Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

BACKGROUND: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown. METHODS: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 µg per kilogram of body weight per hour) or propofol (5 to 50 µg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months. RESULTS: Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 µg per kilogram per hour, and 208 received propofol at a median dose of 10.21 µg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups. CONCLUSIONS: Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.

INTRODUCTION: Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. OBJECTIVES: In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. METHODS: 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. RESULTS: D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. CONCLUSIONS: In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.

Treatment of venous thromboembolism: guidelines translated for the clinician.

Venous thromboembolism is a major cause of morbidity and mortality affecting over 2 million people in the United States each year. The American College of Chest Physicians (ACCP) published their first consensus statement on antithrombotic therapy in 1986, and the most recent guidelines from the ACCP on this topic were released in 2008. We aim to summarize the most recent ACCP guidelines on therapy for venous thromboembolism with practical application and interpretation for the practicing physician. We will briefly review the rating system used in the guidelines for the level of evidence and the strength of the recommendation. We will then discuss the recommendations for initial anticoagulant therapies including low molecular weight heparin, unfractionated heparin, and fondaparinux for patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE). A discussion of the guidelines on duration of anticoagulant therapy with a vitamin K antagonist is also included. In addition, we will address the use of thrombolytic therapy and inferior vena cava filter placement for DVT and PE. Prevention of postphlebitic syndrome is discussed as well. We will conclude with a brief discussion of future directions including several novel therapeutic anticoagulants.

Prevention of venous thromboembolism in medical patients and outpatients.

The majority of fatal cases of pulmonary embolism in hospitalized patients occur in acutely ill, medically treated patients. Current guidelines, based on a large number of prospective, randomized, controlled trials evaluating the safety and efficacy of pharmacologic venous thromboembolism (VTE) prophylaxis in medical patients, now recommend using VTE prophylaxis in this population. Unfortunately, prophylaxis rates in medical patients are unacceptably low, despite efforts to develop strategies for improving implementation of prophylaxis regimens. Studies indicate that a substantial proportion of patients with VTE present after hospital discharge, but no clinical trials evaluating VTE prophylaxis for medical outpatients have yet been published. In this Review, we examine the literature on VTE prophylaxis in hospitalized medical patients, and evaluate the available data for the outpatient setting.

Thrombolytic therapy for venous thromboembolism: current clinical practice.

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening condition for which thrombolytic therapy may be beneficial. The appropriate setting for the use of thrombolytic therapy remains controversial. More than 10 years ago we described the case-based practice patterns for the use of thrombolytics in VTE, and now, in the context of recent studies and guidelines, we sought to reevaluate the use of thrombolytics and to determine whether beliefs have changed. METHODS: Active pulmonologists in 11 southeastern states were selected to complete a web-based questionnaire that included background questions and hypothetical case scenarios involving VTE and potential treatment with thrombolytics. RESULTS: Eighty-one physicians completed the survey and 84% reported using thrombolytic therapy for VTE within the last 2 years. In the absence of absolute contraindications, 99% of respondents would strongly consider using systemic thrombolytic therapy for massive pulmonary embolism (PE) with hypotension, 83% would strongly consider thrombolysis for a large PE with severe hypoxemia, and 62% would strongly consider thrombolysis for PE with echocardiographic evidence of right ventricular dysfunction. In a patient with massive PE and hypotension with certain contraindications, 91% of respondents would still strongly consider thrombolysis. CONCLUSIONS: Most practicing pulmonologists would strongly consider administering thrombolytic therapy for massive PE with hypotension or hypoxemia, and a majority favor thrombolysis for PE in the setting of echocardiographic evidence of right heart dysfunction. Despite the evolving data and guidelines for the management of VTE, our findings are similar to prior survey results, emphasizing the need for further physician education and future randomized trials to clarify the therapy for this potentially deadly condition.

Pleural fluid exchange in rabbits.

BACKGROUND AND OBJECTIVES: The study was designed to better characterize pleural fluid absorption in rabbits with the following two objectives: to determine the relative absorption of saline versus high-protein solutions, and to identify the relative rates of absorption of dextran molecules of varying sizes. METHODS: Twenty New Zealand white rabbits received a 12-mL intrapleural injection of saline solution and a 10% protein solution on opposite sides, each solution containing dextran molecules with varying MWs. At sacrifice at 1, 4, 8, 18 and 24 h, the volume of pleural fluid and the concentrations of the dextran molecules were determined. RESULTS: Saline was absorbed faster than the high-protein fluid (P < 0.001). Dextran concentrations in the saline were significantly higher than those in the protein solution at all times after injection (P = 0.005; P < 0.001, respectively). The higher-MW dextrans were cleared more slowly than the lower-MW dextrans in a continuously graded manner. CONCLUSIONS: Saline was absorbed faster than a solution with a high protein content. There was a continuous spectrum in the rate of absorption of the dextran molecules, with the larger molecules being absorbed more slowly.