16 Jun 06
Posted in rhAPC, Sepsis at 20:19 by Laci
By AF Shorr, GR Bernard, J-F Dhainaut, JR Russell, WL Macias, DR Nelson and DP Sundin
Critical Care 2006, 10:R92
Protein C, because of its central role in hemostasis, plays an integral role in the host response to infection. Protein C depletion, resulting from increased consumption, degradation, and/or decreased synthesis, is characteristic of sepsis and has been shown to predict morbidity and mortality. The objective of this study was to determine whether early directional changes in protein C levels correlate with outcome.
Methods
Patients in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) clinical trial were assessed and categorized by baseline protein C (n = 1574). Deficiency was categorized as: severe deficiency, protein C levels = 40% of normal protein C activity (n = 615, 39% of patients); deficient, protein C levels 41–80% of normal protein C activity (n = 764, 48.5% of patients); and normal, >80% of normal protein C activity (n = 195, 12.4% of patients). Logistic regression analysis of 28-day mortality for placebo patients was used to investigate whether baseline and day 1 protein C levels were independent risk factors for mortality. The impact of treatment with drotrecogin alfa (activated) (DrotAA) was also assessed.
Results
Protein C levels at baseline and day 1 were independent risk factors in placebo patients. If baseline protein C levels of severely deficient placebo patients remained = 40% at day 1 their odds of death increased (odds ratio = 2.75, P < 0.0001), while if levels improved to >40% by day 1 their risk of death decreased (odds ratio = 0.43, P = 0.03). If baseline protein C levels of placebo patients were >40% but decreased by = 10% on day 1, their risk of death increased (odds ratio = 1.87, P = 0.02). DrotAA treatment improved protein C levels by day 1 compared with placebo (P = 0.008) and reduced the risk of death in severely deficient (= 40%) patients at baseline. Treatment also decreased the number of severely protein C deficient (= 40%) patients and decreased the number of deficient (41–80%) patients and normal (>80%) patients who had a = 10% decrease in protein C levels by day 1.
Conclusion
Baseline protein C levels were an independent predictor of sepsis outcome. Day 1 changes in protein C, regardless of baseline levels, were also predictive of outcome. The association of DrotAA treatment, increased protein C levels, and improved survival may partially explain the mechanism of action.
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06 Jun 06
Posted in Bleeding, rFVIIa, Trauma at 17:31 by Laci
By KD Boffard, B Riou, B Warren, PIT Choong, S Rizoli, et al
J Trauma 2005;59:8–18
Background
Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma.
Methods
Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 ug/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose.
Results
Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p=0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p=0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p=0.10) and massive transfusion (7% vs. 19%; p=0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups.
Conclusion
Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.
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05 Jun 06
Posted in Critical Care, General at 18:02 by Laci
By J-L Vincent, HDMH Spapen, J Creteur, MI Piagnerelli, M Diltoer, A Roman, E Stevens et al
Critical Care Medicine. 2006;34(6):1661-1667
Objective
To describe the erythropoietin pharmacokinetic profile after once-weekly epoetin alfa treatment in critically ill patients. Secondary objectives were to compare pharmacodynamic and safety profiles between active treatment and placebo in these patients.
Design
Randomized, double-blind, placebo-controlled study.
Setting
Medical, surgical, or mixed medical/surgical intensive care units.
Patients
A total of 73 anemic critically ill adults with an expected stay of >3 days and a hematocrit value of <38%.
Interventions
Patients were randomized 2:1 to epoetin alfa, 40,000 IU, administered subcutaneously once weekly (n = 48) or matching placebo (n = 25) for up to 4 wks.
Measurements and Main Results
Serum erythropoietin concentration and hematologic variables (percentage reticulocytes [RETI], hemoglobin [Hb], and total red blood cell [RBC] counts) were measured, and area under the serum concentration-time curve from time 0 to the last blood sampling time at time t (t: 120, 144, or 168 hrs) postdose (AUC0-Tlast) for these three variables was determined. Mean serum erythropoietin concentrations in placebo patients were slightly higher than typical physiologic levels of erythropoietin in healthy subjects, although not appropriate for the degree of anemia in these patients. Overall, exposure of endogenous erythropoietin in the placebo group (in terms of AUC0-Tlast) was only about 20% of exposure to exogenous erythropoietin in the epoetin alfa group. Baseline hemoglobin levels were the same in both groups (9.9 g/dL). Mean change in hemoglobin level from baseline through day 29 was 1.9 g/dL and 1.6 g/dL in the epoetin alfa and placebo groups, respectively. Mean AUC(RETI)0-Tlast was higher with epoetin alfa than with placebo and was related to the AUC of erythropoietin. There were no apparent differences in AUC(Hb)0-Tlast and AUC(RBC)0-Tlast between epoetin alfa and placebo groups, which was most likely due to bleeding and transfusion events. Epoetin alfa was safe and well tolerated, with a rate of treatment-emergent complications similar to that seen with placebo.
Conclusion
Epoetin alfa, once weekly, augmented the erythropoietic response in critically ill patients as indicated by the increased erythropoietin levels and larger AUC(RETI)0-Tlast in treated patients.
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04 Jun 06
Posted in Anesthesia at 10:46 by Laci
By BC Jacobson, SC. Somers, CS Fuchs, CP Kelly, CA Camargo
N Engl J Med 2006;354:2340-2348
Background
Overweight and obese persons are at increased risk for gastroesophageal reflux disease. An association between body-mass index (BMI) — the weight in kilograms divided by the square of the height in meters — and symptoms of gastroesophageal reflux disease in persons of normal weight has not been demonstrated.
Methods
In 2000, we used a supplemental questionnaire to determine the frequency, severity, and duration of symptoms of gastroesophageal reflux disease among randomly selected participants in the Nurses’ Health Study. After categorizing women according to BMI as measured in 1998, we used logistic-regression models to study the association between BMI and symptoms of gastroesophageal reflux disease.
Results
Of 10,545 women who completed the questionnaire (response rate, 86 percent), 2310 (22 percent) reported having symptoms at least once a week, and 3419 (55 percent of those who had any symptoms) described their symptoms as moderate in severity. We observed a dose-dependent relationship between increasing BMI and frequent reflux symptoms (multivariate P for trend <0.001). As compared with women who had a BMI of 20.0 to 22.4, the multivariate odds ratios for frequent symptoms were 0.67 (95 percent confidence interval, 0.48 to 0.93) for a BMI of less than 20.0, 1.38 (95 percent confidence interval, 1.13 to 1.67) for a BMI of 22.5 to 24.9, 2.20 (95 percent confidence interval, 1.81 to 2.66) for a BMI of 25.0 to 27.4, 2.43 (95 percent confidence interval, 1.96 to 3.01) for a BMI of 27.5 to 29.9, 2.92 (95 percent confidence interval, 2.35 to 3.62) for a BMI of 30.0 to 34.9, and 2.93 (95 percent confidence interval, 2.24 to 3.85) for a BMI of 35.0 or more. Even in women with a normal baseline BMI, an increase in BMI of more than 3.5, as compared with no weight changes, was associated with an increased risk of frequent symptoms of reflux (odds ratio, 2.80; 95 percent confidence interval, 1.63 to 4.82).
Conclusions
BMI is associated with symptoms of gastroesophageal reflux disease in both normal-weight and overweight women. Even moderate weight gain among persons of normal weight may cause or exacerbate symptoms of reflux.
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