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.

Robust gelatin hydrogels for local sustained release of bupivacaine following spinal surgery.

Adequate treatment of pain arising from spinal surgery is a major clinical challenge. Opioids are the mainstay of current treatment methods, but the frequency and severity of their side effects display a clear need for opioid-free analgesia. Local anesthetics have been encapsulated into sustained-release drug delivery systems to provide postoperative pain relief. However, these formulations are limited by rapid diffusion out of the surgical site. To overcome this limitation, we synthesized ring-shaped hydrogels incorporating bupivacaine, designed to be co-implanted with pedicle screws during spinal surgery. Hydrogels were prepared by riboflavin-mediated crosslinking of gelatin functionalized with tyramine moieties. Additionally, oxidized ß-cyclodextrin was introduced into the hydrogel formulation to form dynamic bonds with tyramine functionalities, which enables self-healing behavior and resistance to shear. Feasibility of hydrogel implantation combined with pedicle screws was qualitatively assessed in cadaveric sheep as a model for instrumented spinal surgery. The in-situ crystallization of bupivacaine within the hydrogel matrix provided a moderate burst decrease and sustained release that exceeded 72 hours in vitro. The use of bupivacaine crystals decreased drug-induced cytotoxicity in vitro compared to bupivacaine HCl. Thus, the presented robust hydrogel formulation provides promising properties to enable the stationary release of non-opioid analgesics following spinal surgery. STATEMENT OF SIGNIFICANCE: Currently, postoperative pain following spinal surgery is mainly treated with opioids. However, the use of opioids is associated with several side effects including addiction. Here we developed robust and cytocompatible gelatin hydrogels, prepared via riboflavin-mediated photocrosslinking, that can withstand orthopedic implantation. The implantability was confirmed in cadaveric instrumented spinal surgery. Further, hydrogels were loaded with bupivacaine crystals to provide sustained release beyond 72 hours in vitro. The use of crystallized bupivacaine decreased cytotoxicity compared to bupivacaine HCl. The present formulation can aid in enabling opioid-free analgesia following instrumented spinal surgery.

Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain.

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A∂-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum. However, literature regarding sensory innervation of human bone is scarce. This observational study aimed to quantify sensory nerve fiber density in periosteum, cortical bone, and bone marrow of axial and appendicular human bones using immunohistochemistry and confocal microscopy. Multivariate Poisson regression analysis demonstrated that the total number of sensory and sympathetic nerve fibers was highest in periosteum, followed by bone marrow, and cortical bone for all bones studied. Bone from thoracic vertebral bodies contained most sensory nerve fibers, followed by the upper extremity, lower extremity, and parietal neurocranium. The number of nerve fibers declined with age and did not differ between male and female specimens. Sensory nerve fibers were organized as a branched network throughout the periosteum. The current results provide an explanation for the severe pain accompanying skeletal disease, fracture, or surgery. Further, the results could provide more insight into mechanisms that generate and maintain skeletal pain and might aid in developing new treatment strategies. PERSPECTIVE: This article presents the innervation of human bone and assesses the effect of age, gender, bone compartment and type of bone on innervation density. The presented data provide an explanation for the severity of bone pain arising from skeletal diseases and their surgical treatment.

A computationally simple central monitoring procedure, effectively applied to empirical trial data with known fraud.

OBJECTIVES: Central monitoring of multicenter clinical trials becomes an ever more feasible quality assurance tool, in particular for the detection of data fabrication. More widespread application, across both industry sponsored as well as academic clinical trials, requires central monitoring methodologies that are both effective and relatively simple in implementation. STUDY DESIGN AND SETTING: We describe a computationally simple fraud detection procedure intended to be applied repeatedly and (semi-)automatically to accumulating baseline data and to detect data fabrication in multicenter trials as early as possible. The procedure is based on anticipated characteristics of fabricated data. It consists of seven analyses, each of which flags approximately 10% of the centers. Centers that are flagged three or more times are considered "potentially fraudulent" and require additional investigation. The procedure is illustrated using empirical trial data with known fraud. RESULTS: In the illustration data, the fraudulent center is detected in most repeated applications to the accumulating trial data, while keeping the proportion of false-positive results at sufficiently low levels. CONCLUSION: The proposed procedure is computationally simple and appears to be effective in detecting center-level data fabrication. However, assessment of the procedure on independent trial data sets with known data fabrication is required.

Predicting enrollment performance of investigational centers in phase III multi-center clinical trials.

Failure to meet subject recruitment targets in clinical trials continues to be a widespread problem with potentially serious scientific, logistical, financial and ethical consequences. On the operational level, enrollment-related issues may be mitigated by careful site selection and by allocating monitoring or training resources proportionally to the anticipated risk of poor enrollment. Such procedures require estimates of the expected recruitment performance that are sufficiently reliable to allow centers to be sensibly categorized. In this study, we investigate whether information obtained from feasibility questionnaires can potentially be used to predict which centers will and which centers will not meet their enrollment targets by means of multivariable logistic regression analysis. From a large set of 59 candidate predictors, we determined the subset that is optimal for predictive purposes using Least Absolute Shrinkage and Selection Operator (LASSO) regularization. Although the extent to which the results are generalizable remains to be determined, they indicate that the prediction accuracy of the optimal model is only a marginal improvement over the intercept-only model, illustrating the difficulty of prediction in this setting.

Efficient Source Data Verification Using Statistical Acceptance Sampling: A Simulation Study.

BACKGROUND: One approach to increase the efficiency of clinical trial monitoring is to replace 100% source data verification (SDV) by verification of samples of source data. An intuitive strategy for determining appropriate sampling plans (ie, sample sizes and the maximum tolerable number of transcription errors in the samples) is to use acceptance sampling methodology. Expanding upon earlier work in which the use of acceptance sampling strategies for sampling-based SDV was proposed, we describe an alternative acceptance sampling strategy that, instead of relying on sampling standards, evaluates all possible sampling plans algorithmically, thereby ensuring that selected sampling plans conform to prespecified criteria. METHODS: Empirical trial data guided the design of the proposed strategy. In addition, extensive simulations, also based on the empirical data, were performed to assess the performance in terms of workload reductions and the post-SDV error proportion of applying the proposed strategy. RESULTS: 13 different scenarios were simulated, but results of the default scenario show that the average pre-SDV error proportion per trial of .056 was reduced to .023 by inspecting only 40.5% of the case report form entries. Of the inspected data entries, almost half (18.0/40.5) was, on average, SDV-ed as part of the sampling process; remaining entries were inspected during full inspections after too many errors were observed in the samples. CONCLUSION: Our results suggest that major reductions in workload can be achieved, while maintaining acceptable data quality levels. However, the results also indicate that the proposed strategy is conservative and further improvement is possible.

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.