortality of sepsis. METHODS: In a prospective study, serum eNampt and resistin were determined in 102 critically ill patients fulfilling the diagnostic criteria of SEPSIS-3, at enrollment and one week after, and in 102 healthy controls matched on age, gender and month of diagnosis. RESULTS: Serum eNampt and resistin were significantly higher in septic patients than controls (p < 0.001), and higher in septic shock compared to sepsis (p < 0.001). Both eNampt and resistin decreased significantly during the first week of sepsis (p < 0.001). However, patients with septic shock presented a sustained elevation of eNampt and resistin compared to patients with sepsis. Both adipocytokines were positively correlated with sepsis severity scores and lactate. Baseline eNampt was a better discriminator of sepsis and septic shock compared to C-reactive protein and procalcitonin. Serum eNampt and resistin were higher in nonsurvivors than in survivors during the first week of sepsis. Prolonged and sustained elevation of both eNampt and resistin, as reflected by a lower percentage change from their baseline values, was independently associated with 28-day mortality (HR: 0.05, 95% C.I. 0.01-0.28, p = 0.001; HR: 0.19, 95% C.I. 0.07-0.50, p = 0.001, respectively), after adjustment for significant clinical and laboratory biomarkers. CONCLUSION: Circulating eNampt and resistin, and their kinetics may represent useful diagnostic and prognostic biomarkers in critically ill septic patients. More prospective studies are needed to elucidate their ontological and pathophysiological role in sepsis.

Angiopoietin-2 Levels as Predictors of Outcome in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome.

Pulmonary endothelium dysfunction is a key characteristic of ARDS. The aim of this study was to investigate endothelium-derived markers, such as angiopoietin-2 (Ang-2) and endothelial cell-specific molecule-1 (endocan), at the vascular and alveolar compartments as outcome predictors in ARDS. Fifty-three consecutive ARDS patients were studied. The primary outcome was 28-day mortality. Secondary endpoints were days of unassisted ventilation and days with organ failure other than ARDS, during the 28-day study period. Nonsurvivors presented higher lung injury scores and epithelial lining fluid (ELF) Ang-2 levels compared to survivors, with no significant differences in plasma Ang-2, endocan, and protein C concentrations between the two groups. In logistic regression analysis, ELF Ang-2 levels > 705 pg/ml were the only independent variable for 28-day mortality among the previous four. Plasma endocan values > 13 ng/pg were the only parameter predictive against days of unassisted ventilation during the 28-day study period. Finally, lung injury score > 2.25 and ELF Ang-2 levels > 705 pg/ml were associated with increased number of days with organ failure, other than ARDS. Our findings suggest that Ang-2 levels are increased in the alveolar compartment of ARDS patients, and this may be associated both with increased mortality and organ failure besides lung.

Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.

BACKGROUND: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis. METHODS: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3. RESULTS: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109). CONCLUSIONS: MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.

Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.

Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH.

The Role of Bronchoscopic Findings and Bronchoalveolar Lavage Fluid Cytology in Early Diagnosis of Ventilator-Associated Pneumonia.

BACKGROUND: Early diagnosis of ventilator-associated pneumonia (VAP) is necessary to reduce morbidity and improve survival of critically ill patients in the ICU. The purpose of the present study is to examine the performance of macroscopic bronchoscopic findings and cytological analysis of bronchoalveolar lavage fluid (BALF) as an early diagnostic tool for VAP, either alone or in combination with clinically oriented scores (modified Clinical Pulmonary Infection Score [CPIS] or Johanson criteria). METHODS: BAL was performed in 54 consecutive mechanically ventilated subjects. The predictive value of isolated or combined clinical characteristics, BALF, and/or other laboratory measurements in diagnosing VAP was analyzed by logistic regression analysis. A separate diagnostic score was derived from a linear combination of independent variables included in the multivariate model and compared with CPIS, Johanson criteria, and their combinations with BALF cytology (receiver operating characteristic curve analysis). RESULTS: Integrating relative neutrophil cell count in CPIS or Johanson criteria optimized their specificity (>80%) but decreased sensitivity (<70%). Radiographic progression and the presence of distal purulent secretions on bronchoscopy were independently associated with VAP diagnosis. A new score that incorporates clinical, radiographic, and early bronchoscopic findings presented excellent diagnostic accuracy (area under curve = 0.96, sensitivity 94.3%, specificity 84.2%). CONCLUSIONS: The diagnostic performance of classical clinical scores for VAP did not improve after combination with BALF cytology. A new composite score proved to be more accurate than previous scores in early VAP diagnosis.

Esmolol: immunomodulator in pyelonephritis by Pseudomonas aeruginosa.

BACKGROUND: Based on previous animal studies showing promising immunomodulatory efficacy esmolol, a selective ß1-blocker, it was assumed that administration of esmolol in experimental pyelonephritis by multidrug-resistant Pseudomonas aeruginosa would prolong survival and modulate immune response. METHODS: Acute pyelonephritis was induced in 80 rabbits and assigned to eight groups receiving normal saline (controls), esmolol, amikacin, or both agents as pretreatment and as treatment. Blood was sampled for measurement of malondialdehyde and tumor necrosis factor alpha. Animals were followed up for survival, and after death quantitative tissue cultures were performed. The in vitro effect of esmolol on bacterial growth and on the oxidative burst of neutrophils of healthy controls and of sepsis patients was studied. RESULTS: Survival of pretreatment groups administered single esmolol or esmolol and amikacin was prolonged compared with that of controls (P = 0.018 and P = 0.014, respectively); likewise, survival of treatment groups administered single esmolol or both agents was prolonged compared with that of controls (P = 0.007 and P = 0.014, respectively). Circulating malondialdehyde was significantly lower in pretreated animals administered esmolol or esmolol and amikacin compared with that in controls and in treated animals administered both agents compared with in controls (P = 0.020). In these groups, the bacterial load of the lung was significantly lower compared with controls. Serum tumor necrosis factor alpha did not change. Amikacin was increased in serum of esmolol-treated animals at levels which inhibited the in vitro growth of the studied isolate. Esmolol did not modify the in vitro growth of P aeruginosa and the oxidative burst of neutrophils. CONCLUSIONS: It is concluded that esmolol prolonged survival after experimental infection by multidrug-resistant P aeruginosa. Survival benefit may be related with pleiotropic actions connected with modulation of pharmacokinetics and attenuation of inflammation.

Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation.

BACKGROUND: Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury. METHODS: Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days -2, -1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey's post hoc tests. RESULTS: Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin. CONCLUSION: High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.

Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers.

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.

Rhodotorula mucilaginosa associacted meningitis: A subacute entity with high mortality. Case report and review.

A fatal case of meningitis due to Rhodotorula mucilaginosa in a 28 year-old HIV-negative male with a history of Hodgkin lymphoma who underwent salvage chemotherapy is presented. Reviewing the literature we identified 13 cases with central nervous system infection due Rhodotorula spp. The disease usually occurs in HIV negative immunosupressed middle-aged males. It takes the form of subacute or chronic meningitis accompanied by fever with an overall mortality of 46.2% despite antifungal therapy.

Yeast central nervous system infection in a critically ill patient: a case report.

INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.

Coronary flow reserve is associated with tissue ischemia and is an additive predictor of intensive care unit mortality to traditional risk scores in septic shock.

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.

Acrometastases.

Metastases distal to the elbow and the knee (acrometastases) are rare, accounting for approximately 0.1 % of all cases. Acrometastases can appear in patients of every age, with men being twice as likely as women to be affected. The most common primary cancer site is the lung (>50 %), followed by the colon, breast and genito-urinary tract. They mainly appear in cancer patients with wide-spread disseminated disease. Rarely, they may be the first presentation of occult silent cancer, mimicking a benign condition. Current evidence supports that the tumor cells reach the bones of the hands through the circulation and not the lymphatic system; the malignant cells from the lungs have an easy access through the arterial circulation of the arms. The rare incidence of foot acrometastases is believed to be due to the lack of red marrow in these bones, a further distance from the primary cancer site, and the valveless paravertebral venous plexuses (Batson's plexuses), which allow retrograde tumor cell embolization through the iliofemoral venous system. Treatment depends on staging and tumor extent. Amputative surgery is the more common approach, especially for cancers with poor response to radiation therapy and chemotherapy. In the majority of cases, disarticulation of the ray is required to achieve wide margin resection. In the foot, amputation can be that of a ray, midfoot or transtibial, depending on the location and spread of the tumor. If unresectable, palliative treatment with radiation therapy, bisphosphonates and chemotherapy is recommended. The prognosis of the patients with acrometastatic cancer is poor; the mean survival time after diagnosis is <6 months. An exception seems to be the patients with renal cell carcinoma, if treated with radical surgical resection, and a long latency period between nephrectomy and metastasis has occurred.

L-asparaginase fatal toxic encephalopathy during consolidation treatment in an adult with acute lymphoblastic leukemia.

PATIENT: Male, 51 FINAL DIAGNOSIS: Encephalopaty toxic Symptoms: Confusion • disorientation • drowsiness • fever MEDICATION: L-asparaginase Clinical Procedure: - Specialty: Oncology. OBJECTIVE: Unknown ethiology. BACKGROUND: Novel therapies have improved survival in malignancies of lymphoid origin. This improvement, however, has been at the cost of chemotherapy-related toxicities. L-asparaginase is frequently included in combination chemotherapies for acute lymphoblastic leukemia. Its use is frequently limited by significant adverse effects, such as coagulation abnormalities and cerebrovascular complications. L-asparaginase-associated encephalopathy is most often observed during the induction phase of chemotherapy and usually carries a favorable prognosis. CASE REPORT: We describe the profile of an adult with acute lymphoblastic leukemia treated with L-asparaginase, who developed toxic leukoencephalopathy during the second phase of consolidation treatment. He presented with decreased level of consciousness, which progressed to deep coma and finally brain death. MRI disclosed extensive lesions, consistent with toxic encephalopathy. CONCLUSIONS: Even mild neurological symptoms should raise suspicion of these possibly fatal chemotherapy related toxicities.

The role of procalcitonin and IL-6 in discriminating between septic and non-septic causes of ALI/ARDS: a prospective observational study.

BACKGROUND: The aim was to evaluate the clinical usefulness of a single plasma and bronchoalveolar lavage fluid (BALF) PCT and IL-6 measurement in discriminating septic from non-septic causes of acute respiratory distress syndrome (ARDS) and forecasting clinical outcomes. METHODS: One hundred patients were enrolled within 48 h of ALI/ARDS recognition. Demographic, clinical data, severity indices were recorded and PCT and IL-6 concentrations were measured in plasma and BALF. RESULTS: Plasma PCT and IL-6 values were significantly higher in septic compared to non-septic individuals (p=0.001 and 0.0005, respectively), while there were no differences in their respective BALF values. As far as identification of septic vs. non-septic ARDS is concerned, the comparison of the areas under the curves favored PCT vs. IL-6 [0.88, (95% CI 0.81-0.95) vs. 0.71, (95% CI 0.60-0.81); χ(2)=9.04, p=0.003]. A plasma PCT level of 0.815 ng/mL was associated with 74.1% sensitivity and 97.6% specificity in identifying septic ARDS cases; this corresponded to a diagnostic odds ratio value of 116. Linear regression multivariable analysis disclosed a significant relation of plasma PCT with SOFA score in septic ARDS patients (p<0.001), while neither BALF PCT nor IL-6 levels were associated with clinical outcome. CONCLUSIONS: Early plasma - but not BALF - PCT concentrations can discriminate between septic and non-septic ARDS causes and are associated with the severity of multiple organ dysfunction syndrome in septic ARDS patients. However, neither plasma or BALF IL-6 levels nor BALF PCT levels carry any prognostic potential. A single plasma PCT value higher than 0.815 ng/mL makes a non-septic cause of ARDS highly unlikely.

Invasive aspergillosis in the intensive care unit.

Invasive aspergillosis is a devastating infection affecting severely immunocompromised patients, most frequently with hematologic malignancies. In recent years, a surge in the incidence of invasive aspergillosis has been reported in critically ill patients without the classical risk factors. The mortality of the disease is equally high in the group of intensive care unit (ICU) patients, while the clinical signs and symptoms are nonspecific and the diagnosis remains a challenge. New noninvasive diagnostic methods in combination with better tolerated antifungal drugs aim for early diagnosis and improved prognosis of invasive aspergillosis. In this review, we discuss the epidemiology, the diagnostic strategy and algorithms, and the therapeutic choices of this severe infection in critically ill patients.

Acid-induced acute lung injury in mice is associated with P44/42 and c-Jun N-terminal kinase activation and requires the function of tumor necrosis factor α receptor I.

Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor α (TNF-α) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. Hydrochloric acid instillation induced an inflammatory response in the lungs of wild-type mice, evidenced as increased bronchoalveolar lavage total cells, neutrophils, and total protein; histologic lung injury score; and respiratory system elastance, whereas TNF-α receptor I mRNA levels were maintained. These alterations could be prevented by pretreatment with etanercept or genetic deletion of the 55-kd TNF-α receptor I, but not by deletion of the TNF-α gene. Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3-positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-α receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-α receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-α receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase.

Serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels.

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.

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and circulating ACE levels are not associated with outcome in critically ill septic patients.

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.

Static and dynamic mechanics of the murine lung after intratracheal bleomycin.

BACKGROUND: Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure. METHODS: Single intratracheal injections of saline (50 µL) or bleomycin (2 mg/Kg in 50 µL saline) were administered to C57BL/6 (n=40) and Balb/c (n=32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (RN), tissue damping (G) and elastance coefficient (H), hysteresivity (η), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD post hoc tests. RESULTS: Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and G and H non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. G and H, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, H and G was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls. CONCLUSIONS: Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.