Lack of concentration-dependent local toxicity of highly concentrated (5%) versus conventional 0.5% bupivacaine following musculoskeletal surgery in a rat model.

PURPOSE: Various sustained-release formulations incorporate high bupivacaine concentrations but data on local toxicity is lacking. This study explores local toxic effects of highly concentrated (5%) bupivacaine compared to clinically used concentrations in vivo following skeletal surgery, to assess the safety of sustained-release formulations with high bupivacaine concentrations. METHODS: Sixteen rats underwent surgery, in which screws with catheters affixed were implanted in the spine or femur in a factorial experimental design, allowing single-shot or continuous 72 h local administration of 0.5%, 2.5% or 5.0% bupivacaine hydrochloride. During the 30-day follow-up, animal weight was recorded and blood samples were obtained. Implantation sites underwent histopathological scoring for muscle damage, inflammation, necrosis, periosteal reaction/thickening and osteoblast activity. Effects of bupivacaine concentration, administration mode and implantation site on local toxicity scores were analyzed. RESULTS: Chi-squared tests for score frequencies revealed a concentration-dependent decrease in osteoblast count. Moreover, spinal screw implantation led to significantly more muscle fibrosis but less bone damage than femoral screw implantation, reflecting the more invasive muscle dissection and shorter drilling times related to the spinal procedure. No differences between bupivacaine administration modes regarding histological scoring or body weight changes were observed. Weight increased, while CK levels and leukocyte counts decreased significantly during follow-up, reflecting postoperative recovery. No significant differences in weight, leukocyte count and CK were found between interventional groups. CONCLUSION: This pilot study found limited concentration-dependent local tissue effects of bupivacaine solutions concentrated up to 5.0% following musculoskeletal surgery in the rat study population.

Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults.

BACKGROUND: Pneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown. METHODS: In a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease. RESULTS: In the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community-acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group. CONCLUSIONS: Among older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA ClinicalTrials.gov number NCT00744263.).

Effects of recruitment strategies and demographic factors on inclusion in a large scale vaccination trial in adults 65 years and older.

Large-scale randomized studies generate the highest level evidence for medical interventions. Yet, successful recruitment frequently is challenging, especially when targeting elderly populations. Although several studies investigated specific recruitment barriers, there is little quantitative understanding of such barriers. We therefore determined associations between patient related and study-related factors and study inclusion in healthy elderly (>65 years) invited to participate in a double-blind placebo-controlled randomized study to determine effectiveness and safety of a 13-valent pneumococcal vaccine for community-acquired pneumonia in the Netherlands. Inclusions for this study took place between September 2008 and January 2010. The analysis was performed on replies to invitations sent between February 2009 and October 2009. In our analyses 260,700 replies from this period resulted in 48,982 candidates included in the study (18.8%). Study inclusion was associated with travel time to the vaccination site (decline of 0.6% per 4 min travel time, adjusted odds ratio (OR) 0.972, 95% CI 0.964-0.980), number of published advertorials in local newspapers (increase of 0.4% per consecutively placed advertorial, adjusted OR 1.030, 95% CI 1.026-1.035), age (decline of 0.7% per year, adjusted OR 0.953, 95% CI 0.951-0.955) and male gender (adjusted OR 0.588 versus female, 95% CI 0.576-0.599). Introduction letters sent on behalf of general practitioners prior to the actual invitation letter were not associated with study inclusion. Careful consideration of these parameters in study preparation may facilitate more successful patient recruitment in clinical trials in healthy elderly.