Use of an integrated clinical trial database to evaluate the effect of timing of drotrecogin alfa (activated) treatment in severe sepsis

INTRODUCTION: Several studies have indicated that early identification and treatment of patients with severe sepsis using standard supportive care improves outcomes. Earlier treatment with drotrecogin alfa (activated) (DrotAA) may also improve outcomes in severe sepsis. Using a recently constructed integrated severe sepsis database, our objectives in this study were to describe the influence of baseline clinical characteristics on timing of DrotAA treatment in patients with severe sepsis, to evaluate the efficacy of DrotAA with respect to timing of administration, and to examine the association between early intervention with DrotAA and patient outcomes, using adjustments for imbalances. METHODS: The database comprises data from 4,459 patients with severe sepsis (DrotAA, n = 3,228; placebo, n = 1,231) included in five clinical trials conducted in tertiary care institutions in 28 countries. Placebo data came only from randomized trials, whereas data for the DrotAA group came from randomized (PROWESS) and open-label/observational (ENHANCE) trials. RESULTS: Increased time-to-treatment with DrotAA was significantly associated with more organ dysfunction, greater need of mechanical ventilation, vasopressor use, or recent surgery. Earlier treatment was associated with higher baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. Adjusted and unadjusted survival analyses suggested that compared with placebo, DrotAA treatment provided a potential survival benefit, regardless of time to treatment. Survival curves of DrotAA patients treated early compared with those treated late began to separate at 14 days. By 28 days, patients treated earlier had higher survival than those treated later (76.4% versus 73.5%, p = 0.03). Sepsis-induced multiorgan dysfunction was the most common cause of death followed by refractory shock and respiratory failure. Modeling of the treatment effect, as a function of time to treatment, suggested increased benefit with earlier treatment. CONCLUSION: Using an integrated database of five severe sepsis trials and appropriate statistical adjustments to reduce sources of potential bias, earlier treatment with DrotAA seemed to be associated with a lower risk-adjusted mortality than later treatment. These data suggest that earlier treatment with DrotAA may provide most benefit for appropriate patients

Laterality versus ankle dorsiand plantarflexion maximal torques

Purpose: The aim of the study was to analyze the connections between the functional asymmetries of lower limbs, taking into account morphological feet features, and ankle dorsi- and plantarflexion maximal torques in men and women. Methods: The study population consisted of 56 young subjects among which there were 30 women and 26 men. The assessment of upper and lower limbs’ side dominance was performed on the basis of surveys, verified with simple motor tasks that resembled the actions characteristic of the upper and lower limbs. The measurements of body build, as well as foot build, were performed with the use of accepted instruments according to the anthropometry standards. The measurements of longitudinal foot arches were conducted using the pantographic method. Ankle dorsi- and plantarflexion maximal torque values were measured under static conditions. Results: We found a positive correlation between the functional dominance of lower limb and greater strength only for ankle plantarflexion maximal torque values in correct laterality variants in women and in only one variant in men. No correlation was found between foot morphological asymmetry and the ankle dorsiand plantarflexion maximal torque values, either in women or in men. Conclusion: Our results support the idea that the functional lower limb dominance is not equivalent to the greater muscle strength

Laterality versus jumping performance in men and women

Purpose: The aim of this study was to investigate relationships between functional asymmetry of lower limbs, taking into account morphological features of the feet, and jumping ability in men and women. Methods: The study population consisted of 56 subjects, 30 women (age: 20.29 ± 0.59 years; body mass: 58.13 ± 4.58 kg, body height: 165.60 ± 5.03 cm) and 26 men (age: 20.41 ± 0.78 years, body mass: 78.39 ± 8.42 kg, body height: 181.15 ± 6.52 cm). The measurements of longitudinal arches were performed with the plantographic method on the basis of Clarke’s angle mapped on a computer foot print. The measurements of jumping performance during bilateral (two legs) and unilateral (single-leg) counter movement jump (CMJ) were done on force plate. All subjects jumped three times each type of jump (total 9 jumps): three right leg, three left leg and three two legs. We put the test results through a detailed statistical analysis with the Statistica 8.0. The t-test for dependent variables and the Wilcoxon signed-rank test for divergent variances of the features compared. The analysis of relationships between the chosen podometric and plantographic features and jumping performance was conducted on the basis of the Pearson product-moment correlation coefficient (for the features which presented normal distribution, according to the Shapiro–Wilk test). Results: The correlations between values of height of single-leg jumps (right and left) and bilateral jumps, and foot indices were found in few cases only in men who had greater values of jump height with the non-dominant limb. We did not find a significant difference in jumping ability between the dominant limb and the non-dominant limb in women. We found bilateral deficits in jumping ability in the study groups, though we did not find significant differences (P ≤ 0.05) between the values for women (a mean of 6.5%) and for men (a mean of 8.4%). Conclusion: We found significant gender differences of the correlations between the values of height of jumps (single-leg and bilateral jumps) and foot indices

Low resonance frequency vibration affects strength of paretic and non-paretic leg differently in patients with stroke

The objective of the study was to investigate the chronic effect of low frequency whole body vibration (WBV) on isometric and eccentric strength of knee extensors with different force exertion capacity. It was hypothesized that (1) four-week WBV intervention with the low frequency domain would enhance muscle strength and (2) the improvement would be more pronounced in the weaker muscle. To test our hypothesis twenty patients with acute stroke were recruited. Ten patients were randomly assigned to vibration and the remaining ten patients served for control.The patients in the vibration group received WBV with 20 Hz frequency three times per week standing on a vibration platform in half squat position meanwhile flexing and extending the joints and placing the weight from one leg to the other. Knee extensor strength was determined under isometric and eccentric contraction before and after WBV intervention. Myoelectrical activity (EMG) of the vastus lateralis muscle was also measured.Significant improvement was revealed in the vibration group only. The maximum isometric torque and EMG activity increased significantly for both paretic and non-paretic leg, but the improvement was threefold greater in the vibration group. No significant alteration was found in rate of torque development. Maximum eccentric torque and EMG increased significantly for the paretic leg only. Mechanical work enhanced significantly in the paretic side only.The results of our study indicate that the selection of the effective vibration frequency depends upon the physical condition of neuromuscular system. Low vibration frequency intervention can increase the strength in weak muscles due to neuromuscular impairment and restricted physical activity

ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: one-year safety and efficacy evaluation.

OBJECTIVE: To demonstrate that drotrecogin alfa (activated) has an acceptable safety profile 1 yr from randomization. DESIGN: One-year follow-up of patients participating in a placebo-controlled clinical study of drotrecogin alfa (activated) in severe sepsis patients at low risk of death (the ADDRESS study). SETTING: The study was conducted at 516 hospitals in 34 countries. PATIENTS: The study included 2,640 patients. INTERVENTIONS: One-year follow-up was performed as an addendum to the placebo-controlled ADDRESS study. Treatment groups were compared using the chi-square test and Kaplan-Meier estimates. MEASUREMENTS AND MAIN RESULTS: Survival status at 1 yr was obtained for 90% of patients enrolled in the study (n = 2,376). The difference in mortality rate between drotrecogin alfa (activated) and placebo patients was numerically smaller at 1 yr (34.2% and 34.0%, respectively, p = .94) than at 28 days (18.5% and 17.0%, respectively, p = .34). In the subgroups defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score (or=25), the differences in mortality rate between treatment groups at 1 yr were consistent with those observed at 28 days; no significant differences in mortality rates between treatment groups were observed. No additional serious adverse events were reported during the period between hospital discharge and 1 yr. CONCLUSIONS: No increased risk of death or evidence of harm at 1 yr was associated with drotrecogin alfa (activated) administration in patients with severe sepsis at lower risk of death

Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis

AbstractBackgroundThe goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF).MethodsUsing data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥2years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1second (FEV1) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies.ResultsIn total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV1 and received more oral (p<0.013) and inhaled (p<0.001) antibiotic therapy. Mean FEV1 decline did not change significantly after MARPA detection (−2.22% predicted/year before detection and −2.43 after, p=0.45). There was no relationship between persistent infection or FEV1 quartile and FEV1 decline.ConclusionsNewly detected MARPA was not associated with a significant change in the rate of FEV1 decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline

Efficacy of Pirfenidone in the Context of Multiple Disease Progression Events in Patients With Idiopathic Pulmonary Fibrosis

Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown. Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed. The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002). Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event. ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov