The value of admission Troponin I to predict outcomes in suspected infections in elderly patients admitted in Internal Medicine: results from the SOFA-T collaboration, a multi-center study.

Elderly patients affected by suspected infection and declining clinical conditions can be admitted to stepdown units (SDU), but a risk stratification is necessary to optimize their management. Admission troponin I (aTnI) has a prognostic role, however, one of the most commonly used stratification tools, the Sequential Organ Failure Assessment score (SOFA), does not consider myocardial injury. With this paper, we aimed to evaluate the prognostic accuracy of a new score, named SOFA-T, considering both SOFA score and aTnI in a cohort of elderly patients admitted to the stepdown beds of two Internal Medicine departments. Patients aged > 65 years admitted in SDU of two different hospitals of the same region in a 12-months timeframe were retrospectively assessed obtaining age, sex, days of admission, in-hospital death, SOFA, aTnI and comorbidities. The best aTnI cutoff for in-hospital death was calculated with ROC curve analysis; dichotomous variables were compared with chi-squared test; continuous variables were compared with t test or Mann-Whitney test. We obtained a cohort of 390 patients. The best aTnI cutoff was 0.31 ng/ml: patients with increased aTnI had higher risk of in-hospital death (OR: 1.834; 95% CI 1.160-2.900; p = 0.009), and higher SOFA (6.81 ± 2.71 versus 5.97 ± 3.10; p = 0.010). Adding aTnI to SOFA increased significantly the area under the curve (AUCSOFA = 0.68; 95% CI 0.64-0.73; AUCSOFA-T = 0.71; 95% CI 0.65-0.76; p = 0.0001), with a slight improvement of the prognostic performance. In elderly patients admitted to SDU for suspected infection, sepsis or septic shock, aTnI slightly improves the accuracy of SOFA score of the in-hospital death prediction.

Clinical management and outcome of major bleeding in patients on treatment with vitamin K antagonists.

BACKGROUND: The optimal management of major bleeding associated with vitamin K antagonists remains unclear. OBJECTIVES: The aim of the study was to assess the determinants of outcome of vitamin K antagonists-associated major bleeding and the outcome of bleeding in relation with the therapeutic management. METHODS: Patients hospitalized for major bleeding while on vitamin K antagonists were included in a prospective, cohort study. Major bleeding was defined according to the criteria of the International Society of Thrombosis Haemostasis. The primary study outcome was death at 30days from major bleeding. RESULTS: 544 patients were included in this study, of which 282 with intracranial hemorrhage. Prothrombin complex concentrates were used in 51% and in 23% of patients with intracranial hemorrhage or non-intracranial major bleeding, respectively (p<0.001); fresh frozen plasma was used in 7% and in 17% of patients with intracranial hemorrhage or non-intracranial major bleeding (p<0.001). Death at 30days occurred in 100 patients (18%), 72 patients with intracranial hemorrhage and 28 patients with non-intracranial major bleeding. Age over 85years, low Glasgow Coma Scale score and shock were independent predictors of death at 30days. Invasive procedures were associated with decreased risk of death. CONCLUSIONS: Among the patients hospitalized for major bleeding while on vitamin K antagonists, the risk for death is substantial. The risk for death is associated with the clinical severity of major bleeding as assessed by the GCS score and by the presence of shock more than with the initial localization of major bleeding (ICH vs other sites).

Highly sensitive amperometric enzyme immunoassay for alpha-fetoprotein in human serum.

A sandwich amperometric enzyme immunoassay with flow injection for alpha-fetoprotein in human serum has been developed with alkaline phosphatase as the enzyme label. p-Hydroxyphenyl phosphate was used as the substrate for alkaline phosphatase. The hydrolysis product, hydroquinone, was detected by oxidative amperometry in a flow injection system. The amperometric wall jet detector was fitted with a glassy carbon working electrode held at 350 mV vs. Ag/AgCl. The detection limit of hydroquinone in 30 mM borate buffer pH 9.5 was 1.2 x 10(-10) M (linearity range: 10(-9)-5.12 x 10(-6 M). A detection limit for free alkaline phosphatase of 1.2 x 10(-15) M (linearity range: 10(-15)-10(-13) M), or about 36 000 molecules, was observed (same borate buffer and incubations of 10 min at 25 degrees C). These conditions were maintained for the amperometric alpha-fetoprotein immunoassay. For comparison purposes, a photometric detection system was set up, with p-nitrophenyl phosphate as enzyme substrate and the same pair of antibodies and incubation conditions. The detection limit for alpha-fetoprotein obtained by amperometry, 0.07 ng/ml (linearity range = 5-500 ng/ml), was 14 times lower than by photometry. The amperometric enzyme immunoassay correlates well with a commercial colorimetric immunoassay (r = 0.986, slope = 0.967, n = 240).

Adsorption in sepsis.

The pathophysiology of sepsis offers a highly complicated scenario. In sepsis, endotoxin or other gram-positive-derived products induce a complex and dynamic cellular response, giving rise to several mediators known to be relevant in the pathogenesis of septic shock such as specific mediators, substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of translational or transductional pathways, and precursor molecules. In this review, we delve into some new concepts stemming up from the use of sorbents in continuous plasma filtration. Nonspecific simultaneous removal of several mediators of the inflammatory cascade have led to improved outcomes in animal models of septic shock and to improved hemodynamics in a pilot clinical study. It seems of great importance to explore all possible treatment techniques that may have a direct impact on circulating mediators of sepsis and that also may interfere with the imbalance between proinflammatory and anti-inflammatory substances in the critically ill patient with multiple organ failure. In this view, the application of sorbents appears to open new and interesting therapeutic options. The search for innovative treatments specifically targeted to the special needs of the critically ill patients seems therefore more important than the attempt to adjust concepts and technologies that are normally applied to patients with chronic renal failure.

Alterations of the cytokine network in hemodialysis.

This study focuses on the mechanisms responsible for monocyte activation and enhanced cytokine production in hemodialysis. Particular emphasis is given to recent recognition of a link between cytokine production and chronic inflammation following long-term complications in today's hemodialysis population, namely cardiovascular disease and malnutrition.

Is steam sterilization really making any difference in dialysis-induced cytokine release?

Ethylene oxide (ETO) is presently the most commonly used sterilization method for medical devices. Although alternative sterilization modes such as steam sterilization have been suggested, the effect of steam on dialysis-induced cytokine release is unknown. We enrolled 9 patients on chronic hemodialysis and evaluated at different intervals IL-1beta production while treated with ETO (NC 1785-Bellco) and steam sterilized NC 1785S-Bellco) Synthetically Modified Cellulose (SMC). A basal test during treatment with NC 1785 was performed (A); the same test was set up 4 weeks after treatment with NC 1785S (B) and, lastly, 4 weeks after returning to NC 1785 (C). Peripheral blood mononuclear cells (PBMC) were purified before and after the dialysis session, were isolated on a Ficoll/Hypaque gradient and incubated for 24 h. Spontaneous IL-1beta release was evaluated in the supernatant and in the lysate. In A, IL-1beta levels were (in pg/ml/10(6) cells, in supematant and lysate, respectively): 5.8 +/- 4.8 and 7.6+/-5.2 in pre-HD and 4.68 +/- 3.6 and 9.7 +/- 6.65 in post-HD. These levels showed a clear reduction in B: 2.5 +/- 2.2 and 4.4 +/- 3.1 in pre-HD, and 4.35+/- 6.6 and 7.52 +/- 7.22 in post-HD. In the C test, 4 weeks after the return to the ETO membrane, IL-1beta levels remained unchanged: 2.9 +/- 1.8 and 4.5 +/- 3.1 in pre-HD; and 2.6 +/- 3 and 5.7 +/- 6.6 in post-HD. Statistical analysis showed significant changes in the pre-HD levels both in supematant (p < 0.04) and in lysate (p < 0.04). Steam sterilization of SMC induced a lower spontaneous IL-1beta release, but this effect was not statistically significant due to the large inter-individual variation. Hence, contrary to claims of better biocompatibility, steam sterilization does not result in a reduced production of pro-inflammatory IL-1beta.

Choosing new adsorbents for endogenous ultrapure infusion fluid: performances, safety and flow distribution.

Adsorption may notably contribute to the removal of uremic toxins and to the efficiency of hemodialysis. We examined different uncoated stationary matrixes, charcoals and synthetic resins to establish their adsorptive capacities in relation to low (urea, creatinine) and high molecular weight (beta2-microglobulin, myoglobin) compounds in in vitro conditions (steady state and flow-through) using isotonic solutions or uremic ultrafiltrate. Trace metal, particle release analyses and scanning electron microscopy of different adsorbents were performed. Dynamic flow-distribution studies were made using 99Technetium and analysing the different regions of interest by single head gamma-camera. We show that adsorbents may differ greatly as to their adsorptive capacity depending on flow rate, nature, and total mass of the compounds to be removed from the ultrafiltrate. These studies suggest a methodological approach for screening stationary matrixes for possible application in hemodialysis.

[Contact phase activation can occur with certain types of activated carbon]. / Attivazione della fase contatto, durante emodiafiltrazione con la tecnica HFR, può verificarsi con alcuni tipi di carbone attivato.

HFR is an integrated hemodiafiltration system that utilizes a double chamber filter to separate convection from diffusion. The ultrafiltrate is regenerated by passage through a sorbent cartridge made up of resin and activated carbon. A small percentage of patients using this technique had gastrointestinal symptoms that included nausea/vomiting, diarrhea and/or stomach cramps approximately 1-2 hours after the start of HFR. We undertook a series of investigations to try and elucidate the cause of these reactions. Since the majority of the patients were taking ACE inhibitors, attention was focused on contact phase activation. Healthy and uremic plasma were incubated with different components of the HFR circuit. The activated carbon caused a moderate activation of factor XII and production of kallikrein, while there was no activation for the lines, double filter or resin. Patients taking ACE inhibitors may be at risk for treatments involved with contact phase activation as ACE inhibitors also block the degradation of bradykinin. A new sorbent cartridge has now been developed that contains only resin.

[Clinical experience in HFR with a new resin-only sorbent cartridge]. / Sperimentazione clinica in HFR di una cartuccia rigenerante priva di carbone.

Adsorbent therapies have become increasingly popular over the last several years as they permit an additional method to selectively or non-selectively remove toxins. Adsorbents offer a unique removal strategy as they have an extremely high adsorption capacity due to their great surface area. This paper describes experiments that utilized a synthetic divinylbenzene styrenic resin cartridge to remove uremic toxins from chronic renal failure patients. The resin-only cartridge was tested as an alternative after a small number of patients (primarily taking ACE inhibitors) experienced gastrointestinal problems using hemodiafiltration with on-line regeneration (HFR). Subsequent laboratory evidence suggested that the particular carbon used in the cartridge was able to activate contact phase activation. This could potentially cause problems in patients taking ACE inhibitors, as they are unable to degrade bradykinin efficiently. The resin-only cartridge was tested in at 6 centers throughout Italy and included patients that had experienced previous reactions to the carbon-resin cartridge. At the conclusion of the study, no adverse reactions were reported and the cartridge exhibited excellent removal of b2 microglobulin and angiogenin.

Blood tubing and cytokine production: effect of sterilization.

Blood tubings commonly represent an integral component of hemodialysis circuits. Different factors may influence their biocompatibility, such as the type of material, the sterilization mode and the geometry. In vivo the final biocompatibility may be further complicated by the individual host response, the flow parameters, and the impact of mechanical trauma on blood's cellular components (i.e. erythrocytes). In this in vitro study we evaluated some commercially available blood tubings sterilized by different methods as to their interaction with normal leukocyte population and tested the response of these cells in terms of cytokines (IL-1beta, IL-1Ra, TNF-alpha). As a positive control, leukocytes were incubated with 0.5 ng/mL of bacterial lipopolysaccharide (LPS) or with Cuprophan of comparable surface. The results showed that cytokine production was markedly reduced, particularly in the case of gamma-ray-sterilized tubings. Of interest, it was not always related to the adherence. However in some cases, particularly of gamma-ray sterilization, adherence was none, despite the cytokine production.

Rest and exercise hemodynamics of stentless porcine bioprostheses in aortic position.

Mechanical and conventional stented bioprostheses, because of need for anticoagulants, hemodynamic characteristics and long-term durability, do not represent the optimal heart valve replacement device. In this study we compared the hemodynamic function of a stented aortic bioprosthesis (St Jude Bioimplant), implanted in 10 patients, with a stentless porcine aortic bioprosthesis (Biocor) implanted in 7 patients, by means of Doppler echocardiography early postoperative at rest (T1) and 6 months later at rest (T2a) and during exercise (T2b). Mean and peak systolic gradients across stentless porcine prostheses were significantly lower than across stented bioprostheses (T1 p = 0.008 and p = 0.004; T2a p < 0.0001 and p < 0.0001; T2b p < 0.0001 and p < 0.0001, respectively). Our results show that systolic and diastolic mechanical stress on biological components of a glutaraldehyde-fixed stentless porcine aortic bioprosthesis is much lesser than on stented bioprostheses. This feature has appeared evident at rest and much more after exercise testing. The reduction of systolic and diastolic stress is expected to determine lower calcification degree and longer durability of stentless porcine aortic bioprostheses. Moreover, aortic valve replacement by means of stentless bioprostheses allows the implantation of a 1 size (2 mm) larger device, appearing favourable especially in small aortic annulus. On the basis of these promising results we suggest that stentless bioprostheses are a valid alternative to stented bioprostheses for aortic valve replacement. However, patient population is too small and the follow-up is too short to draw a definite statement about long-term hemodynamic performance of this device.

[Left atrial enlargement during the exercise test: a new electrocardiographic sign of transitory ischemia]. / Impegno atriale sinistro durante test da sforzo: un nuovo segno elettrocardiografico di ischemia transitoria.

In patients with coronary artery disease, electrocardiographic signs of left atrial enlargement (LAE-negative P wave deflection greater than or equal to 1 mm2 in lead V1) are associated with increased left ventricular end diastolic pressure (LVEDP). We investigated the possibility that transient LAE could represent an additional criterion for diagnosing myocardial ischemia during exercise testing (EST). We studied 48 consecutive patients with chronic stable angina, positive EST and 201 Tl scintigraphy, and angiographically proven CAD; 200 other consecutive patients with atypical chest pain and normal stress/rest 201 Tl scintigraphy served as controls. During EST, transient LAE developed in 34/48 patients with CAD but in only 1/200 controls (p less than 0.001). When present, LAE preceded ST changes (6.1 +/- 1 min vs 8.2 +/- 2 min) and recovered earlier (4.7 +/- 4 min vs 5.8 +/- 3 min). The prevalence of 2-3 vessel CAD was significantly higher in patients with EST-induced LAE (54% vs 34%, p less than 0.05). In conclusion, transient ECG signs of LAE during EST represent a highly specific sign of reversible ischemia and are frequently associated with multivessel CAD. Although less sensitive than classical ST criteria, this sign may prove useful in patients exhibiting equivocal ST changes and in the presence of ventricular conduction disturbances.

Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon.

We have investigated the distribution of TGF beta using antibodies specific for its intracellular and extracellular forms in full-thickness biopsies of patients with SSc, primary Raynaud's phenomenon (PRP), systemic lupus erythematosus (SLE), and from normal subjects. Nine of 11 SSc biopsies demonstrated intracellular TGF beta in endothelial cells while only 6 exhibited extracellular TGF beta. Endothelial cells in skin biopsies of all PRP patients displayed both intracellular and extracellular TGF beta. All other control biopsies were negative. In patients with PRP, some positively staining fibroblasts were found scattered throughout the dermis. Lastly, extracellular TGF beta was localized in the papillary dermis of PRP and SSc biopsies and in all the dermal layers of SLE patients. No significant staining of TGF beta was observed in the endothelial cells, fibroblasts, or in the extracellular matrix of the majority of biopsies from normal subjects. These data suggest that TGF beta may be one of the cytokines involved in the early stages of pathogenesis of SSc, and that endothelial cells in SSc and PRP may be a source and/or a target of TGF beta.