The influence of contextual factors on healthcare quality improvement initiatives:what works, for whom and in what setting? Protocol for a realist review

Background  Context shapes the effectiveness of knowledge implementation and influences health improvement. Successful healthcare quality improvement (QI) initiatives frequently fail to transfer to different settings, with local contextual factors often cited as the cause. Understanding and overcoming contextual barriers is therefore crucial to implementing effective improvement; yet context is still poorly understood. There is a paucity of information on the mechanisms underlyinghowandwhyQI projects succeed or fail in given settings. A realist review of empirical studies of healthcare QI initiatives will be undertaken to examine the influence and impact of contextual factors on quality improvement in healthcare settings and explore whether QI initiatives can work in all contexts.  Methods  The review will explore which contextual factors are important, and how, why, when and for whom they are important, within varied settings. The dynamic nature of context and change over time will be explored by examining which aspects of context impact at key points in the improvement trajectory. The review will also consider the influence of context on improvement outcomes (provider- and patient-level), spread and sustainability. The review process will follow five iterative steps: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions and (5) disseminate findings. The reviewers will consult with experts and stakeholders in the early stages to focus the review and develop a programme theory consisting of explanatory ‘context–mechanism–outcome’ configurations. Searches for primary evidence will be conducted iteratively. Data will be extracted and tested against the programme theory. A review advisory group will oversee the review process. Review findings will follow RAMESES guidelines and will be disseminated via a report, presentations and peer-reviewed publications.  Discussion  The review will update and consolidate evidence on the contextual conditions for effective improvement and distil new knowledge to inform the design and development of context-sensitive QI initiatives. This review ties in with the study of improvement programmes as vehicles of change and the development of an evidence base around healthcare improvement by addressing whether QI initiatives can work in all contexts.  Systematic review registration  PROSPERO CRD4201706213

Post-reconstruction dermatitis of the breast

BackgroundApproximately one-third of women diagnosed with breast cancer undergo mastectomy with subsequent implant-based or autogenous tissue-based reconstruction. Potential complications include infection, capsular contracture, and leak or rupture of implants with necessity for explantation. Skin rashes are infrequently described complications of patients who undergo mastectomy with or without reconstruction.MethodsA retrospective analysis of breast cancer patients referred to the Dermatology Service for diagnosis and management of a rash post-mastectomy and expander or implant placement or transverse rectus abdominis myocutaneous (TRAM) flap reconstruction was performed. Parameters studied included reconstruction types, time to onset, clinical presentation, associated symptoms, results of microbiologic studies, management, and outcome.ResultsWe describe 21 patients who developed a rash on the skin overlying a breast reconstruction. Average time to onset was 25.7 months after expander placement or TRAM flap reconstruction. Clinical presentations included macules and papules or scaly, erythematous patches and plaques. Five patients had cultures of the rash, which were all negative. Skin biopsy was relatively contraindicated in areas of skin tension, and was reserved for non-responding eruptions. Treatments included topical corticosteroids and topical antibiotics, which resulted in complete or partial responses in all patients with documented follow-ups.ConclusionOur findings suggest that tension and post-surgical factors play a causal role in this hitherto undescribed entity: "post-reconstruction dermatitis of the breast." This is a manageable condition that develops weeks to years following breast reconstruction. Topical corticosteroids and antibiotics result in restoration of skin barrier integrity and decreased secondary infection

Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials

Tong J Gan,1 Neil Singla,2 Stephen E Daniels,3 Douglas A Hamilton,4,5 Peter G Lacouture,6,7 Christian RD Reyes,8 Daniel B Carr4,9 1Department of Anesthesiology, Stony Brook University, NY, 2Lotus Clinical Research, LLC, Pasadena, CA, 3Premier Research, Austin, TX, 4Javelin Pharmaceuticals, Inc., Cambridge, MA, 5New Biology Ventures, LLC, San Mateo, CA, 6Magidom Discovery, LLC, St Augustine, FL, 7Department of Emergency Medicine, Brown University School of Medicine, Providence, RI, 8Hospira Inc., Lake Forest, IL, 9Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA Purpose: Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac. Patients and methods: Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose. Results: Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPβCD-diclofenac versus placebo for the 0–24 through 0–120 hour time periods (P<0.0001), as well as versus ketorolac for the 0–72 through 0–120 hour time periods (P<0.05). HPβCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0–24 hour period onward. When compared to ketorolac, HPβCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0–72 through 0–120 hours) and opioid dose number among patients ≥65 years old (0–24 through 0–120 hours). Conclusion: HPβCD-diclofenac can reduce postoperative opioid requirements. As this analysis was not powered to compare opioid-related adverse event rates, follow-up studies examining the clinical impact of HPβCD-diclofenac’s opioid sparing are warranted. Keywords: postoperative pain, nonsteroidal anti-inflammatory drugs, nonopioid analgesics, multimodal analgesia, diclofenac, cyclodextri

A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-β-cyclodextrin

Ronald Goldwater,1 William G Kramer,2 Douglas A Hamilton,3,4 Eric Lang,4,5 Jianyuan Wang,4 Donna E Madden,4 Peter G Lacouture,6,7 Atulkumar Ramaiya,8 Daniel B Carr4,9 1PAREXEL International, Baltimore, MD, 2Kramer Consulting, LLC, North Potomac, MD, 3New Biology Ventures, LLC, San Mateo, CA, 4Javelin Pharmaceuticals, Cambridge, MA (now Hospira, a Pfizer company, Lake Forest, IL, USA), 5Covance, Princeton, NJ, 6Magidom Discovery, LLC, Lindenhurst, IL, 7Brown University School of Medicine, Providence, RI, 8Global Medical Affairs, Hospira, a Pfizer company, Lake Forest, IL, 9Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA Purpose: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac is an injectable formulation of diclofenac solubilized with HPβCD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HPβCD-diclofenac. Methods: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55–82 years old stratified into three groups and receiving HPβCD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HPβCD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects. Results: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age- and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t1/2), likely due to a decrease in the volume of distribution (Vz) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation. Conclusion: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HPβCD-diclofenac but indicates that diclofenac CL increases with increasing body weight. Keywords: analgesia, pain control, pharmacokinetics, obesity, elderly, NSAI