The complement cascade in lung injury and disease.

BACKGROUND: The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary defense mechanism against pathogens, continuously emerging evidence has uncovered a central role of this complex system in several diseases including lung pathologies. MAIN BODY: Complement factors such as anaphylatoxins C3a and C5a, their receptors C3aR, C5aR and C5aR2 as well as complement inhibitory proteins CD55, CD46 and CD59 have been implicated in pathologies such as the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, and lung cancer. However, the exact mechanisms by which complement factors induce these diseases remain unclear. Several complement-targeting monoclonal antibodies are reported to treat lung diseases. CONCLUSIONS: The complement system contributes to the progression of the acute and chronic lung diseases. Better understanding of the underlying mechanisms will provide groundwork to develop new strategy to target complement factors for treatment of lung diseases.

Adrenal function in relation to cytokines and outcome in non-critically ill patients with COVID-19.

PURPOSE: We aimed to identify whether hypothalamic-pituitary-adrenal (HPA) axis dysfunction is related to deterioration in a percentage of patients who progress to severe COVID-19. METHODS: In this cohort observational study, we evaluated HPA axis activation by measuring cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S) levels, whole blood expression levels of the key glucocorticoid receptor, GCR-α, and the glucocorticoid-induced leucine zipper (GILZ), and cytokines, as markers of the inflammatory phase, in 149 patients with respiratory infection admitted in the ward, without known adrenal disease and/or confounding medications (glucocorticoids). One hundred and four (104) patients were SARS-CoV-2 positive (C +) and controls consisted of 45 SARS-CoV-2-negative patients (NC). RESULTS: No differences in cortisol levels were observed between the C + and the NC patients. Cortisol levels correlated with ACTH (r = 0.284, p = 0.001) and IL-6 (r = 0.289, p = 0.04). In C + patients, cortisol levels mainly correlated with IL-6 levels (r = 0.28; p = 0.017). GCR-α expression was significantly higher in C + patients compared to NC. Patients with higher cortisol levels were more likely to progress to respiratory function deterioration or die. Both GCR-α and GILZ expression were significantly higher in C + non-survivors. CONCLUSION: Our findings indicate that cortisol serves as an indicator of disease severity. GILZ expression appears to be a more effective marker of mortality prediction in moderate COVID-19 cases. However, routine measurement of GILZ levels is currently unavailable. Elevated levels of cortisol may be indicative of patients with moderate COVID-19 who are at a higher risk of deterioration. This information can aid in identifying individuals who require early medical attention.

Ghrelin alterations during experimental and human sepsis.

BACKGROUND: Ghrelin is a hormone mainly produced by cells of the gastric mucosa, which has been shown to possess anti-inflammatory and immunomodulatory properties. The objective of the study was to investigate ghrelin levels during sepsis, as well as in an experimental sepsis model. METHODS: All consecutive admissions to the ICU of a tertiary hospital in Athens, Greece were screened for eligibility during the study. Thirty four non-septic patients upon ICU admission who subsequently developed sepsis were enrolled. Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and at sepsis development. Total and active ghrelin, leptin, and cytokines were measured. Moreover, lipopolysaccharide (LPS) was administered to mice in order to induce endotoxemia and at specified time points, blood and tissue samples were collected. RESULTS: In patients, serum total and active ghrelin concentrations were significantly elevated in sepsis compared to baseline (553.8 ±â€¯213.4 vs 193.5 ±â€¯123.2, p < 0.001; 254.3 ±â€¯70.6 vs 56.49 ±â€¯16.3, p < 0.001). Active ghrelin levels at the sepsis stage were inversely correlated with SOFA score and length of stay in the ICU (p = 0.023 and p = 0.027 respectively). In the mouse endotoxemia model ghrelin levels were elevated following LPS treatment, and the same trend was observed for leptin, TNFα and IL-6. Ghrelin administration managed to reduce IL-6 levels in mouse serum and in BALF. Pulmonary expression of ghrelin and its receptor GHSR1a was found decreased in LPS-treated mice. CONCLUSIONS: In a well-defined cohort of ICU patients, we have demonstrated that active and total ghrelin increase in sepsis. The same is true for the experimental sepsis model used in the study. The inverse correlation of active ghrelin levels with SOFA score and length of ICU stay among septic patients is indicative of a potential protective role of active ghrelin during the septic process.

Accuracy of T2 magnetic resonance assays as point-of-care methods in the intensive care unit.

BACKGROUND: Novel molecular diagnostic methods are being evaluated in order to expedite pathogen identification in patients with bacteraemia. AIMS: To evaluate the feasibility and diagnostic accuracy of the T2 magnetic resonance (T2MR) assays - T2 Bacteria (T2B) and T2 Resistance (T2R) - as point-of-care tests in the intensive care unit compared with blood-culture-based tests. METHODS: Prospective cross-sectional study of consecutive patients with suspected bacteraemia. Diagnostic accuracy was evaluated using blood culture as the reference method. FINDINGS: In total, 208 cases were included in the study. The mean time from sampling to report was lower for the T2MR assays compared with blood-culture-based methods (P<0.001). The rate of invalid reports was 6.73% for the T2B assay and 9.9% for the T2R assay. For the T2B assay, overall positive percentage agreement (PPA) was 84.6% [95% confidence interval (CI) 71.9-93.1%], negative percentage agreement (NPA) was 64.3% (95% CI 55.4-72.6%), positive predictive value (PPV) was 48.9% (95% CI 42.5-55.3%) and negative predictive value (NPV) was 91.2% (95% CI 84.4-95.2%). Cohen's kappa coefficient was 0.402. For the T2R assay, overall PPA was 80% (95% CI 51.9-95.7%), NPA was 69.2% (95% CI 54.9-81.3%), PPV was 42.9% (95% CI 31.7-54.8%) and NPV was 92.3% (95% CI 81.1-97.1%). Cohen's kappa coefficient was 0.376. CONCLUSION: T2MR assays have high NPV for rapid exclusion of bacteraemia, and could potentially assist with antimicrobial stewardship when applied as point-of-care diagnostic tests in the intensive care unit.

Serum of patients with septic shock stimulates the expression of Trem-1 on U937 monocytes.

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 (TNFalpha), interleukin-1beta (IL-1alpha), 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). TNFalpha, IL-1alpha, 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 TNFalpha 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.

Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease.

PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (+/-SD) hematocrit of 53% +/- 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% +/- 5%). All patients had chronic hypoxemia (PaO2 <60 mm Hg). RESULTS: Both plasma renin and aldosterone levels were threefold greater in patients with secondary erythrocytosis compared to controls. No difference in erythropoietin levels was observed between patients with or without secondary erythrocytosis. Renin levels (r = 0.45; P = 0.02) but not erythropoietin levels (r = 0.15; P = 0.47) were correlated with hematocrit in the entire sample. Renin levels and PaO2 were the only variables independently and significantly associated with hematocrit values in a multiple linear regression model. CONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.

Phrenic nerve dysfunction after cardiac operations: electrophysiologic evaluation of risk factors.

BACKGROUND AND STUDY OBJECTIVE: Phrenic nerve injury may occur after cardiac surgery; however, its cause has not been extensively investigated with electrophysiology. The purpose of this study was to determine by electrophysiologic means the importance of various possible risk factors in the development of phrenic nerve dysfunction after cardiac surgical operations. DESIGN: A prospective study was conducted. SETTING: A tertiary teaching hospital provided the background for the study. PATIENTS: Sixty-three cardiac surgery patients on whom surgical operations were performed by the same surgical team constituted the study group. Mean (+/-SD) age and ejection fraction were 63+/-5 years and 50+/-10%, respectively. INTERVENTIONS: Measurement of phrenic nerve conduction latency time after transcutaneous stimulation preoperatively and at 24 h and 7 and 30 days postoperatively. RESULTS: Thirteen patients had abnormal phrenic nerve function postsurgery, 12 on the left side and one bilaterally. Logistic regression analysis revealed that among the potential risk factors investigated, use of ice slush for myocardial preservation was the only independent risk factor related to phrenic nerve dysfunction (p=0.01), carrying an 8-fold higher incidence for this complication. In contrast, age, ejection fraction of the left ventricle, operative/bypass/aortic cross-clamp time, left internal mammary artery use, and diabetes mellitus were not found to be associated with phrenic neuropathy. The postoperative outcome of patients who received ice slush compared with that of those who had cold saline solution did not differ in terms of early morbidity and mortality. CONCLUSION: Among the risk factors investigated, only the use of ice slush was significantly associated with postoperative phrenic nerve dysfunction. Therefore, ice should be avoided in cardiac surgery, since it does not seem to provide additional myocardial protection.

Respiratory complications after coronary artery bypass surgery with unilateral or bilateral internal mammary artery grafting.

BACKGROUND AND STUDY OBJECTIVE: Use of bilateral internal mammary artery (IMA) grafts during coronary artery revascularization procedures carries the potential for increased incidence of postoperative respiratory complications compared with use of unilateral IMA grafts. The purpose of this study was to compare the incidence of respiratory complications such as hypoxemia, atelectasis, pleural effusion, and diaphragmatic dysfunction in patients who received one or both IMAs as conduit grafts. DESIGN: Prospective, comparative study. SETTING: Surgical ICU at a tertiary teaching hospital. PATIENTS: Seventy-five patients with bilateral and 75 patients with unilateral IMA grafts. MEASUREMENTS: Serial postoperative PaO2/fraction of inspired oxygen measurements, radiographic scores of atelectasis and pleural effusion, duration of mechanical ventilation, length of ICU and hospital stay, and incidence of pneumothorax, pneumonia, and wound infection. RESULTS: There was a higher incidence (51% vs 25%; p=0.002) and severity (0.48+/-0.09 vs 0.15+/-0.05 on the first postoperative day, 0.39+/-0.07 vs 0.27+/-0.07 on the fourth postoperative day, mean+/-SEM; p=0.004) of postoperative right lower lobe atelectasis in the group who received bilateral IMA grafts than in those who received left IMA grafts. This finding probably reflects the effects of additional surgical intervention on the right side of the chest. Incidence and severity of pleural effusion, gas exchange impairment, duration of mechanical ventilation, ICU and hospital stay, and incidence of pneumothorax, pneumonia, and wound infection were not influenced by use of bilateral IMA grafts (p>0.05). CONCLUSION: We conclude that use of bilateral IMA grafts during coronary artery revascularization does not increase the incidence of postoperative respiratory complications compared with unilateral IMA grafting.

Low-dose amiodarone-related complications after cardiac operations.

OBJECTIVE: High-dose preoperative amiodarone therapy has been implicated as a risk factor for serious complications after cardiac operations. To investigate the effect of preoperative low-dose amiodarone treatment on early postoperative outcome after cardiac operations, we prospectively studied 88 patients. METHODS: Forty-four patients were receiving amiodarone (mean daily dose +/- standard deviation, 205 +/- 70 mg/day) and 44 patients were controls matched in pairs. The following parameters were recorded after the operation in all patients: (1) the ratio of oxygen tension to inspired oxygen fraction on arrival in the intensive care unit and 2, 4, 6, 10, 14, 18, and 22 hours thereafter; (2) the occurrence of acute respiratory distress syndrome; (3) early postoperative cardiac complications; and (4) the type and number of inotropic agents or vasopressors (or both) needed. RESULTS: No difference in the ratio of oxygen tension to inspired oxygen fraction was noted at the various time intervals between amiodarone-treated patients and control patients. Overall, only one patient had acute respiratory distress syndrome in the amiodarone group, but he had multiple other factors known to predispose to acute lung injury. Several cardiac complications, such as pulmonary edema, temporary pacing, and need for intraaortic balloon pump counterpulsation, were observed more frequently in amiodarone-treated patients than in control patients. In addition, amiodarone-treated patients required more frequent inotropic support (73% vs 43%, p = 0.003) and more inotropic drugs or vasopressors (or both) per patient than did control patients (1.4 +/- 1.1 vs 0.6 +/- 0.8, p = 0.002). CONCLUSION: Preoperative low-dose amiodarone therapy does not seem to be related to significant postoperative lung toxicity, but it is associated with various cardiac complications and an increased need for more intense inotropic support after cardiac operations. These findings may be related to the drug's depressant effect on the myocardium.

Effects of severity of chronic obstructive pulmonary disease on thyroid function.

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 (FT4I = RT3U/30TT4 and FT3I = 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 > or = 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 7.80 +/- 1.60 microg/dL for TT4, 1.12 +/- 0.20 ng/mL for TT3, 29.0 +/- 1.88 for RT3U, 7.54 +/- 1.34 for FT4I, 1.07 +/- 0.16 for FT3I, 18.71 +/- 5.89 ng/dL for rT3, and 1.15 +/- 0.6 microU/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.

Detection of expiratory flow limitation during exercise in COPD patients.

The negative expiratory pressure (NEP) method was used to detect expiratory flow limitation at rest and at different exercise levels in 4 normal subjects and 14 patients with chronic obstructive pulmonary disease (COPD). This method does not require performance of forced expirations, nor does it require use of body plethysmography. It consists in applying negative pressure (-5 cmH2O) at the mouth during early expiration and comparing the flow-volume curve of the ensuing expiration with that of the preceding control breath. Subjects in whom application of NEP does not elicit an increase in flow during part or all of the tidal expiration are considered flow limited. The four normal subjects were not flow limited up to 90% of maximal exercise power output (Wmax). Five COPD patients were flow limited at rest, 9 were flow limited at one-third Wmax, and 12 were flow limited at two-thirds Wmax. Whereas in all patients who were flow limited at rest the maximal O2 uptake was below the normal limits, this was not the case in most of the other patients. In conclusion, NEP provides a rapid and reliable method to detect expiratory flow limitation at rest and during exercise.

Pulmonary function and respiratory muscle strength in chronic heart failure: comparison between ischaemic and idiopathic dilated cardiomyopathy.

OBJECTIVE: To compare pulmonary function and respiratory muscle strength in patients with ischaemic and idiopathic dilated cardiomyopathy, well matched for indices of heart failure. METHODS: The study involved 30 patients with ischaemic cardiomyopathy and 30 with idiopathic dilated cardiomyopathy. The groups were well matched for age, weight, and clinical severity of cardiac dysfunction as assessed by ejection fraction and the New York Heart Association functional class. There were more smokers in the ischaemic group (p < 0.05), but indices of pulmonary function were comparable. RESULTS: Mean (SD) maximum static inspiratory pressure was lower in dilated cardiomyopathy than in ischaemic cardiomyopathy (73 (20) v 84 (22) cm H2O, p < 0.05), as was the maximum static expiratory pressure (90 (20) v 104 (21) cm H2O, p < 0.05). CONCLUSIONS: For a given degree of cardiac dysfunction, the respiratory muscles are weaker in patients with idiopathic dilated cardiomyopathy than in those with ischaemic cardiomyopathy.

Relationship between nosocomial Acinetobacter species occurring in two geographical areas (Greece and the UK).

Fifty-two isolates of Acinetobacter spp. obtained from three Greek and one UK hospital, were studied using partial 16 S ribosomal DNA sequence analysis, repetitive extragenic palindromic sequence-based polymerase chain reaction (REP-PCR) mediated fingerprinting and DNA macro-restriction analysis. The aim was twofold: first, to discern the major differences in the population of Acinetobacter spp. between the two countries. Second, to compare a simple PCR-based typing scheme with pulsed-field gel electrophoresis (PFGE). The multi-resistant Greek isolates were within DNA groups 2 and TU13, and clustered into three types both by REP-PCR and PFGE. By contrast, the more susceptible Oxford isolates were heterogeneous on 16 S RNA sequence analysis and distinguishable on typing. The need for studies that elucidate the phylogeny of Acinetobacter spp. inside and outside hospitals are important, as this will help clarify the relationship between organisms that are increasingly recognized as causes of severe infections.

Effects of severity of long-standing congestive heart failure on pulmonary function.

To investigate the effects of severity of long-standing congestive heart failure (CHF) on pulmonary function, we studied 53 (47 men) consecutive patients, all heart transplant candidates. Their mean (+/- SD) age and ejection fraction were 47 +/- 12 years and 23 +/- 7%, respectively. All patients underwent spirometry, lung volume, diffusion capacity (DLCO), maximum inspiratory (PImax) and expiratory pressure (PEmax) measurement. Maximum cardiopulmonary exercise test on a treadmill was also performed to determine maximum oxygen consumption (VO2max). On the basis of VO2max, the patients were then divided into those with a VO2max > 14 ml min-1 kg-1 (group 1, n = 30) and those with a VO2max < or = 14 ml min-1 kg-1 (group 2, n = 23). In comparison with group 1, group 2 patients had lower FEV1/FVC (70 +/- 8% vs 75 +/- 7%, P = 0.008), lower FEF25-75 (46 +/- 21 vs 70 +/- 26%pred, P < 0.001), lower TLC (76 +/- 15 vs 85 +/- 13%pred, P = 0.02) and lower PImax (68 +/- 20 vs 87 +/- 22 cmH2O, P = 0.003), but comparable DLCO (84 +/- 15 vs 88 +/- 20%pred, P = N.S.), and PEmax (99 +/- 25 vs 96 +/- 22 cmH2O, P = N.S.). In conclusion, our data suggest that respiratory abnormalities, such as restrictive defects, airway obstruction, and inspiratory muscle weakness, are more pronounced in patients with severe CHF than in those with mild-to-moderate disease. Further studies are required to investigate the extent to which these abnormalities contribute to dyspnoea during daily activities in patients with heart failure.

Pattern of breathing during progressive exercise in chronic heart failure.

This descriptive study analyzed serial, individual changes in the exercise pattern of breathing (POB) of patients with stable chronic heart failure (CHF). Twenty-two CHF patients underwent maximal, symptom-limited cardiopulmonary exercise test on a treadmill. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), the ventilatory equivalent for carbon dioxide (VE/VCO2) and estimated dead-space to tidal volume ratio (VD/VT) were continuously recorded. The VE/VCO2 slope was calculated in every subject as the slope of the regression line relating VE to VCO2 during exercising testing. Pattern of breathing was investigated by constructing the individual VT-f relationship for each patient separately. In 16 (73%) patients (group 1), the VT-f plot was initially linear, but subsequently exhibited an inflection point at which VT stopped increasing with further increases in f. In six (27%) patients (group 2) no inflection point was evident on the VT-f relation; in four of these patients the VT-f relation remained linear but shifted to the right throughout testing, and two patients decreased VT before peak exercise achieving high breathing frequencies. Comparing group 1 to group 2 patients, they had higher VEmax (68+/-23 vs. 44+/-10 l/min, P=0.02) and VO2max (17+/-5 vs. 12+/-3 ml/min/kg, P=0.01). In contrast, the two groups did not differ in terms of age, weight, height, diagnosis, ejection fraction or VE/VCO2 slope. In conclusion, patients with CHF adopt variable breathing patterns during exercise; specific patterns are associated with greater impairment in functional capacity.

Adipose tissue lipolysis and circulating lipids in acute and subacute critical illness: effects of shock and treatment.

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.

Elevated adipose tissue lactate to pyruvate (L/P) ratio predicts poor outcome in critically ill patients with septic shock: a microdialysis study.

BACKGROUND: Sepsis is a disease affecting tissue metabolism; in vivo microdialysis (MD) is a bedside technique enabling researchers to monitor tissue metabolic changes. We conducted this study aiming to evaluate the relationship between lactate to pyruvate (L/P) ratio, a sensitive marker of tissue oxygenation and perfusion, and mortality in critically ill septic patients. METHODS: We enrolled 105 patients with septic shock hospitalized in the mixed intensive care unit of a tertiary hospital. A MD catheter was inserted in the subcutaneous adipose tissue of the upper thigh and interstitial fluid samples were collected and analyzed for glucose, lactate, pyruvate, and glycerol. RESULTS: Multivariate regression analysis showed that among variables registered on day 1, APACHE II and SOFA scores, blood lactate and microdialysis-assessed tissue L/P ratio were independently associated with 28-day mortality. Even in patients with normal (<2 mmol/L) blood lactate, adipose tissue L/P ratio showed a strong trend to statistical significance. During the 6-day study period, non-survivors had significantly higher L/P ratios compared to survivors (P=0.001) and mixed model analysis revealed a different pattern of evolution in time with non-survivors experiencing an increase while survivors had a late decline in their L/P ratio. The AUC for L/P ratio was similar to that of APACHE II (P=0.67) and SOFA score (P=0.73). Comparison of the Kaplan-Meier 28-day survival curves of patients with normal (≤ 25) versus elevated (>25) L/P ratios showed that the latter survived significantly less (P=0.02; log-rank test). CONCLUSION: Elevated adipose tissue L/P ratio is associated with poor outcome in critically ill patients with septic shock. Microdialysis deserves to be further studied as a research tool in the multi-modal monitoring of septic critically ill patients.

Failure of tigecycline to treat severe Clostridium difficile infection.

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.

The effect of homocysteine on the clinical outcomes of ventilated patients with severe sepsis.

BACKGROUND: There is considerable evidence that elevated plasma homocysteine levels are associated with a prothrombotic milieu, whereas activation of the coagulation cascade is an important component of the pathogenesis of sepsis. The protein C pathway has been reported to play a central role both in the propagation of sepsis and a hyperhomocysteinemia-induced hypercoagulable state. Our primary aim was to measure plasma homocysteine levels in mechanically ventilated patients with severe sepsis/septic shock and to assess the association of these levels with relevant clinical outcomes. METHODS: The study cohort included 102 mechanically ventilated patients with severe sepsis or septic shock. Demographics, comorbidities, clinical data and severity scores were recorded. Plasma homocysteine, vitamin B12, folate, creatinine, and protein C levels were measured in all study subjects upon enrollment, and genotyping for the C677T and A1298C polymorphisisms of the methylenetetrahydrofolate reductase (MTHFR) gene and for factor V Leiden (FVL) mutations was performed as well. The primary outcomes were mortality at 28 and 90 days; secondary outcomes included the number of days without renal or cardiovascular failure and the ventilator-free days during the study period. RESULTS: Homocysteine levels were not significantly associated with any primary or secondary outcomes in the multivariable analysis. In addition, a synergistic effect of homocysteine with protein C levels was not detected. CONCLUSION: Our data suggest that plasma homocysteine levels may not inform the prognosis of mechanically ventilated patients with severe sepsis/septic shock.