Albumin Italian Outcome Sepsis Trial Research Articles

Use of Albumin as a Resuscitative Fluid in the Intensive Care Unit.

Use of Albumin as a Resuscitative Fluid in the Intensive Care Unit.

Expert consensus on the use of human serum albumin in critically ill patients.

Expert consensus on the use of human serum albumin in critically ill patients.

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS

BackgroundSeptic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock.MethodsThis was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization.ResultsPlasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points.ConclusionCirculating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time.Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.

The role of resistin and myeloperoxidase in severe sepsis and septic shock: Results from the ALBIOS trial.

Inflammatory biomarkers are useful in detecting patients with sepsis. The prognostic role of resistin and myeloperoxidase (MPO) has been investigated in sepsis. Plasma resistin and MPO were measured on days 1, 2 and 7 in 957 patients enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. The association between resistin and MPO levels on day 1, 2 and 7 and 90-day mortality was assessed. Plasma resistin and MPO concentrations were higher at day 1 and decreased until day 7. Both biomarkers were positively correlated with each other and with physiological parameters. Higher levels of resistin and MPO on day 1 were associated with the development of new organ failures. Patients experiencing death at 90days showed higher levels of resistin and MPO compared with survivors. At day 1, only MPO in the 4th quartile (Q4), but not resistin, was found to predict 90-day death (adjusted hazard ratio [aHR] 1.55 vs Q1). At day 2, resistin in the Q3 and Q4 predicted a>40% increase in mortality as also did MPO in the Q4. On day 7, Q4 resistin was able to predict 90-day mortality, while all quartiles of MPO were not. High levels of MPO, but not of resistin, on day 1 were able to predict 90-day mortality. These findings may either suggest that early hyper-activation of neutrophils is detrimental in patients with sepsis or reflect the burden of the inflammatory process caused by sepsis. Further studies are warranted to deepen these aspects (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).

Persistence of Central Venous Oxygen Desaturation During Early Sepsis Is Associated With Higher Mortality: A Retrospective Analysis of the ALBIOS Trial

Relevance of low (< 70%) central venous oxygen saturation (Scvo2) during early sepsis has been recently questioned by three negative trials (Protocol-Based Care for Early Septic Shock, Australasian Resuscitation in Sepsis Evaluation, and Protocolized Management in Sepsis) on early goal-directed therapy; however, subjects included in those trials had Scvo2 at enrollment as high as 71 ± 13%, 73 ± 11%, and 70 ± 12%. Here we assess the association between Scvo2< 70%at 6h and 90-day mortality in subjects enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial, focusing on those with initial Scvo2< 70%. Regardless of treatment assignment (to receive albumin or not), all subjects enrolled in the ALBIOS trial received early goal-directed therapy aiming for Scvo2≥ 70%at 6 h. Using multivariable logistic regression analyses, we tested the association between Scvo2< 70%at 6h and 90-day mortality in those with initial Scvo2< 70%(n= 514) or≥ 70%(n= 961). Scvo2< 70%at 6h was independently associated with higher 90-day mortality in subjects with initial Scvo2< 70%(OR, 1.84; 95%CI, 1.19-2.85; P= .007) but not in those with initial Scvo2≥ 70%(OR, 1.25; 95%CI, 0.79-1.95; P= .357). Scvo2< 70%at enrollment and at 6h was associated with history and/or signs of cardiac dysfunction but not with greater severity of disease or more aggressive resuscitation (required per protocol). In the ALBIOS trial, persistence of low Scvo2 was associated with higher 90-day mortality, possibly because it reflected underlying cardiac dysfunction. Subjects with Scvo2< 70%may benefit most from individually tailored interventions aimed at normalizing the balance between systemic oxygen delivery and consumption. ClinicalTrials.gov; No. NCT00707122; URL: www.clinicaltrials.gov.

Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis.

Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis. Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). Forty ICUs in Italy. Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95). Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1. Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality. Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis

The biological role of adrenomedullin (ADM), a hormone involved in hemodynamic homeostasis, is controversial in sepsis because administration of either the peptide or an antibody against it may be beneficial. Plasma biologically active ADM (bio-ADM) was assessed on days 1, 2, and 7 after randomization of 956 patients with sepsis or septic shock to albumin or crystalloids for fluid resuscitation in the multicenter Albumin Italian Outcome Sepsis trial. We tested the association of bio-ADM and its time-dependent variation with fluid therapy, vasopressor administration, organ failures, and mortality. Plasma bio-ADM on day 1 (median [Q1-Q3], 110 [59-198] pg/mL) was higher in patients with septic shock, associated with 90-day mortality, multiple organ failures and the average extent of hemodynamic support therapy (fluids and vasopressors), and serum lactate time course over the first week. Moreover, it predicted incident cardiovascular dysfunction in patients without shock at enrollment (OR [95%CI], 1.9 [1.4-2.5]; P< .0001, for an increase of 1 interquartile range of bio-ADM concentration). bio-ADM trajectory during the first week of treatment clearly predicted 90-day mortality after adjustment for clinically relevant covariates (hazard ratio [95%CI], 1.3 [1.2-1.4]; P< .0001), and its reduction below 110 pg/mL at day 7 was associated with a marked reduction in 90-day mortality. Changes over the first 7days of bio-ADM concentrations were not dependent on albumin treatment. In patients with sepsis, the circulating, biologically active form of ADM may help individualizing hemodynamic support therapy, while avoiding harmful effects. Its possible pathophysiologic role makes bio-ADM a potential candidate for future targeted therapies. ClinicalTrials.gov; No.: NCT00707122.

Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial.

The long pentraxin PTX3 is a key component of the humoral arm of innate immunity related to sepsis severity and mortality. We evaluated the clinical and prognostic significance of circulating PTX3 in the largest cohort ever reported of patients with severe sepsis or septic shock. Plasma PTX3 was measured on days 1, 2 and 7 after randomization of 958 patients to albumin or crystalloids for fluid resuscitation in the multicentre Albumin Italian Outcome Sepsis (ALBIOS) trial. We tested the association of PTX3 and its changes over time with clinical severity, prevalent and incident organ dysfunctions, 90-day mortality and treatment. PTX3 was high at baseline (72 [33-186] ng/mL) and rose with the severity and number of organ dysfunctions (P < 0·001) and the incidence of subsequent new failures. The PTX3 concentration dropped from day 1 to 7, but this decrease was less pronounced in patients with septic shock (P = 0·0004). Higher concentrations of PTX3 on day 1 predicted incident organ dysfunctions. Albumin supplementation was associated with lower levels of PTX3 in patients with septic shock (P = 0·005) but not in those without shock. In a fully adjusted multivariable model, PTX3 on day 7 predicted 90-day mortality. Smaller drops in PTX3 predicted higher 90-day mortality. In severe sepsis and septic shock, early high PTX3 predict subsequent new organ failures, while a smaller drop in circulating PTX3 over time predicts an increased risk of death. Patients with septic shock show lower levels of PTX3 when assigned to albumin than to crystalloids.

Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock.

Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). Forty ICUs in Italy. Nine hundred and ninety-five patients with severe sepsis or septic shock. Randomization to albumin and crystalloid solutions or crystalloid solutions alone. Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of supporting therapy.

Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial

IntroductionSepsis, a leading cause of death in critically ill patients, is the result of complex interactions between the infecting microorganisms and the host responses that influence clinical outcomes. We evaluated the prognostic value of presepsin (sCD14-ST), a novel biomarker of bacterial infection, and compared it with procalcitonin (PCT).MethodsThis is a retrospective, case–control study of a multicenter, randomized clinical trial enrolling patients with severe sepsis or septic shock in ICUs in Italy. We selected 50 survivors and 50 non-survivors at ICU discharge, matched for age, sex and time from sepsis diagnosis to enrollment. Plasma samples were collected 1, 2 and 7 days after enrollment to assay presepsin and PCT. Outcome was assessed 28 and 90 days after enrollment.ResultsEarly presepsin (day 1) was higher in decedents (2,269 pg/ml, median (Q1 to Q3), 1,171 to 4,300 pg/ml) than in survivors (1,184 pg/ml (median, 875 to 2,113); P = 0.002), whereas PCT was not different (18.5 μg/L (median 3.4 to 45.2) and 10.8 μg/L (2.7 to 41.9); P = 0.31). The evolution of presepsin levels over time was significantly different in survivors compared to decedents (P for time-survival interaction = 0.03), whereas PCT decreased similarly in the two groups (P = 0.13). Presepsin was the only variable independently associated with ICU and 28-day mortality in Cox models adjusted for clinical characteristics. It showed better prognostic accuracy than PCT in the range of Sequential Organ Failure Assessment score (area under the curve (AUC) from 0.64 to 0.75 vs. AUC 0.53 to 0.65).ConclusionsIn this multicenter clinical trial, we provide the first evidence that presepsin measurements may have useful prognostic information for patients with severe sepsis or septic shock. These preliminary findings suggest that presepsin may be of clinical importance for early risk stratification.