Comparing different thrombolytic dosing regimens for treatment of acute pulmonary embolism

Background\ud Optimal dosing of recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE).\ud \ud Methods\ud Objective\ud The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE.\ud \ud Design\ud A prospective, randomized, open label trial.\ud \ud Setting\ud A multicenter trial in China.\ud \ud Subjects\ud 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction.\ud \ud Intervention\ud Patients were randomly assigned to receive a treatment regimen of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53).\ud \ud Outcomes\ud The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, was also evaluated.\ud \ud Results\ud Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similar in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs. 10%), especially in patients with a body weight, 65 kg (14.8% vs. 41.2%, P = 0.049). No fatal recurrent PTE was found in either group.\ud \ud Conclusions\ud Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE

Pushing the envelope to reduce sedation in critically ill patients

Background\ud Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a beneficial effect, and in the general intensive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation.\ud \ud Methods\ud Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n = 70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n = 70, control group). Both groups were treated with bolus doses of morphine (2.5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00466492.\ud \ud Findings\ud 27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had significantly more days without ventilation (n = 55; mean 13.8 days, SD 11.0) than did those receiving interrupted sedation (n = 58; mean 9.6 days, SD 10.0; mean difference 4.2 days, 95% CI 0.3-8.1; p = 0.0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1.86, 95% CI 1.05-3.23; p = 0.0316), and, for the first 30 days studied, in hospital (3.57, 1.52-9.09; p = 0.0039), than was interrupted sedation. No difference was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agitated delirium was more frequent in the intervention group than in the control group (n = 11, 20% vs. n = 4, 7%; p = 0.0400).\ud \ud Interpretation\ud No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this effect can be reproduced in other facilities

Understanding genetics of sepsis: will new technology help?

High-throughput techniques, such as genome-wide scans, will allow genotyping of a large number of single-nucleotide polymorphisms throughout the human genome. There is intense interest to apply this technology to understand genetics of complex traits, including severe sepsis. To effectively utilize this technology, large cohorts of septic patients will have to be recruited. Careful attention should be paid to different aspects of study design and analyses as large, multicenter cohorts are assembled for genome-wide association studies

Diabetes and sepsis outcomes – it is not all bad news

Patients with diabetes mellitus have an increased risk of developing infections and sepsis. In this issue of Critical Care Esper and colleagues report on a large survey, involving 12.5 million sepsis cases, that examined the impact of pre-existing diabetes on organ dysfunction during sepsis. Their main conclusion was that diabetes patients, relative to non-diabetics, were less likely to develop respiratory failure and more likely to develop renal failure during the course of sepsis

Glucocorticoid therapy for trauma--ready for prime time?

Methods\ud Objective\ud To test the efficacy of hydrocortisone therapy in trauma patients.\ud \ud Design\ud Multicenter randomized, double blind, placebocontrolled study.\ud \ud Setting\ud Seven intensive care units (ICUs) in France during November 2006 to August 2009.\ud \ud Subjects\ud 150 patients with severe trauma who required ICU stay for at least 48 hours were included in the study.\ud \ud Intervention\ud Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/day for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response.\ud \ud Outcomes\ud Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, ICU length of stay, hyponatremia, and death.\ud \ud Results\ud An intention-to-treat (ITT) analysis included 149 patients and the modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital -acquired pneumonia by day 28 (hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.83; P = 0.007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = 0.01). Mechanical ventilation-free days increased with hydrocortisone use by 4 days (95% CI, 2-7; P = 0.001) in the ITT analysis and 6 days (95% CI, 2-11; P < 0.001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs. none in the hydrocortisone group (absolute difference, −9%; 95% CI, −16% to −3%; P = 0.01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, −5% to 11%; P = 0.44).\ud \ud Conclusions\ud In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia

Additions to the Human Plasma Proteome via a Tandem MARS Depletion iTRAQ-Based Workflow

Robust platforms for determining differentially expressed proteins in biomarker and discovery studies using human plasma are of great interest. While increased depth in proteome coverage is desirable, it is associated with costs of experimental time due to necessary sample fractionation. We evaluated a robust quantitative proteomics workflow for its ability (1) to provide increased depth in plasma proteome coverage and (2) to give statistical insight useful for establishing differentially expressed plasma proteins. The workflow involves dual-stage immunodepletion on a multiple affinity removal system (MARS) column, iTRAQ tagging, offline strong-cation exchange chromatography, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Independent workflow experiments were performed in triplicate on four plasma samples tagged with iTRAQ 4-plex reagents. After stringent criteria were applied to database searched results, 689 proteins with at least two spectral counts (SC) were identified. Depth in proteome coverage was assessed by comparison to the 2010 Human Plasma Proteome Reference Database in which our studies reveal 399 additional proteins which have not been previously reported. Additionally, we report on the technical variation of this quantitative workflow which ranges from ±11 to 30%

Arguing for Adaptive Clinical Trials in Sepsis

Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. © 2011 Yende et al

The Effects of Age on Inflammatory and Coagulation-Fibrinolysis Response in Patients Hospitalized for Pneumonia

Objective: To determine whether inflammatory and hemostasis response in patients hospitalized for pneumonia varies by age and whether these differences explain higher mortality in the elderly. Methods: In an observational cohort of subjects with community-acquired pneumonia (CAP) recruited from emergency departments (ED) in 28 hospitals, we divided subjects into 5 age groups (85% subjects, older subjects had modestly increased hemostasis markers and IL-6 levels (p,0.01). Conclusions: Modest age-related increases in coagulation response occur during hospitalization for CAP; however these differences do not explain the large differences in mortality. Despite clinical recovery, immune resolution may be delayed in older adults at discharge. © 2010 Kale et al