No evidence of tocilizumab treatment efficacy for severe to critical SARS-CoV2 infected patients: Results from a retrospective controlled multicenter study.

ABSTRACT: To assess tocilizumab (TCZ) efficacy associated to standard of care (SOC) compared to SOC alone in severe coronavirus associated disease 2019 (COVID-19) patients. In a matched case-control study from 3 French Hospital COVID-19 Departments, 27 patients with severe COVID-19 treated with TCZ and SOC were matched for baseline epidemiological and clinical features and compared to 27 severe COVID-19 patients treated with SOC alone. Baseline characteristics of the study population were comparable between groups. Eleven patients (20%) died. TCZ was not associated with clinical improvement as compared to SOC regarding oxygen-free status (44% vs 63%) and death (18.5% vs 22%), despite a higher decrease of the C-reactive protein at Day 7 (10.7 vs 52 mg/L; P < 10-3). Compared to the 43 patients alive at the end-of follow-up, patients who died were older (78 vs 64 years; P < 10-3), with 82% of them older than 72 years vs only 23% of live patients (P < 10-3). Age (OR = 1.15; 95%CI = 1.04-1.3; P = .008) and age over 72 years (OR) = 14.85; 95%CI = 2.7-80; P = .002) were independently associated with mortality. TCZ in addition to SOC for severe COVID-19 patients did not reduce mortality, subsequent need for invasive mechanical ventilation nor did it shorten the time of oxygen support, despite better control of the inflammatory response. More powerful and randomized controlled trials are warranted to determine if TCZ is effective in the management of COVID-19.

TIPS for management of portal-hypertension-related complications in patients with cirrhosis.

Portal hypertension is primarily due to liver cirrhosis, and is responsible for complications that include variceal bleeding, ascites and hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt (TIPS) is a low-resistance channel between the portal vein and the hepatic vein, created by interventional radiology, that aims to reduce portal pressure. TIPS is a potential treatment for severe portal-hypertension-related complications, including esophageal and gastric variceal bleeding. TIPS is currently indicated as salvage therapy in this setting when patients fail to respond to standard endoscopic and medical treatment. More recently, early TIPS has been shown to be effective in decreasing risk of rebleeding after variceal hemorrhage and mortality in Child-Pugh B patients with active hemorrhage at endoscopy, and in Child-Pugh C patients. TIPS is also an efficient treatment for refractory ascites and hepatic hydrothorax. In contrast, the role of TIPS in the hepatorenal syndrome has not been precisely defined. The aim of this review was to specifically describe the current role of TIPS in management of portal hypertension in patients with cirrhosis.

Nuclear magnetic resonance-based serum metabolomic analysis reveals different disease evolution profiles between septic shock survivors and non-survivors.

BACKGROUND: Septic shock is the most severe phase of sepsis and is associated with high rates of mortality. However, early stage prediction of septic shock outcomes remains difficult. Metabolomic techniques have emerged as a promising tool for improving prognosis. METHODS: Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) models separating the serum metabolomes of survivors from those of non-survivors were established with samples obtained at the intensive care unit (ICU) admission (H0) and 24 h later (H24). For 51 patients with available H0 and H24 samples, multi-level modeling was performed to provide insight into different metabolic evolutions that occurred between H0 and H24 in the surviving and non-surviving patients. Relative quantification and receiver operational characteristic curves (ROC) were applied to estimate the predictability of key discriminatory metabolites for septic shock mortality. RESULTS: Metabolites that were involved in energy supply and protein breakdown were primarily responsible for differentiating survivors from non-survivors. This was not only seen in the H0 and H24 discriminatory models, but also in the H0-H24 paired models. Reanalysis of extra H0-H24 paired samples in the established multi-level model demonstrated good performance of the model for the classification of samplings. According to the ROC results, nine discriminatory metabolites defined consistently from the unpaired model and the H0-H24 time-trend change (ΔH24-H0) show good prediction of mortality. These results suggest that NMR-based metabolomic analysis is useful for a better overall assessment of septic shock patients. CONCLUSIONS: Dysregulation of the metabolites identified by this study is associated with poor outcomes for septic shock. Evaluation of these compounds during the first 24 h after ICU admission in the septic shock patient may be helpful for estimating the severity of cases and for predicting outcomes. TRIAL REGISTRATION: All human serum samples were collected and stored, provided by the "center of biologic resources for liver disease", in Jean Verdier Hospital, Bondy, France (BB-0033-00027).

Efficacy and tolerance of early administration of tranexamic acid in patients with cirrhosis presenting with acute upper gastrointestinal bleeding: a study protocol for a multicentre, randomised, double-blind, placebo-controlled trial (the EXARHOSE study).

INTRODUCTION: The management of acute upper gastrointestinal bleeding (UGIB) is challenging in patients with cirrhosis, as it is responsible for severe complications and high mortality rates. Tranexamic acid (TXA) may help control the bleeding by counterbalancing cirrhosis-related hyperfibrinolysis. Still, there is a lack of unbiased data to conclude on its efficacy. The aim of this study is to evaluate the efficacy of TXA in the early treatment of acute UGIB in patients with cirrhosis. METHODS AND ANALYSIS: This study is a multicentre, randomised, double-blind, placebo-controlled trial, for adult patients with cirrhosis presenting with an acute UGIB and allocated to one of two arms: TXA or placebo (saline). Physicians from emergency mobile services, emergency departments (EDs) or intensive care units (ICUs) can include patients. Besides study intervention, standard care for UGIB will be performed as recommended. Intervention will consist an intravenous infusion of 10 mL of TXA (1 g) or saline, immediately followed by three identical intravenous infusions over 8 hours each (total dose of 4 g of TXA or 40 mL of placebo over 24 hours). Main analyses will be conducted in intention to treat on every patient included, then in modified intention to treat on patients with underlying lesion of portal hypertension visualised by endoscopy. The main objective is to show efficacy of TXA until day 5 on a composite criterion (bleeding control, rebleeding episodes and mortality). Secondary objectives aim at showing the efficacy of TXA on each individual component of the main outcome measure and others at 6 weeks and later (transjugular intrahepatic portosystemic shunt procedure, cirrhosis-specific complications, length of stay in ICU and in hospital, safety and tolerance of TXA, liver transplantation). Included patients will be followed up to 1 year after inclusion.500 patients will be necessary to show a reduction in the prevalence of the primary outcome from 30% to 18% with a bilateral alpha risk of 5% and a power of 80%. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Comité de Protection des Personnes Ile-de-France 1 (CPP-IDF1). Results will be disseminated via publications in peer-review medical journals and scientific forums. PROTOCOL VERSION: This protocol is based on the latest version, as established on 11 October 2017 and validated by the IRB CPP Ile-de-France 1. TRIAL REGISTRATION NUMBER: NCT03023189.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Determination of candidate metabolite biomarkers associated with recurrence of HCV-related hepatocellular carcinoma.

Hepatitis C virus (HCV) infection is associated with a high risk of developing hepatocellular carcinoma (HCC) and HCC recurrence remains the primary threat to outcomes after curative therapy. In this study, we compared recurrent and non-recurrent HCC patients treated with radiofrequency ablation (RFA) in order to identify characteristic metabolic profile variations associated with HCC recurrence. Gas chromatography-mass spectrometry (GC-MS) -based metabolomic analyses were conducted on serum samples obtained before and after RFA therapy. Significant variations were observed in metabolites in the glycerolipid, tricarboxylic acid (TCA) cycle, fatty acid, and amino acid pathways between recurrent and non-recurrent patients. Observed differences in metabolites associated with recurrence did not coincide before and after treatment except for fatty acids. Based on the comparison of serum metabolomes between recurrent and non-recurrent patients, key discriminatory metabolites were defined by a random forest (RF) test. Two combinations of these metabolites before and after RFA treatment showed outstanding performance in predicting HCV-related HCC recurrence, they were further confirmed by an external validation set. Our study showed that the determined combination of metabolites may be potential biomarkers for the prediction of HCC recurrence before and after RFA treatment.

Significance of oliguria in critically ill patients with chronic liver disease.

Clinical guidelines recommend using Kidney Disease Improving Global Outcomes (KDIGO) criteria for the diagnosis and classification of acute kidney injury (AKI) in patients with chronic liver disease (CLD). Concerns have been raised about the use of urine output (UO) criteria in CLD. We examined the significance of oliguria meeting the urine output criteria for AKI (AKI-UO) and examined its association with clinical outcomes in CLD patients. Using an 8-year clinical database from a large university medical center, 3458 patients with CLD were identified. AKI occurred in 2854 (82.5%) patients when they fulfilled any KDIGO criteria. When serum creatinine (SC) and UO criteria were used, 604 patients (17.5%) had no evidence of AKI and had the lowest hospital mortality rate (5%). Using AKI-UO criteria alone, 2103 patients (60.8%) were classified as stage 2-3 AKI. When only SC criteria were applied, 1281 (61%) of those patients with stage 2-3 AKI-UO were misclassified as either no AKI or AKI stage 1. Patients reclassified with AKI according to UO criteria (AKI-UO) had nearly a 3-fold increased rate of hospital mortality compared with patients without any AKI (14.6% versus 5%; P < 0.001) and more than a 50% increased mortality compared with stage 1 AKI-SC (14.6% versus 9%; P < 0.001). Patients with transient oliguria (AKI-UO stage 1) had increased mortality rates compared with patients without oliguria (14.9% versus 6.9%; P < 0.001). CONCLUSION: CLD patients have a high incidence of AKI. Compared with creatinine criteria alone, incorporating UO into the diagnostic criteria increased the measured incidence of AKI. Stage 2-3 AKI-UO has a high negative impact on hospital mortality. (Hepatology 2017;66:1592-1600).

Nuclear magnetic resonance metabolomics and human liver diseases: The principles and evidence associated with protein and carbohydrate metabolism.

During the last decade, metabolomics has become widely used in the field of human diseases. Numerous studies have demonstrated that this is a powerful technique for improving the understanding, diagnosis and management of various types of liver disease, such as acute and chronic liver diseases, and liver transplantation. Nuclear magnetic resonance (NMR) spectroscopy is one of the two most commonly applied methods for metabolomics. The aim of the present review was to investigate the results from recent key publications focusing on aspects of protein and carbohydrate metabolism. The review includes existing procedures, which are currently used for NMR data acquisition and statistical analysis. In addition, notable results obtained by these studies on protein and carbohydrate metabolism concerning human liver diseases are presented.

Metabolomics with Nuclear Magnetic Resonance Spectroscopy in a Drosophila melanogaster Model of Surviving Sepsis.

Patients surviving sepsis demonstrate sustained inflammation, which has been associated with long-term complications. One of the main mechanisms behind sustained inflammation is a metabolic switch in parenchymal and immune cells, thus understanding metabolic alterations after sepsis may provide important insights to the pathophysiology of sepsis recovery. In this study, we explored metabolomics in a novel Drosophila melanogaster model of surviving sepsis using Nuclear Magnetic Resonance (NMR), to determine metabolite profiles. We used a model of percutaneous infection in Drosophila melanogaster to mimic sepsis. We had three experimental groups: sepsis survivors (infected with Staphylococcus aureus and treated with oral linezolid), sham (pricked with an aseptic needle), and unmanipulated (positive control). We performed metabolic measurements seven days after sepsis. We then implemented metabolites detected in NMR spectra into the MetExplore web server in order to identify the metabolic pathway alterations in sepsis surviving Drosophila. Our NMR metabolomic approach in a Drosophila model of recovery from sepsis clearly distinguished between all three groups and showed two different metabolomic signatures of inflammation. Sham flies had decreased levels of maltose, alanine, and glutamine, while their level of choline was increased. Sepsis survivors had a metabolic signature characterized by decreased glucose, maltose, tyrosine, beta-alanine, acetate, glutamine, and succinate.

Application of LC-MS-based metabolomics method in differentiating septic survivors from non-survivors.

Septic shock is the most severe form of sepsis, which is still one of the leading causes of death in the intensive care unit (ICU). Even though early prognosis and diagnosis are known to be indispensable for reaching an optimistic outcome, pathogenic complexities and the lack of specific treatment make it difficult to predict the outcome individually. In the present study, serum samples from surviving and non-surviving septic shock patients were drawn before clinical intervention at admission. Metabolic profiles of all the samples were analyzed by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. One thousand four hundred nineteen peaks in positive mode and 1878 peaks in negative mode were retained with their relative standard deviation (RSD) below 30 %, in which 187 metabolites were initially identified by retention time and database in the light of the exact molecular mass. Differences between samples from the survivors and the non-survivors were investigated using multivariate and univariate analysis. Finally, 43 significantly varied metabolites were found in the comparison between survivors and non-survivors. Concretely, metabolites in the tricarboxylic acid (TCA) cycle, amino acids, and several energy metabolism-related metabolites were up-regulated in the non-survivors, whereas those in the urea cycle and fatty acids were generally down-regulated. Metabolites such as lysine, alanine, and methionine did not present significant changes in the comparison. Six metabolites were further defined as primary discriminators differentiating the survivors from the non-survivors at the early stage of septic shock. Our findings reveal that LC-MS-based metabolomics is a useful tool for studying septic shock. Graphical abstract ᅟ.

Sequential Serum Metabolomic Profiling after Radiofrequency Ablation of Hepatocellular Carcinoma Reveals Different Response Patterns According to Etiology.

Radiofrequency ablation (RFA) is commonly performed as a curative approach in patients with hepatocellular carcinoma (HCC); however, the risk of tumor recurrence is difficult to predict due to a lack of reliable clinical and biological markers, and identification of new biomarkers poses a major challenge for improving prognoses. Metabolomics is a promising technique that may lead to the identification and characterization of new disease fingerprints. The objective of the present study was to explore, preoperatively and at various time points post-RFA, the metabolic profile of serum samples from HCC patients to identify factors associated with treatment response and recurrence. Sequential sera obtained before and after RFA procedures for 120 patients with HCC due to cirrhosis were investigated using nuclear magnetic resonance metabolomics. A multilevel orthogonal projection to latent structure analysis was used to discriminate intraindividual metabolic changes in response to RFA treatment. Recurrence-free survival differed depending on the underlying cause of cirrhosis. The statistical model showed significant differences depending on whether the liver disease had a viral or nonviral etiology before RFA intervention (explained variance of R(2)Y = 0.89 and predictability of Q(2)Y = 0.34). These profiles were also associated with specific and distinct metabolic responses after RFA.

Nuclear magnetic resonance based metabolomics and liver diseases: Recent advances and future clinical applications.

Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. It is an "omics" technique that is situated downstream of genomics, transcriptomics and proteomics. Metabolomics is recognized as a promising technique in the field of systems biology for the evaluation of global metabolic changes. During the last decade, metabolomics approaches have become widely used in the study of liver diseases for the detection of early biomarkers and altered metabolic pathways. It is a powerful technique to improve our pathophysiological knowledge of various liver diseases. It can be a useful tool to help clinicians in the diagnostic process especially to distinguish malignant and non-malignant liver disease as well as to determine the etiology or severity of the liver disease. It can also assess therapeutic response or predict drug induced liver injury. Nevertheless, the usefulness of metabolomics is often not understood by clinicians, especially the concept of metabolomics profiling or fingerprinting. In the present work, after a concise description of the different techniques and processes used in metabolomics, we will review the main research on this subject by focusing specifically on in vitro proton nuclear magnetic resonance spectroscopy based metabolomics approaches in human studies. We will first consider the clinical point of view enlighten physicians on this new approach and emphasis its future use in clinical "routine".

Prognostic factors in necrotizing soft-tissue infections (NSTI): A cohort study.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is uncommon but life-threatening. A recent meta-analysis estimated the overall mortality at 23.5%. OBJECTIVE: We sought to identify risk factors associated with mortality in a cohort of patients with NSTI in a tertiary care center. METHODS: We identified 512 patients with NSTI between 1996 and 2012 in the national hospital database Program for Medicalization of Information Systems and examined risk factors of mortality with NSTI by univariate and multivariate analysis. RESULTS: We included 109 patients with a confirmed diagnosis of NSTI; 31 (28%) died at a median follow-up of 274 days (range 2-6135 days). On multivariate analysis, independent risk factors of mortality were age older than 75 years (hazard ratio [HR] 4.4, 95% confidence interval [CI] 1.8-10.3), multifocal NSTI (HR 5.9, 95% CI 1.9-18.5), severe peripheral vascular disease (HR 5.1, 95% CI 1.5-17.0), hospital-acquired infection (HR 3.9, 95% CI 1.4-10.7), severe sepsis (HR 7.4, 95% CI 1.7-33.1), and septic shock on hospital admission (HR 13.9, 95% CI 3.8-50.4). LIMITATIONS: This was a retrospective cohort, which disallows a precise record of the delay between diagnosis and surgery. CONCLUSION: Our findings for this robust cohort of patients with a definite diagnosis of NSTI could help clinicians stratify NSTI severity at clinical course onset.

Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.

BACKGROUND & AIMS: Albumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains unknown. We investigated this issue through a multicenter randomized controlled trial. METHODS: A total of 193 cirrhotic patients with a Child-Pugh score greater than 8 and sepsis unrelated to SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kg on day 1 and 1g/kg on day 3; albumin group [ALB]: n=96) or antibiotics alone (control group [CG]: n=97). The primary endpoint was the 3-month renal failure rate (increase in creatinine ⩾50% to reach a final value ⩾133 µmol/L). The secondary endpoint was 3-month survival rate. RESULTS: Forty-seven (24.6%) patients died (ALB: n=27 vs. CG: n=20; 3-month survival: 70.2% vs. 78.3%; p=0.16). Albumin infusion delayed the occurrence of renal failure (mean time to onset, ALB: 29.0 ± 21.8 vs. 11.7 ± 9.1 days, p=0.018) but the 3-month renal failure rate was similar (ALB: 14.3% vs. CG: 13.5%; p=0.88). By multivariate analysis, MELD score (p<0.0001), pneumonia (p=0.0041), hyponatremia (p=0.031) and occurrence of renal failure (p<0.0001) were predictors of death. Of note, pulmonary edema developed in 8/96 (8.3%) patients in the albumin group of whom two died, one on the day and the other on day 33 following albumin infusion. CONCLUSIONS: In cirrhotic patients with infections other than SBP, albumin infusion delayed onset of renal failure but did not improve renal function or survival at 3 months. Infusion of large amounts of albumin should be cautiously administered in the sickest cirrhotic patients.

PLS/OPLS models in metabolomics: the impact of permutation of dataset rows on the K-fold cross-validation quality parameters.

Among all the software packages available for discriminant analyses based on projection to latent structures (PLS-DA) or orthogonal projection to latent structures (OPLS-DA), SIMCA (Umetrics, Umeå Sweden) is the more widely used in the metabolomics field. SIMCA proposes many parameters or tests to assess the quality of the computed model (the number of significant components, R2, Q2, pCV-ANOVA, and the permutation test). Significance thresholds for these parameters are strongly application-dependent. Concerning the Q2 parameter, a significance threshold of 0.5 is generally admitted. However, during the last few years, many PLS-DA/OPLS-DA models built using SIMCA have been published with Q2 values lower than 0.5. The purpose of this opinion note is to point out that, in some circumstances frequently encountered in metabolomics, the values of these parameters strongly depend on the individuals that constitute the validation subsets. As a result of the way in which the software selects members of the calibration and validation subsets, a simple permutation of dataset rows can, in several cases, lead to contradictory conclusions about the significance of the models when a K-fold cross-validation is used. We believe that, when Q2 values lower than 0.5 are obtained, SIMCA users should at least verify that the quality parameters are stable towards permutation of the rows in their dataset.

Serum 1H-NMR metabolomic fingerprints of acute-on-chronic liver failure in intensive care unit patients with alcoholic cirrhosis.

INTRODUCTION: Acute-on-chronic liver failure is characterized by acute deterioration of liver function in patients with compensated or decompensated, but stable, cirrhosis. However, there is no accurate definition of acute-on-chronic liver failure and physicians often use this term to describe different clinical entities. Metabolomics investigates metabolic changes in biological systems and identifies the biomarkers or metabolic profiles. Our study assessed the metabolomic profile of serum using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy to identify metabolic changes related to acute-on-chronic liver failure. PATIENTS: Ninety-three patients with compensated or decompensated cirrhosis (CLF group) but stable liver function and 30 patients with cirrhosis and hospitalized for the management of an acute event who may be responsible of acute-on-chronic liver failure (ACLF group), were fully analyzed. Blood samples were drawn at admission, and sera were separated and stored at -80°C until (1)H-NMR spectral analysis. Using orthogonal projection to latent-structure discriminant analyses, various metabolites contribute to the complete separation between these both groups. RESULTS: The predictability of the model was 0.73 (Q(2) Y) and the explained variance was 0.63 (R(2) Y). The main metabolites that had increased signals related to acute-on-chronic liver failure were lactate, pyruvate, ketone bodies, glutamine, phenylalanine, tyrosine, and creatinine. High-density lipids were lower in the ALCF group than in CLF group. CONCLUSION: A serum metabolite fingerprint for acute-on-chronic liver failure, obtained with (1)H-NMR, was identified. Metabolomic profiling may aid clinical evaluation of patients with cirrhosis admitted into intensive care units with acute-on-chronic liver failure, and provide new insights into the metabolic processes involved in acute impairment of hepatic function.

Recombinant human activated protein C for adults with septic shock: a randomized controlled trial.

RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 µg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).

Identification of serum proton NMR metabolomic fingerprints associated with hepatocellular carcinoma in patients with alcoholic cirrhosis.

PURPOSE: Metabolomics depicts metabolic changes in biologic systems using a multiparametric analysis technique. This study assessed the metabolomic profiles of serum, obtained by proton nuclear magnetic resonance (NMR) spectroscopy, from cirrhotic patients with and without hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The study included 154 consecutive patients with compensated biopsy-proven alcoholic cirrhosis. Among these, 93 had cirrhosis without HCC, 28 had biopsy-proven HCC within the Milan criteria and were eligible for curative treatment (small HCC), and 33 had HCC outside the Milan criteria (large HCC). Proton spectra were acquired at 500 MHz. An orthogonal partial latent structure [orthogonal projection to latent structure (OPLS)] analysis model was built to discriminate large HCC spectra from cirrhotic spectra. Small HCC spectra were secondarily projected using previously built OPLS discriminant components. RESULTS: The OPLS model showed discrimination between cirrhotic and large HCC spectra. Metabolites that significantly increased with large HCC were glutamate, acetate, and N-acetyl glycoproteins, whereas metabolites that correlated with cirrhosis were lipids and glutamine. Projection of small HCC samples into the OPLS model showed a heterogeneous distribution between large HCC and cirrhotic samples. Small HCC patients with metabolomic profile similar to those of large HCC group had higher incidences of recurrence or death during follow-up. CONCLUSIONS: Serum NMR-based metabolomics identified metabolic fingerprints that could be specific to large HCC in cirrhotic livers. From a metabolomic standpoint, some patients with small HCC, who are eligible for curative treatments, seem to behave as patients with advanced cancerous disease. It would be useful to further prospectively investigate these patients to define a subgroup with a worse prognosis.