Presepsin as a potential marker for bacterial infection relapse in critical care patients. A preliminary study.

BACKGROUND: Systemic bacterial infection carries a high risk of mortality in critical care patients. Improvements in diagnostic procedures are required for effective management of sepsis. Recently, the soluble CD14 subtype, or presepsin, has been suggested as a reliable marker of sepsis, and we set out to compare its diagnostic performance with that of procalcitonin (PCT). We focused on a cohort of septic patients who, during their hospitalization, relapsed after a period of clinical relief from symptoms. METHODS: In total 21 adult patients were studied during their hospitalization in the Critical Care Unit of Policlinico Umberto I hospital; 74 plasma samples were collected at multiple time points, and presepsin levels were measured using a PATHFAST analyzer. RESULTS: Presepsin and PCT were significantly lower in healthy controls than in sepsis or severe sepsis (p<0.001), both enabled a significant difference to be detected between systemic inflammatory response syndrome (SIRS) and severe sepsis (p<0.05). The area under the curve (AUC) calculated from the receiver operating characteristic (ROC) curve analysis was 0.888 for presepsin and 0.910 for PCT. In those patients in whom a clinical recurrence of sepsis was observed, while PCT levels normalized during the transient remission phase, presepsin levels (>1000 pg/mL) remained high. CONCLUSIONS: This study confirms the importance of monitoring a combination of several biomarkers in order to obtain a reliable diagnosis. Maximal presepsin levels could alert clinicians not to suspend antibiotic treatments and to carefully monitor septic patients' state of health, even after clinical symptoms have disappeared and PCT levels returned to normal.

Cholemic Nephropathy as Cause of Acute and Chronic Kidney Disease. Update on an Under-Diagnosed Disease.

Cholemic nephropathy (CN) is a recognized cause of acute kidney injury (AKI) in patients with severe hyperbilirubinemia (sHyb) and jaundice. Pathophysiological mechanisms of CN are not completely understood, but it seems caused both by direct toxicity of cholephiles and bile casts formation in nephrons enhanced by prolonged exposure to sHyb, particularly in the presence of promoting factors, as highlighted by a literature reviewed and by personal experience. The aim of our update is to retrace CN in its pathophysiology, risk factors, diagnosis and treatment, underlining the role of sHyb, promoting factors, and CN-AKI diagnostic criteria in the different clinical settings associated with this often-concealed disease. Our purpose is to focus on clinical manifestation of CN, exploring the possible transition to CKD. Cholemic nephropathy is an overlooked clinical entity that enters differential diagnosis with other causes of AKI. Early diagnosis and treatment are essential because renal injury could be fully reversible as rapidly as bilirubin levels are reduced. In conclusion, our proposal is to introduce an alert for considering CN in diagnostic and prognostic scores that include bilirubin and/or creatinine with acute renal involvement, with the aim of early diagnosis and treatment of sHyb to reduce the burden on renal outcome.

Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study.

INTRODUCTION: Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements. METHODS: We enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 microg.kg-1.h-1), vasopressin (.03 U.min-1) or norepinephrine (15 microg.min-1; n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA. RESULTS: There were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03 U of vasopressin or 15 microg.min-1 of norepinephrine, 1.3 microg.kg-1.h-1 of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 microg.kg-1.min-1 at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL-1; each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL). CONCLUSIONS: The present study provides evidence that continuous infusion of low-dose terlipressin--when given as first-line vasopressor agent in septic shock--is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements.

Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial.

INTRODUCTION: Previous findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock. METHODS: We performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, a thermodye dilution catheter, gastric tonometry, acid-base homeostasis, as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements with group and time as factors. Time-independent variables were compared with one-way analysis of variance. RESULTS: No differences were found in any of the investigated parameters. CONCLUSIONS: The present study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock. TRIAL REGISTRATION: ClinicalTrial.gov NCT00639015.

Early elevation of interleukin-1beta and interleukin-6 levels after bare or drug-eluting stent implantation in patients with stable angina.

INTRODUCTION: Drug-eluting stent (DES) implantation represents an important innovation in the treatment of coronary artery disease. However, inflammatory-related complications, including subacute thrombosis and in-stent restenosis, are still important limitations to percutaneous coronary intervention (PCI). The aim of this study was to compare early local release of interleukin 1beta (IL-1beta) and IL-6 proinflammatory cytokines after elective placement of either bare metal stents or DES. MATERIALS AND METHODS: IL-1beta and IL-6 levels were assayed in plasma obtained from the coronary sinus both before and 20 min after stent implantation in 59 patients with stable angina, who were randomly assigned to receive bare, paclitaxel-, or sirolimus-eluting stents during elective PCI. RESULTS: We found that IL-1beta and IL-6 levels were significantly increased in the coronary sinus of patients receiving either bare, paclitaxel- or sirolimus-eluting stents 20 min after stent implantation as compared with basal concentrations. The variation in the level of both cytokines was comparable among the three study groups. CONCLUSIONS: A local release of proinflammatory cytokines occurs shortly after coronary stent placement, including DES, which is possibly related to plaque rupture and/or endothelium traumatism following the stenting procedure. This suggests that precocious anti-inflammatory treatment could be of benefit to further improve the PCI clinical outcome.

Falsely elevated tacrolimus concentrations measured using the ACMIA method due to circulating endogenous antibodies in a kidney transplant recipient.

BACKGROUND: Therapeutic monitoring of whole-blood concentration of tacrolimus, a potent immunosuppressive drug used after organ transplantation, is essential to avoid toxic effects and to maintain the correct dosage. Although the reference method for the determination of tacrolimus concentrations is LC-MS/MS, several certified immunoassays are widely used for routine examinations. We report falsely elevated blood tacrolimus concentrations using the antibody-conjugated magnetic immunoassay (ACMIA) from Siemens Healthcare Diagnostics for the analysis of a patient who had undergone renal transplantation. METHODS: Whole-blood samples from a patient with elevated tacrolimus concentrations not consistent with the clinical picture were analysed with an alternative immunoassay and were investigated for interference by performing double dilution tests, by incubating in heterophilic blocking tubes and by evaluating plasmatic interfering factors. RESULTS: Double dilution tests showed a clear nonlinearity, suggesting that antibody interference not related to heterophilic antibodies had occurred; false-positive concentrations of cyclosporin obtained when using an antibody-conjugated to ß-galactosidase suggested the presence of endogenous antibodies directed against ß-galactosidase. CONCLUSION: In patients receiving tacrolimus, continued surveillance by laboratory staff and clinicians is necessary when using a method not requiring external pre-treatment, such as the Siemens ACMIA method.

Alterations in serum anti-alpha-galactosyl antibodies in patients with Crohn's disease and ulcerative colitis.

Anti-galactosyl alpha1-3-galactosyl (anti-Gal) is a natural serum antibody abundantly produced in humans in response to immune stimulation by enteric bacteria. Marked elevation of its titer has been detected in parasitic diseases and in some autoimmune disorders. Because persistent intestinal infection and defective mucosal barrier have been suggested as potential etiologic agents of inflammatory bowel disease, the aim of this study was to analyze the sera levels of anti-Gal antibodies in patients with Crohn's disease and ulcerative colitis. An ELISA assay was performed to analyze circulating antibody using the disaccharide Gal (alpha 1-3)Gal coupled to human serum albumin as antigen and alkaline phosphatase-conjugated rabbit anti-human immunoglobulin G, A, M as antibody. Immunoglobulin classes were assayed using class-specific antibodies. The optical densities of sera from Crohn's disease (1.83 +/- 0.63) and ulcerative colitis (1.45 +/- 0.7) were significantly higher (P < 0.0001 and P < 0.0005, respectively) than those of the control group (0.97 +/- 0.39). In Crohn's disease the increase was distributed among the three immunoglobulin classes; in ulcerative colitis a significant increase was observed only for immunoglobulin A. The increased levels of circulating antibodies against Gal (alpha 1-3)Gal in the presence of intestinal bacterial strains expressing antigenic epitopes and breakdown of mucosal barrier could contribute to the dysregulated immune response observed in inflammatory bowel disease.

Modulation of tachykinin and cytokine release in patients with coronary disease undergoing percutaneous revascularization.

Plasma levels of substance P (SP) and neurokinin A (NKA) tachykinin and of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) cytokines were assayed in plasma obtained from peripheral blood of 19 patients presenting with stable chronic coronary stenosis and 12 patients with acute coronary syndrome (ACS). Plasma samples were obtained before, during, and after percutaneous coronary intervention (PCI) consisting of implantation of a metallic stent. Fourteen healthy subjects without any evident risk factors for coronary artery disease (CAD) were also included for comparison at basal time. We found that plasma levels of both IFN-gamma and TNF-alpha were significantly higher in patients with chronic or acute CAD than those in control subjects at the time of presentation. NKA and IFN-gamma levels were also significantly increased in ACS patients compared with those in patients with stable disease. The analysis performed during and after PCI revealed that IFN-gamma levels increased 15 min after stent implantation in both chronic and ACS patients and that TNF-alpha levels increased in chronic patients only compared to basal values. In addition, a significant decrease of both NKA and SPA levels 48 h after the end of the revascularization procedure was observed in ACS patients. These data suggest that modulation of tachykinin and/or cytokine release with proinflammatory activity in chronic or acute cardiac ischemia and during following coronary stenting might play an important role in heart tissue damage and in long-term inflammatory complications of PCI.