Christopher Doig

Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.

It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.

Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study

IntroductionSevere acute renal failure (sARF) is associated with considerable morbidity, mortality and use of healthcare resources; however, its precise epidemiology and long-term outcomes have not been well described in a non-specified population.MethodsPopulation-based surveillance was conducted among all adult residents of the Calgary Health Region (population 1 million) admitted to multidisciplinary and cardiovascular surgical intensive care units between May 1 1999 and April 30 2002. Clinical records were reviewed and outcome at 1 year was assessed.ResultssARF occurred in 240 patients (11.0 per 100,000 population/year). Rates were highest in males and older patients (≥65 years of age). Risk factors for development of sARF included previous heart disease, stroke, pulmonary disease, diabetes mellitus, cancer, connective tissue disease, chronic renal dysfunction, and alcoholism. The annual mortality rate was 7.3 per 100,000 population with rates highest in males and those ≥65 years. The 28-day, 90-day, and 1-year case-fatality rates were 51%, 60%, and 64%, respectively. Increased Charlson co-morbidity index, presence of liver disease, higher APACHE II score, septic shock, and need for continuous renal replacement therapy were independently associated with death at 1 year. Renal recovery occurred in 78% (68/87) of survivors at 1 year.ConclusionsARF is common and males, older patients, and those with underlying medical conditions are at greatest risk. Although the majority of patients with sARF will die, most survivors will become independent from renal replacement therapy within a year.

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE : Further evidence for survival and safety and implications for early treatment

Objective:To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis. Design:Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003. Setting:ENHANCE took place in 25 countries at 361 sites. Patients:Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol. Interventions:Drotrecogin alfa (activated) was infused at a dose of 24 &mgr;g/kg/hr for 96 hrs. Measurements and Main Results:The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0–24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01). Conclusions:ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels.

Objective:To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab′)2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. Design:Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting:One hundred fifty-seven intensive care units in the United States and Canada. Patients:Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions:Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. Measurements and Main Results:In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. Conclusions:Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

Cost of acute renal failure requiring dialysis in the intensive care unit: clinical and resource implications of renal recovery.

ObjectiveAcute renal failure can be treated with continuous renal replacement therapy (CRRT) or intermittent hemodialysis. There is no difference in mortality, although patients treated with CRRT may have a higher rate of renal recovery. Given these considerations, an estimate of the costs by modality may help in choosing the method of dialysis. As such, the objective of this study was to estimate the cost of CRRT and intermittent hemodialysis in the intensive care unit and to explore the impact of renal recovery on subsequent clinical outcomes and costs among survivors. DesignRetrospective cohort study of all patients who developed acute renal failure and required dialysis between April 1, 1996, and March 31, 1999. SettingTwo tertiary care intensive care units in Calgary, Canada. PatientsA total of 261 critically ill patients. InterventionsNone. MeasurementsAll patients were followed to determine in-hospital and subsequent clinical outcomes (survival and frequency of renal recovery). The immediate and potential long-term costs of CRRT and intermittent hemodialysis were measured. Main ResultsThe cost of performing CRRT ranged from Can

Meta‐analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy

3,486 to Can

An Aggressive Surgical Approach Leads to Improved Survival in Patients With Gallbladder Cancer: A 12-Year Study at a North American Center

5,117 per week, depending on the modality and the anticoagulant used, and it was significantly more expensive than intermittent hemodialysis (Can

Organ donor management in Canada: recommendations of the forum on Medical Management to Optimize Donor Organ Potential

1,342 per week). Survivors with renal recovery spent significantly fewer days in hospital (11.3 vs. 22.5 days, p < .001) and incurred less healthcare costs (

Functional alpha 4-integrin : a newly identified pathway of neutrophil recruitment in critically ill septic patients

11,192 vs.

Evaluating meta-analyses in the general surgical literature: a critical appraisal.

73,273, p < .001) over the year after hospital discharge compared with survivors who remained on dialysis. ConclusionsImmediate cost savings could be achieved by increasing the use of intermittent hemodialysis rather than CRRT for patients with acute renal failure in the intensive care unit. Because of the high cost of ongoing dialysis, CRRT may still be an economically efficient treatment if it improves renal recovery among survivors; further study in this area is required.