128 results found
Abdul-Aziz MH, Lipman J, Akova M, et al., 2015, Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort., Journal of Antimicrobial Chemotherapy, Vol: 71, Pages: 196-207, ISSN: 0305-7453
OBJECTIVES: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. METHODS: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. RESULTS: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025]. CONCLUSIONS: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.
Herrmann IK, Bertazzo S, O'Callaghan D, et al., 2015, Differentiating sepsis from non-infectious systemic inflammation based on microvesicle-bacteria aggregation, Nanoscale, Vol: 7, Pages: 13511-13520, ISSN: 2040-3364
Sepsis is a severe medical condition and a leading cause of hospital mortality. Prompt diagnosis and early treatment has a significant, positive impact on patient outcome. However, sepsis is not always easy to diagnose, especially in critically ill patients. Here, we present a conceptionally new approach for the rapid diagnostic differentiation of sepsis from non-septic intensive care unit patients. Using advanced microscopy and spectroscopy techniques, we measure infection-specific changes in the activity of nano-sized cell-derived microvesicles to bind bacteria. We report on the use of a point-of-care-compatible microfluidic chip to measure microvesicle-bacteria aggregation and demonstrate rapid (≤1.5 hour) and reliable diagnostic differentiation of bacterial infection from non-infectious inflammation in a double-blind pilot study. Our study demonstrates the potential of microvesicle activities for sepsis diagnosis and introduces microvesicle-bacteria aggregation as a potentially useful parameter for making early clinical management decisions.
O'Callaghan DJ, O'Dea KP, Scott AJ, et al., 2015, Monocyte Tumor Necrosis Factor-α-Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation., Critical Care Medicine, Vol: 43, Pages: 1375-1385, ISSN: 1530-0293
OBJECTIVES: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α-converting enzyme baseline and inducible activity profiles. DESIGN: Observational clinical study. SETTING: Mixed surgical/medical teaching hospital ICU. PATIENTS: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α-converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients' monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α-converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α-converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α-converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α-converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α-converting enz
Mills TC, Chapman S, Hutton P, et al., 2015, Variants in the mannose-binding lectin gene MBL2 do not associate with sepsis susceptibility or survival in a large European cohort, Clinical Infectious Diseases, Vol: 61, Pages: 695-703, ISSN: 1537-6591
BACKGROUND: Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. METHODS: We genotyped and analysed four important MBL2 SNPs (rs5030737, rs1800450, rs1800451 and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the UK. We analysed the following predefined subgroups and outcomes: 28-day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the UK. RESULTS: There were no significant associations (all p-values were greater than 0.05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. CONCLUSIONS: In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.
O'Callaghan DJ, Gordon AC, 2015, What's new in vasopressin?, Intensive Care Medicine, Vol: 41, Pages: 2177-2179, ISSN: 1432-1238
Tridente A, Clarke GM, Walden A, et al., 2015, Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort., Critical Care, Vol: 19, ISSN: 1364-8535
INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of ICU stay in 977 patients from 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary end-points were ICU, hospital and 28 day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and gender, were performed for each endpoint. Trends remaining significant after Bonferroni correction for multiple testing were entered into a multivariate Cox PH model to determine independent associations with mortality. RESULTS: Trends over the first 7 days ICU stay independently associated with 6 month mortality were worsening thrombocytopaenia (mortality HR = 1.02, 95% CI 1.01-1.03, p < 0.001) and renal function (total daily urine output HR = 1.02, 95%CI 1.01-1.03, p < 0.001; renal SOFA sub-score HR = 0.87, 95%CI 0.75-0.99, p = 0.047), maximum bilirubin level (HR = 0.99, 95%CI 0.99-0.99, p = 0.02) and GCS SOFA sub-score (HR = 0.81, 95%CI 0.68-0.98, p = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28 day mortality). We detected the same pattern when analysing trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables and in radiologica
Gordon A, 2015, Disease Management - Sepsis, Guidelines for the Provision of Intensive Care Services, Pages: 67-70
Gordon AC, 2015, Evidence about inotropes: when is enough, enough?, Intensive Care Medicine, Vol: 41, Pages: 695-697, ISSN: 1432-1238
Rautanen A, Mills TC, Gordon AC, et al., 2015, Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study, LANCET RESPIRATORY MEDICINE, Vol: 3, Pages: 53-60, ISSN: 2213-2600
Antcliffe D, Wolfer A, O'Dea KP, et al., 2015, Profiling Of Eicosanoids And Cytokines As An Aid To Diagnosing Pneumonia On Intensive Care, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wilkinson KM, Krige A, Brearley SG, et al., 2014, Thoracic Epidural analgesia versus Rectus Sheath Catheters for open midline incisions in major abdominal surgery within an enhanced recovery programme (TERSC): study protocol for a randomised controlled trial., Trials, Vol: 15, Pages: 400-400
Antcliffe D, Jimenez B, Veselkov K, et al., 2014, DIAGNOSING PNEUMONIA ON THE INTENSIVE CARE UNIT WITH SERUM H-1 NMR SPECTROSCOPY, 27th Annual Congress of the European-Society-of-Intensive-Care-Medicine (ESICM), Publisher: SPRINGER, Pages: S237-S238, ISSN: 0342-4642
Hatcher J, Myers A, Donaldson H, et al., 2014, Comment on: Effects of selective digestive decontamination (SDD) on the gut resistome., Journal of Antimicrobial Chemotherapy, Pages: dku288-dku288
Orme RMLE, Perkins GD, McAuley DF, et al., 2014, An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial, Trials, Vol: 15, Pages: 1-10
Roberts JA, Paul SK, Akova M, et al., 2014, DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current beta-Lactam Antibiotic Doses Sufficient for Critically Ill Patients?, CLINICAL INFECTIOUS DISEASES, Vol: 58, Pages: 1072-1083, ISSN: 1058-4838
Walden AP, Clarke GM, McKechnie S, et al., 2014, Patients with community acquired pneumonia admitted to European Intensive Care Units: an epidemiological survey of the GenOSept cohort, Critical Care, Vol: 18
IntroductionCommunity acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe.MethodsKaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality.ResultsData from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome.ConclusionsThe mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome.
Gordon AC, Mason AJ, Perkins GD, et al., 2014, The interaction of vasopressin and corticosteroids in septic shock: A pilot randomized controlled trial, Critical Care Medicine, Vol: 42, Pages: 1325-1333, ISSN: 0090-3493
OBJECTIVES: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. DESIGN: Prospective open-label randomized controlled pilot trial. SETTING: Four adult ICUs in London teaching hospitals. PATIENTS: Sixty-one adult patients who had septic shock. INTERVENTIONS: Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. MEASUREMENTS AND MAIN RESULTS: Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. CONCLUSIONS: Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or
Tridente A, Clarke GM, Walden A, et al., 2014, Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort, INTENSIVE CARE MEDICINE, Vol: 40, Pages: 202-210, ISSN: 0342-4642
Gordon AC, Myburgh JA, 2014, Vasodilators and antihypertensives, Oh's Intensive Care Manual, Editors: Bersten, Soni, Pages: 923-934, ISBN: 9780702047626
Dunning JW, Merson L, Rohde GGU, et al., 2014, Open source clinical science for emerging infections, The Lancet Infectious Diseases, Vol: 14, Pages: 8-9, ISSN: 1473-3099
Gordon AC, Mason AJ, Perkins GD, et al., 2014, Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH), BMJ Open, Vol: 4
Introduction Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.Methods and analysis This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0–0.06 U/min) or noradrenaline (0–12 µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50 mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation.Ethics and dissemination The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration number: ISRCTN 20769191 and EudraCT 2011-005363-24.
Gordon AC, Russell JA, 2013, Vasopressin Guidelines in Surviving Sepsis Campaign: 2012, CRITICAL CARE MEDICINE, Vol: 41, Pages: E482-E483, ISSN: 0090-3493
Antcliffe DB, Veselkov K, Pearce JTM, et al., 2013, TRAJECTORY ANALYSIS OF CLINICAL VARIABLES TO IMPROVE DIAGNOSIS OF VENTILATOR ASSOCIATED PNEUMONIA IN PATIENTS Wan BRAIN INJURY, ESICM 26th Annual Congress, Publisher: SPRINGER, Pages: S312-S313, ISSN: 0342-4642
Dombrowski SU, Prior ME, Duncan E, et al., 2013, Clinical components and associated behavioural aspects of a complex healthcare intervention: Multi-methods study of selective decontamination of the digestive tract in critical care., Australian critical care : official journal of the Confederation of Australian Critical Care Nurses
Mehta S, Granton J, Gordon AC, et al., 2013, Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine, Critical Care, Vol: 17, ISSN: 1364-8535
Introduction: Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock; and compared the effect of vasopressin (VP) vs norepinephrine (NE) on troponin, CK, and ECGs.Methods: This was a prospective substudy of a randomized trial. Adults with septic shock randomly received a blinded infusion of low-dose VP (0.01-0.03 U/min) or NE (5-15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65-75 mmHg. Troponin I/T, CK, and CKMB were measured and 12-lead ECGs were recorded prior to study drug, and 6 hours, 2 days and 4 days after study drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs.Results: We enrolled 121 patients [median age 63.9 years (IQR 51.1,75.3), mean APACHE II 28.6 (SD 7.7)]: 65 in VP group and 56 in NE group. At the 4 timepoints, 26%, 36%, 32% and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels, and rates of ischemic ECG changes were similar in the VP and NE groups. In multivariable analysis only APACHE II was associated with 28-day mortality (OR 1.07, 95% CI 1.01-1.14, p=0.033).Conclusions: Troponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality.Trial registration: Controlled-trials.com ISRCTN94845869.
Nieminen MS, Fruhwald S, Heunks LMA, et al., 2013, Levosimendan: current data, clinical use and future development., Heart Lung Vessel, Vol: 5, Pages: 227-245, ISSN: 2282-8419
Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.
Shankar-Hari M, Singer M, Cornelius V, et al., 2012, LOW IMMUNOGLOBULIN I; LEVELS AT ADMISSION REDUCES THE ODDS FOR 28 DAY MORTALITY COMPARED TO NORMAL LEVELS: PROSPECTIVE COHORT STUDY IN SEVERE SEPSIS, INTENSIVE CARE MEDICINE, Vol: 38, Pages: S54-S54, ISSN: 0342-4642
Gordon AC, Wang N, Walley KR, et al., 2012, The cardio-pulmonary effects of vasopressin compared to norepinephrine in septic shock., Chest, Vol: 142, Pages: 593-605
Abstract BACKGROUND:Vasopressin is known to be an effective vasopressor in the treatment of septic shock but uncertainty remains about its effect on other hemodynamic parameters. METHODS:We examined the cardio-pulmonary effects of vasopressin compared to norepinephrine in 779 adult patients who had septic shock recruited to the Vasopressin and Septic Shock Trial (VASST). More detailed cardiac output data was analyzed for the subset of 241 patients managed with a pulmonary artery catheter and data was collected for the first 96 hours after randomization. We compared the effects of vasopressin versus norepinephrine in all patients and also according to severity of shock (< or ≥ 15μg/min of norepinephrine) and cardiac output at baseline. RESULTS:Equal blood pressures were maintained in both treatment groups with a significant reduction in norepinephrine requirements in the vasopressin treated patients. The major haemodynamic difference between the two groups was a significant reduction in heart rate in the vasopressin treated patients (p < 0.0001) and this was most pronounced in the less severe shock stratum (treatment x shock stratum interaction, p = 0.03). There were no other major cardio-pulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between vasopressin and norepinephrine treated patients. There was significantly greater use of inotropic drugs in the vasopressin group compared to the norepinephrine group. CONCLUSIONS:Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion. (Controlled Trials number, ISRCTN94845869.).
O'Callaghan DJP, Jayia P, Vaughan-Huxley E, et al., 2012, An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome, CRITICAL CARE, Vol: 16, ISSN: 1466-609X
Annane D, Mira JP, Ware LB, et al., 2012, Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated), Annals of intensive care, Vol: 2, Pages: 15-15
ABSTRACT: BACKGROUND: A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (activated) (DAA) may be clinically useful as a companion diagnostic. This trial was designed to validate biomarkers (improved response polymorphisms (IRPs)). Each IRP (A and B) contains two single nucleotide polymorphisms that were associated with a differential DAA treatment effect. METHODS: DAA is typically given to younger patients with greater disease severity; therefore, a well-matched control group is critical to this multicenter, retrospective, controlled, outcome-blinded, genotype-blinded trial. Within each center, DAA-treated patients will be matched to controls treated within 24 months of each other taking into account age, APACHE II, cardiovascular, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, and infection site. A propensity score will estimate the probability that a patient would have received DAA given their baseline characteristics. Two-phase data transfer will ensure unbiased selection of matched controls. The first transfer will be for eligibility and matching data and the second transfer for outcomes and genotypic data. The primary analysis will compare the effect of DAA in IRP + and IRP - groups on in-hospital mortality through day 28. DISCUSSION: A design-based approach matching DAA-free to DAA-treated patients in a multicenter study of patients who have severe sepsis and high risk of death will directly compare control to DAA-treated groups for mortality by genotype. Results, which should be available in 2012, may help to identify the group of patients who would benefit from DAA and may provide a model for future investigation of sepsis therapies.
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