Performance of the CURB-65 Score in Predicting Critical Care Interventions in Patients Admitted With Community-Acquired Pneumonia.

STUDY OBJECTIVE: Confusion, uremia, elevated respiratory rate, hypotension, and aged 65 years or older (CURB-65) is a clinical prediction rule intended to stratify patients with pneumonia by expected mortality. We assess the predictive performance of CURB-65 for the proximal endpoint of receipt of critical care intervention in emergency department (ED) patients admitted with community-acquired pneumonia. METHODS: We performed a retrospective analysis of electronic health records from a single tertiary center for ED patients admitted as inpatients with a primary diagnosis of pneumonia from 2010 to 2014. Patients with a history of malignancy, tuberculosis, bronchiectasis, HIV, or readmission within 14 days were excluded. We assessed the predictive accuracy of CURB-65 for receipt of critical care interventions (ie, vasopressors, large-volume intravenous fluids, invasive catheters, assisted ventilation, insulin infusions, or renal replacement therapy) and inhospital mortality. Logistic regression was performed to assess the increase in odds of critical care intervention or inhospital mortality by increasing CURB-65 score. RESULTS: There were 2,322 patients admitted with community-acquired pneumonia in the study cohort; 630 (27.1%) were admitted to the ICU within 48 hours of ED triage and 343 (14.8%) received a critical care intervention. Of patients with a CURB-65 score of 0 to 1, 181 (15.6%) were admitted to the ICU, 74 (6.4%) received a critical care intervention, and 7 (0.6%) died. Of patients with a CURB-65 score of 2, 223 (27.0%) were admitted to the ICU, 127 (15.4%) received a critical care intervention, and 47 (5.7%) died. Among patients with CURB-65 score greater than or equal to 3, 226 (67.0%) were admitted to the ICU, 142 (42.1%) received a critical care intervention, and 43 (12.8%) died. The areas under the receiver operating characteristic for CURB-65 as a predictor of critical care intervention and mortality were 0.73 and 0.77, whereas sensitivity of CURB-65 score greater than or equal to 2 in predicting critical care intervention was 78.4%; for mortality, 92.8%. CONCLUSION: Patients with CURB-65 score less than or equal to 2 were often admitted to the ICU and received critical care interventions. Given this finding and the relatively low sensitivity of CURB-65 for critical care intervention, clinicians should exercise caution when using CURB-65 to guide disposition. Future ED-based clinical prediction rules may benefit from calibration to proximal endpoints.

Outcomes in variceal hemorrhage following the use of a balloon tamponade device.

BACKGROUND: Variceal hemorrhage is associated with high morbidity and mortality. A balloon tamponade device (BTD), such as the Sengstaken-Blakemore or Minnesota tube, may be used in cases of variceal hemorrhage. While these devices may be effective at controlling acute bleeding, the effect on patient outcomes remains less clear. We sought to describe the number of patients with variceal hemorrhage and a BTD who survive to discharge, survive to one-year, and develop complications related to a BTD. METHODS: In this retrospective study, we identified patients at a single, tertiary care center who underwent placement of a BTD for upper gastrointestinal hemorrhage between 2003 and 2014. Patient characteristics and outcomes were summarized using descriptive statistics. RESULTS: 34 patients with a BTD were identified. Median age was 57.5 (IQR 47-63) and 76% (26/34) were male. Approximately 59% (20/34) of patients survived to discharge, and 41% (13/32) were alive after one year. Two patients were lost to follow-up. Of those surviving to discharge, 95% (19/20) had undergone transjugular intrahepatic portosystemic shunt (TIPS), while 36% (5/14) of patients who did not survive to discharge had TIPS (p<0.01). One complication, an esophageal perforation, was identified and managed conservatively. CONCLUSION: In this cohort of patients undergoing BTD placement for variceal hemorrhage, approximately 59% of patients were alive at discharge and 41% were alive after one year. Placement of a BTD as a temporizing measure in the management of acute variceal hemorrhage may be helpful, particularly when utilized as a bridge to more definitive therapy.

Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

BACKGROUND: Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism. METHODS: We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay. RESULTS: Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p < 0.001). There was no difference between the groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p = 0.75). Relative pyruvate dehydrogenase activity was lower immediately after the surgery in the thiamine group as compared to the placebo group (15% [11, 37] vs. 28% [15, 84], p = 0.02). Patients receiving thiamine had higher post-operative global oxygen consumption 1 hour after the surgery (difference: 0.37 mL/min/kg [95% CI: 0.03, 0.71], p = 0.03) as well as cellular oxygen consumption. We found no differences in clinical outcomes. CONCLUSIONS: There were no differences in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. Post-operative oxygen consumption was significantly increased among patients receiving thiamine. TRIAL REGISTRATION: clinicaltrials.gov NCT02322892, December 14, 2014.

Cytochrome C in Patients with Septic Shock.

PURPOSE: Cytochrome c is an essential component of the electron transport chain, and circulating cytochrome c might be an indicator of mitochondrial injury. The objective of this study was to determine whether cytochrome c levels are elevated in septic patients, whether there is an association between cytochrome c levels and lactate/inflammatory markers, and whether elevated levels of cytochrome c are associated with poor outcomes. METHODS: This was a single-center, prospective, observational, pilot study within a randomized, placebo-controlled trial. We enrolled adult patients in septic shock and with an elevated lactate (>3 mmol/L). Blood was collected at enrollment and at 12 and 24  h thereafter. Cytochrome c was measured in plasma using an electrochemiluminescence immunoassay. RESULTS: We included 77 patients. Plasma cytochrome c levels were significantly higher in septic patients than in healthy controls (0.70  ng/mL [quartiles: 0.06, 1.99] vs. 0.19  ng/mL [quartiles: 0.03, 1.32], P = 0.008). Cytochrome c levels at enrollment were positively correlated with lactate levels (r(s) = 0.40, P < 0.001) but not with inflammatory markers. Patients who died before hospital discharge had significantly higher cytochrome c levels than survivors (0.99  ng/mL [quartiles: 0.36, 4.09] vs. 0.58  ng/mL [quartiles: 0.03, 1.64], P = 0.01). When analyzed over time, the difference between survivors and nonsurvivors remained significant (P < 0.001). CONCLUSIONS: Cytochrome c levels are higher in septic patients than in controls. In unadjusted analysis, septic nonsurvivors had higher cytochrome c levels than survivors.

Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial.

INTRODUCTION: We previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function. METHODS: We performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models. RESULTS: We enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62 ± 16 years and 47% were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes. CONCLUSIONS: In this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01948063. Registered on 18 February 2013.

Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis.

OBJECTIVE: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. DESIGN: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). SETTING: Research laboratories of Hannover Medical School and Harvard Medical School. PATIENTS: Septic patients/C57Bl/6 mice and human endothelial cells. INTERVENTIONS: Food and Drug Administration-approved library screening. MEASUREMENTS AND MAIN RESULTS: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. CONCLUSIONS: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.