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To identify patient factors associated with improved pain scores, functional hip scores, health-related quality of life, and re-operation rates after arthroscopic management of femoroacetabular impingement (FAI). Using the comprehensive dataset from the multinational Femoroacetabular Impingement Randomized Controlled Trial (FIRST), a total of 13 prognostic factors that were chosen a priori were identified that would be expected to predict post-surgical outcomes. The primary outcome was pain assessed using a Visual Analogue Scale (VAS) and secondary outcomes included hip function (Hip Outcome Score [HOS] and International Hip Outcome Tool [iHOT-12]), health-related quality of life (Short Form-12 [SF-12] and Euro-Qol 5 Dimensions [EQ-5D]), and re-operation rate. A multivariable linear regression was used to analyse the change questionnaire scores from baseline to 12 months post-surgery including all 13 prognostic factors as independent variables. A total of 27 re-operation events were analysed at 24 months using a multivariable logistic regression including only the treatment group variable. Of the 154 patients that had VAS scores completed at 12 months, a lower BMI (adjusted mean difference [aMD], 4.48 for a 5-unit decrease in BMI; 95% confidence interval [CI] 0.33–8.63; p = 0.035) was significantly associated with less pain. There was a significant negative association between increasing age and 1-year EQ-5D scores (aMD, − 0.04 for every 10-year increase in age; 95% CI − 0.07 to − 0.006; p = 0.020). The degree of impingement, severity of osteoarthritis, type of procedure, and adjudicated quality of surgery were not significantly associated with improvement across all outcomes at 12 months. Furthermore, there was no significant association between the treatment variable and the incidence of re-operation at 24 months. This study identified that lower BMI and age are predictive of improved pain and health utility scores, respectively, following arthroscopic management of FAI at 12 months post-surgery. These results may be a helpful adjunct in clinical decisions for this patient population when determining candidacy for surgical intervention. I.

To understand the early outcomes after hip arthroscopy and better define the trajectory of improvement in a prospective cohort of patients who have undergone hip arthroscopic osteochondroplasty for femoroacetabular impingement (FAI) syndrome. Data were analyzed from the Femoroacetabular Impingement RandomiSed controlled Trial (FIRST) on the 108 study patients who underwent osteochondroplasty, with or without labral repair. Study outcomes included patient-reported pain (using a 100-point Visual Analogue Scale (VAS)), hip function (using the Hip Outcome Score (HOS) and International Hip Outcome Tool (iHOT-12)), and health-related quality of life (using the EuroQol 5 Dimensions (EQ-5D)) measured at baseline, 2 weeks, 3 months, 6 months, and 12 months post-operatively. There was a decrease in mean post-operative pain VAS scores from baseline. The first 2 weeks post-operative yielded the greatest reduction in pain with a mean (SD) VAS score of 37.8 (23.4), with score stabilization between 6 months (26.9 (26.9)) and 12 months (25.3 (27.6)). Mean HOS (activities of daily living) scores improved from baseline (59.7 (16.2)) starting at 6 weeks post-operative (64.1 (19.1)). The HOS (Sports) showed no improvement from baseline (41.2 (20.4)) until 3 months (49.1 (27.9)), and continued to improve at 6 months (64.1 (28.7)) and 12 months (68.6 (30.5)). The iHOT-12 scores showed functional improvement from baseline (31.3 (18.8)), as early as 6 weeks (44.9 (22.4)) up to and including 12 months (67.1 (29.7)). EQ-5D index scores showed modest steady improvement from 6 weeks to 12 months post-operative, while the EQ-5D VAS component similarly showed modest and steady improvements from 3 months onward. Results from this study highlight that hip arthroscopic osteochondroplasty with or without labral repair for FAI leads to early pain relief. While all scores improved from baseline, functional gains appear to plateau from 6 months onwards. These data can be used to inform decision-making about timelines for rehabilitation and return to sport, a knowledge gap in the current FAI literature. II.

Aims Using tibial shaft fracture participants from a large, multicentre randomized controlled trial, we investigated if patient and surgical factors were associated with health-related quality of life (HRQoL) at one year post-surgery. Methods The Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) trial examined adults with an open or closed tibial shaft fracture who were treated with either reamed or unreamed intramedullary nails. HRQoL was assessed at hospital discharge (for pre-injury level) and at 12 months post-fracture using the Short Musculoskeletal Functional Assessment (SMFA) Dysfunction, SMFA Bother, 36-Item Short Form 36 (SF-36) Physical, and SF-36 Mental Component scores. We used multiple linear regression analysis to determine if baseline and surgical factors, as well as post-intervention procedures within one year of fracture, were associated with these HRQoL outcomes. Significance was set at p < 0.01. We hypothesize that, irrespective of the four measures used, prognosis is guided by both modifiable and non-modifiable factors and that patients do not return to their pre-injury level of function, nor HRQoL. Results For patient and surgical factors, only pre-injury quality of life and isolated fracture showed a statistical effect on all four HRQoL outcomes, while high-energy injury mechanism, smoking, and race or ethnicity, demonstrated statistical significance for three of the four HRQoL outcomes. Patients who did not require reoperation in response to infection, the need for bone grafts, and/or the need for implant exchanges had statistically superior HRQoL outcomes than those who did require intervention within one year after initial tibial fracture nailing. Conclusion We identified several baseline patient factors, surgical factors, and post-intervention procedures within one year after intramedullary nailing of a tibial shaft fracture that may influence a patient’s HRQoL. Cite this article: Bone Jt Open 2021;2(1):22–32.

Objectives To determine if the Radiographic Union Score for Hip (RUSH) measured at 3 and 6 months after femoral neck fracture were predictive of reoperation for infection, nonunion, delayed union, avascular necrosis, or implant failure within 24 months of initial surgery. Design Secondary analysis of a randomized controlled trial. Logistic regression was performed to investigate associations between lower RUSH and reoperation. Results were reported as odds ratios (OR), 95% confidence intervals (CIs), and associated P values. All tests were 2 tailed with alpha = 0.05. Setting Eighty-one clinical sites across 8 countries. Patients/participants Data from 734 of the clinical trial participants with radiographs at 3 and 6 months after fracture fixation were included. Intervention A reviewer blinded to patients' outcomes independently assigned a RUSH at each follow-up time point. Main outcome measures Revision surgery rate related to intervention. Results Lower RUSH at 3 and 6 months were associated with increased odds of reoperation within 24 months of fracture fixation. For every 2-point decrease in RUSH at 3 months, there was a 16% increase in the odds of a patient experiencing a re-operation (OR, 1.16; 95% CI, 1.10-1.22; P Conclusions Decreased radiographic healing as early as 3 months post fracture fixation is associated with developing patient important femoral neck fracture reoperations. This relationship may guide early treatment decisions, suggesting that 3- and 6-month RUSH are a useful surrogate measure of reoperations within 24 months of fracture fixation. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background: Physical therapy initiated early in an ICU stay may reduce functional deficits in critically ill patients; however, the association of frailty with outcomes in those receiving early in-ICU rehabilitation is unknown. Objective: To estimate the association between frailty and 3 outcomes in patients enrolled in an ICU randomized clinical trial (RCT). Design: Exploratory secondary analyses of the CYCLE pilot RCT (NCT02377830). Setting: 7 Canadian ICUs. Participants: Previously ambulatory critically ill adults. Intervention: Participants were randomized to early in-bed cycling plus routine physiotherapy versus early routine physiotherapy alone. Measurements: Using regression analyses, we modelled the association between pre-hospital Clinical Frailty Scale (CFS) scores, Physical Function in ICU Test-scored (PFIT-s), muscle strength, and mortality at hospital discharge, adjusting for illness severity (APACHE II) and the randomized intervention. We explored the influence of imputing mean PFIT-s and strength scores for decedents, and with listwise deletion of decedents in a sensitivity analysis. Results: Of 66 patients, 2 had missing data, 2 had incomplete data, and 21 died by hospital discharge. At hospital discharge for 66 patients, frailty was not associated with PFIT-s (mean difference (MD) [95% CI]=0.20, [-2.08, 2.74]) or muscle strength (1.96, [-12.6, 16.6]). A sensitivity analysis yielded consistent results. Frailty was also not associated with hospital mortality (odds ratio 0.91, [0.28 to 2.93]). Conclusion: We found no association between pre-hospital frailty, physical function, strength, or mortality at hospital discharge in critically ill patients enrolled in an early rehabilitation trial. Larger sample sizes are needed to further explore the association of frailty with these outcomes at hospital discharge.

IMPORTANCE: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. OBJECTIVE: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). DESIGN, SETTING, AND PARTICIPANTS: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). INTERVENTIONS: Enteral L rhamnosus GG (1 × 10(10) colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. MAIN OUTCOMES AND MEASURES: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. RESULTS: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P

Background Femoral neck fractures in patients ≤ 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial. Methods We will conduct a multicenter, concealed randomized controlled pilot study, using a 2 × 2 factorial design in 60 patients aged 18–60 years with a femoral neck fracture. Eligible patients will be randomized in equal proportions to one of four groups: 1) SHS and vitamin D supplementation (4000 international units (IU) daily dose) for 6 months, 2) cancellous screws and vitamin D supplementation (4000 IU daily dose) for 6 months, 3) SHS and placebo, and 4) cancellous screws and placebo. Participants will be followed for 12 months post-fracture. Feasibility outcomes include initiation of clinical sites, recruitment, follow-up, data quality, and protocol adherence. Clinical outcomes, for both the pilot and planned definitive trials, include a composite of patient-important outcomes (re-operation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion), health-related quality of life and patient-reported function, fracture healing complications, and radiographic fracture healing. A priori success criteria have been established. If the pilot study is deemed successful, study participants will be included in the definitive trial and clinical outcomes for the pilot will not be analyzed. If the pilot study is not deemed successful, clinical outcome data will be analyzed. Discussion Results of this study will inform the feasibility of a definitive trial. If clinical outcome data are analyzed, they will be disseminated through a publication and presentations. Trial registration The FAITH-2 trial, described as a definitive trial, was registered at ClinicalTrials.gov (NCT01908751) prior to enrollment of the first participant. Electronic supplementary material The online version of this article (10.1186/s40814-019-0458-x) contains supplementary material, which is available to authorized users.

BackgroundLimb salvage with endoprosthetic reconstruction is the current standard practice for the surgical management of lower extremity bone tumors in skeletally mature patients and typically includes tumor resection followed by the functional limb reconstruction with modular metallic and polyethylene endoprosthetic implants. However, owing to the complexity and length of these procedures, as well as the immunocompromised nature of patients treated with chemotherapy, the risk of surgical site infection (SSI) is high. The primary research objective of the Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY) trial is to assess whether a 5-day regimen of post-operative antibiotics decreases the risk of SSI at 1 year post-operatively compared to a 1-day regimen. This article describes the statistical analysis plan for the PARITY trial.Methods/designThe PARITY trial is an ongoing multi-center, blinded parallel two-arm randomized controlled trial (RCT) of 600 participants who have been diagnosed with a primary bone tumor, a soft tissue sarcoma that has invaded the bone or oligometastatic bone disease of the femur or tibia that requires surgical resection and endoprosthetic reconstruction. This article describes the overall analysis principles, including how participants will be included in each analysis, the presentation of results, adjustments for covariates, the primary and secondary outcomes, and their respective analyses. Additionally, we will present the planned sensitivity and sub-group analyses.DiscussionOur prior work has demonstrated (1) high rates of SSI after the treatment of lower extremity tumors by surgical excision and endoprosthetic reconstruction, (2) highly varied opinion and practice among orthopedic oncologists with respect to prophylactic antibiotic regimens, (3) an absence of applicable RCT evidence, (4) extensive support from international investigators to participate in a RCT, and (5) the feasibility of conducting a definitive RCT to evaluate a 5-day regimen of post-operative antibiotics in comparison with a 1-day regimen.Trial registrationClinicalTrials.govNCT01479283. Registered on 24 November 2011

Purpose To determine whether arthroscopic osteochondroplasty demonstrated effectiveness in a pragmatic femoroacetabular impingement patient population embedded within FIRST (the Femoroacetabular Impingement RandomiSed controlled Trial). Methods All cohort patients were not randomized and were followed prospectively with a follow-up assessment protocol identical to that in FIRST. The primary outcome was hip pain using a 100-point visual analog scale. Secondary outcomes included hip function (Hip Outcome Score, International Hip Outcome Tool-12), health utility (EuroQol 5 Dimensions), and health-related quality of life (Short Form-12) at 12 months, as well as operatively and nonoperatively treated hip complications at 24 months. We performed multivariable regressions to compare these outcomes between 3 groups of patients: (1) those randomized to lavage in FIRST, (2) those randomized to osteochondroplasty in FIRST, and (3) those who received osteochondroplasty as part of the cohort study. Results All groups had improvements across all questionnaire outcomes from baseline to 12 months, with no significant differences. There were significantly more reoperations in the lavage trial group compared with those in the embedded cohort (adjusted odds ratio [aOR] 3.08; 95% confidence interval [CI] 1.23-7.73; P = .016). There were significantly more nonoperatively treated hip complications in the lavage trial group and in the osteochondroplasty trial group when compared with those in the embedded cohort (aOR 3.81; 95% CI 1.19-12.17; P = .024 and aOR 4.55; 95% CI 1.43-14.42; P = .010, respectively). Conclusions Hip arthroscopic osteochondroplasty and lavage led to improvement in hip pain, function, and health-related quality of life at 12 months across both randomized controlled trial (RCT) and cohort patients. The pragmatic cohort receiving osteochondroplasty had (1) significantly fewer complications than RCT patients, (2) significantly less reoperations than RCT patients randomized to arthroscopic lavage, and (3) fewer, although nonsignificant, reoperations than RCT osteochondroplasty patients. Level of Evidence II, therapeutic.

Background:Femoroacetabular impingement (FAI) is a condition known to cause hip pain in young adults.Purpose:To evaluate the efficacy of the surgical correction of FAI via arthroscopic osteochondroplasty with or without labral repair compared with arthroscopic lavage of the hip joint with or without labral repair.Study Design:Randomized controlled trial; Level of evidence, 1.Methods:A total of 220 male and female participants aged 18 to 50 years with nonarthritic FAI suitable for surgical treatment were recruited for the trial at 10 clinical centers in Canada, Finland, and Denmark between October 2012 and November 2017, of whom 214 were included in the final analysis. In the osteochondroplasty group, cam- and/or pincer-type lesions were resected using fluoroscopic guidance. In the lavage group, the joint was washed out with 3 L of normal saline. Surgeons were instructed to repair the labrum in both groups if it was mechanically unstable once probed, showing visible displacement or chondrolabral separation. The primary outcome was patient-reported pain (using the 100-point visual analog scale [VAS]) at 12 months. Secondary outcomes included hip function (Hip Outcome Score [HOS] and International Hip Outcome Tool), physical and mental health (12-Item Short Form Health Survey), and health utility (EuroQol–5 Dimensions) at 12 months as well as any reoperations and other hip-related adverse events at 24 months.Results:At 12 months, there was no difference in pain (VAS) between the groups (mean difference [MD], 0.11 [95% CI, –7.22 to 7.45]; P = .98). Also, 88.3% (189/214) of participants had a labral tear, of which 60.3% were repaired. For the secondary outcomes, there were no significant differences between treatment groups, with the exception of the HOS activities of daily living domain in which lavage showed significant improvement compared with osteochondroplasty (MD, –5.03 [95% CI, −10.40 to −0.03]; P = .049). By 24 months, there were significantly fewer reoperations reported in the osteochondroplasty group (8/105) than the lavage group (19/104) (odds ratio, 0.37 [95% CI, 0.15-0.89]; P = .026). The primary reasons for a reoperation included hip pain (15/27; 55.6%) and a reinjury of the labrum (11/27; 40.7%).Conclusion:Both the osteochondroplasty and the lavage groups with or without labral repair for FAI had significantly improved pain or function significantly at 1 year. By 2 years, the reoperation rate was significantly lower in the osteochondroplasty group.Registration:NCT01623843 ( ClinicalTrials.gov identifier)

Objective To assess whether the fixation method and vitamin D supplementation affect the risk of patient-important outcomes within 12 months of injury in nongeriatric femoral neck fracture patients. Design A pilot factorial randomized controlled trial. Setting Fifteen North American clinical sites. Participants Ninety-one adults 18-60 years of age with a femoral neck fracture requiring surgical fixation. Intervention Participants were randomized to a surgical intervention (sliding hip screw or cancellous screws) and a vitamin D intervention (vitamin D3 4000 IU daily vs. placebo for 6 months). Main outcome measurements The primary clinical outcome was a composite of patient-important complications (reoperation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion). Secondary outcomes included fracture-healing complications and radiographic fracture healing. Results Eighty-six participants with a mean age of 41 years were included. We found no statistically significant difference in the risk of patient-important outcomes between the surgical treatment arms (hazard ratio 0.90, 95% confidence interval 0.40-2.02, P = 0.80) and vitamin D supplementation treatment arms (hazard ratio 0.96, 95% confidence interval 0.42-2.18, P = 0.92). Conclusions These pilot trial results continue to describe the results of current fixation implants, inform the challenges of improving outcomes in this fracture population, and may guide future vitamin D trials to improve healing outcomes in young fracture populations. Although the pilot trial was not adequately powered to detect treatment effects, publishing these results may facilitate future meta-analyses on this topic. Level of evidence Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Objectives Nonunions of tibial shaft fractures have profound implications on patient quality of life and are associated with physical and mental suffering. Radiographic Union Score for Tibia Fractures (RUST) may serve as an important prognostic tool for identifying patients at a high risk of nonunion. Design We used data from the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) and Fluid Lavage of Open Wounds (FLOW) trials to explore the association of three-month RUST scores with nonunion in patients with tibial shaft fractures treated with intramedullary nailing. We performed a retrospective cohort study nested within two multi-center, randomized controlled trials. Participants The patients included in the current study: (1) sustained a tibial shaft fracture and were enrolled in the SPRINT or FLOW randomized trials, (2) had initial operative management with intramedullary nailing, (3) showed radiographic evidence of an unhealed fracture at the three-month follow-up, and (4) their healing status (union or nonunion) was captured at 12-months postoperatively. Intervention Multivariable binary logistic regression was carried out to identify factors associated with nonunion, including open versus closed injury, fracture severity, fracture gap, and three-month RUST score. We determined the concordance statistic (c statistic) for our regression model both with and without the RUST score. Outcome Measurements and Results Of the 155 tibial fracture patients with complete data available for analysis, the overall rate of nonunion at 12 months was 30% (n=47). The mean three-month RUST score in patients with nonunion at 12 months was 4.8 (standard deviation (SD) 1.1) as compared to 6.3 (SD 1.7) for those healed at 12 months. In our multivariable regression analysis, open fractures conferred five-fold greater odds of nonunion at 12 months as compared to closed fractures (odds ratio (OR) 4.76, 95% confidence interval (CI):1.71-13.30). Further, three-month RUST scores of 4 and 5-6 were associated with a 47% (95% CI: 18%-73%) and 23% (4.5-51.5%) absolute risk increase of nonunion as compared to a score of ≥ 7, respectively. The addition of RUST scores to our adjusted regression model improved the c statistic from 0.70 (95%CI: 0.61-0.79) to 0.81 (95%CI: 0.74-0.88). Conclusion A third of patients with tibial shaft fractures who have failed to heal by three months will show nonunion at one year. Open fractures and lower three-month RUST scores are strongly associated with a higher risk of nonunion at one year. Further research is needed to establish whether prognosis in this high-risk group can be modified.

Objectives: To conduct a pilot trial for the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) protocol to assess feasibility of a definitive trial. Design: Pilot trial. Setting: Twenty-five clinical sites across North America and Australia were initiated, but enrolment occurred in only 15 North American sites. Patients/Participants: Ninety-one randomized adults aged 18 to 60 years with a femoral neck fracture requiring surgical fixation. Intervention: Eligible patients were randomized to receive surgical treatment (sliding hip screw or cancellous screws) AND nutritional supplementation (4000 IU of vitamin D or placebo) for 6 months postfracture. Main Outcome Measurements: Feasibility outcomes included: clinical site initiation, participant enrolment rate, proportion of participants with complete 12-month follow-up, level of data quality, and rate of protocol adherence (number of randomization errors, crossovers between treatment groups, and daily supplementation adherence). Results: Eighty-six of 91 participants randomized into the pilot trial from 15 North American hospitals were deemed eligible. Four of five primary feasibility criteria were not achieved as we were unable to initiate clinical sites outside of North America and Australia due to feasibility constraints, slow participant enrolment (60 participants recruited over 36 mo), low adherence with daily nutritional supplementation at the 6-week (72.1%), 3-month (60.5%), and 6-month (54.7%) follow-up visits, and a high loss to follow-up rate of 22.1% at 12 months. Conclusions: Despite not meeting key feasibility criteria, we increased our knowledge on the logistics and anticipated barriers when conducting vitamin D supplementation trials in this trauma population, which can be used to inform the design and conduct of future trials on this topic.

Background Nonunions of tibial shaft fractures have devastating physical and psychological consequences for patients. It remains unknown if early functional status can identify patients at risk for nonunion. Questions/Purposes To determine if functional status at three months after surgery, as measured by either the short form 36 (SF-36) or the short form 12 (SF-12) health survey physical component summary (SF-12 PCS) score, can serve as a prognostic indicator for nonunion at one year in patients with fractures of the tibial shaft. Patients/Methods This study was an observational cohort study nested within two multicenter, randomized controlled trials. Patients who met the following eligibility criteria were included: (1) sustained a tibial shaft fracture that was treated with intramedullary nailing, (2) were unhealed at the three-month follow-up, (3) had a reported SF-36 or SF-12 PCS score at three months, (4) had the final 12-month follow-up with a reported radiographic healing status (bone union or nonunion), and (5) were enrolled in either the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Shaft Fractures (SPRINT) or Fluid Lavage of Open Wounds (FLOW) randomized trials. Multivariable logistic regression was performed to evaluate the association between healing status at 12 months and seven prognostic variables (open fracture, fracture pattern, nailing technique, smoking, fracture gap, three-month PCS score, and FLOW vs. SPRINT trial). Results A total of 940 patients were included in this study with an overall rate of radiographic nonunion of 13.3% (n=125) at the 12-month follow-up. Absolute nonunion risk increased with incrementally lower PCS scores (8.2%, 12.8%, 15.9%, 23.7% for scores ≥ 40, 30.0-39.99, 20.0-29.99, and < 20, respectively). In the multivariable regression analysis, PCS scores of < 20 were associated with a 2.6-times greater odds and 10% absolute risk increase of non-union, as compared to scores of ≥ 40 (OR 2.58, 95%CI: 1.02-6.53, ARI: 10.3, 95% CI: 0.1 - 28.2), whereas scores between 20 and 30 were associated with a nearly two-times greater odds of nonunion and a 6.4% absolute risk increase of nonunion (OR 1.94, 95%CI: 1.08-3.49, ARI: 6.4, 95% CI 0.6 - 15.3). Open fractures also conferred a 2.8-fold increase in odds of nonunion as compared to closed injuries (OR 2.77, 95%CI: 1.58-4.83), as did complex fractures when compared to simple fractures (OR 2.57, 95%CI: 1.64-4.02). Conclusion A considerable portion of patients with fractures of the tibial shaft treated with intramedullary nailing will experience nonunion at one-year postoperatively. Nonunion can be accurately predicted by patient functional recovery at three months as measured by the PCS of the SF-36 and SF-12 instruments.

© 2019 Lippincott Williams and Wilkins. All rights reserved. Objectives:The FAITH trial evaluated effects of sliding hip screws versus cancellous screws in femoral neck fracture patients. Using FAITH trial data, we quantified changes in living status, use of AIDS, and investigated factors associated with living and walking independently 12 months after fracture.Methods:We conducted a descriptive analysis to quantify patients' changes in living status, use of AIDS, and used multivariable Cox regression analyses to determine factors associated with living and walking independently after fracture.Results:Of patients who lived independently before hip fracture, 3.07% (50-80 years old) and 19.81% (>80 years old) were institutionalized 12 months after injury. Of patients who were walking independently before injury, 33.62% (50-80 years old) and 69.34% (>80 years old) required a walking aid 12 months after injury. Factors associated with higher chances of living independently included the following: Being between 50 and 80 years, having a class I American Society of Anesthesiologists classification, not using a walking aid before fracture, being a nonsmoker or former smoker, and having an acceptable quality of implant placement. Factors associated with higher chances of walking without an aid included the following: Being between 50 and 80 years, having a class I American Society of Anesthesiologists classification, living independently before fracture, being a nonsmoker or former smoker, having an undisplaced fracture, and not requiring revision surgery.Conclusions:Femoral neck fracture patients suffer great losses of independence. Identifying factors associated with living and walking independently after hip fracture may help surgeons better identify which patients are at risk and optimize care of patients with this injury.Level of Evidence:Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Importance The risk of developing a surgical site infection after extremity fracture repair is nearly 5 times greater than in most elective orthopedic surgical procedures. For all surgical procedures, it is standard practice to prepare the operative site with an antiseptic solution; however, there is limited evidence to guide the choice of solution used for orthopedic fracture repair. Objective To compare the effectiveness of iodophor vs chlorhexidine solutions to reduce surgical site infections and unplanned fracture-related reoperations for patients who underwent fracture repair. Design, Setting, and Participants The PREP-IT (Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma) master protocol will be followed to conduct 2 multicenter pragmatic cluster randomized crossover trials, Aqueous-PREP (Pragmatic Randomized Trial Evaluating Pre-Operative Aqueous Antiseptic Skin Solution in Open Fractures) and PREPARE (Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities). The Aqueous-PREP trial will compare 4% aqueous chlorhexidine vs 10% povidone-iodine for patients with open extremity fractures. The PREPARE trial will compare 2% chlorhexidine in 70% isopropyl alcohol vs 0.7% iodine povacrylex in 74% isopropyl alcohol for patients with open extremity fractures and patients with closed lower extremity or pelvic fractures. Both trials will share key aspects of study design and trial infrastructure. The studies will follow a pragmatic cluster randomized crossover design with alternating treatment periods of approximately 2 months. The primary outcome will be surgical site infection and the secondary outcome will be unplanned fracture-related reoperations within 12 months. The Aqueous-PREP trial will enroll a minimum of 1540 patients with open extremity fractures from at least 12 hospitals; PREPARE will enroll a minimum of 1540 patients with open extremity fractures and 6280 patients with closed lower extremity and pelvic fractures from at least 18 hospitals. The primary analyses will adhere to the intention-to-treat principle and account for potential between-cluster and between-period variability. The patient-centered design, implementation, and dissemination of results are guided by a multidisciplinary team that includes 3 patients and other relevant stakeholders. Discussion The PREP-IT master protocol increases efficiency through shared trial infrastructure and study design components. Because prophylactic skin antisepsis is used prior to all surgical procedures and the application, cost, and availability of all study solutions are similar, the results of the PREP-IT trials are poised to inform clinical guidelines and bring about an immediate change in clinical practice. Trial Registration ClinicalTrials.gov Identifiers:NCT03385304andNCT03523962

Aims The Fluid Lavage in Open Fracture Wounds (FLOW) trial was a multicentre, blinded, randomized controlled trial that used a 2 × 3 factorial design to evaluate the effect of irrigation solution (soap versus normal saline) and irrigation pressure (very low versus low versus high) on health-related quality of life (HRQL) in patients with open fractures. In this study, we used this dataset to ascertain whether these factors affect whether HRQL returns to pre-injury levels at 12-months post-injury. Patients and Methods Participants completed the Short Form-12 (SF-12) and the EuroQol-5 Dimensions (EQ-5D) at baseline (pre-injury recall), at two and six weeks, and at three, six, nine and 12-months post-fracture. We calculated the Physical Component Score (PCS) and the Mental Component Score (MCS) of the SF-12 and the EQ-5D utility score, conducted an analysis using a multi-level generalized linear model, and compared differences between the baseline and 12-month scores. Results We found no clinically important differences between irrigating solutions or pressures for the SF-12 PCS, SF-12 MCS and EQ-5D. Irrespective of treatment, participants had not returned to their pre-injury function at 12-months for any of the three outcomes (p < 0.001). Conclusion Neither the composition of the irrigation solution nor irrigation pressure applied had an effect on HRQL. Irrespective of treatment, patients had not returned to their pre-injury HRQL at 12 months post-fracture. Cite this article: Bone Joint J 2018;100-B:88–94.

Introduction There is concern about excessive bleeding when low-molecular-weight heparins (LMWHs) are used for venous thromboembolism (VTE) prophylaxis in renal dysfunction. Our objective was to evaluate whether LMWH VTE prophylaxis was safe and effective in critically ill patients with renal dysfunction by conducting a subgroup analysis of PROTECT, a randomized blinded trial. Methods We studied intensive care unit (ICU) patients with pre-ICU dialysis-dependent end-stage renal disease (ESRD; pre-specified subgroup; n = 118), or severe renal dysfunction at ICU admission (defined as ESRD or non-dialysis dependent with creatinine clearance [CrCl]

Open tibial shaft fractures are one of the most devastating orthopaedic injuries. Surgical treatment options include reamed or unreamed nailing, plating, Ender nails, Ilizarov fixation, and external fixation. Using a network meta-analysis allows comparison and facilitates pooling of a diverse population of randomized trials across these approaches in ways that a traditional meta-analysis does not.Our aim was to perform a network meta-analysis using evidence from randomized trials on the relative effect of alternative approaches on the risk of unplanned reoperation after open fractures of the tibial diaphysis. Our secondary study endpoints included malunion, deep infection, and superficial infection.A network meta-analysis allows for simultaneous consideration of the relative effectiveness of multiple treatment alternatives. To do this on the subject of surgical treatments for open tibial fractures, we began with systematic searches of databases (including EMBASE and MEDLINE) and performed hand searches of orthopaedic journals, bibliographies, abstracts from orthopaedic conferences, and orthopaedic textbooks, for all relevant material published between 1980 and 2013. Two authors independently screened abstracts and manuscripts and extracted the data, three evaluated the risk of bias in individual studies, and two applied Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria to bodies of evidence. We included all randomized and quasirandomized trials comparing two (or more) surgical treatment options for open tibial shaft fractures in predominantly (ie, 80%) adult patients. We calculated pooled estimates for all direct comparisons and conducted a network meta-analysis combining direct and indirect evidence for all 15 comparisons between six stabilization strategies. Fourteen trials published between 1989 and November 2011 met our inclusion criteria; the trials comprised a total of 1279 patients surgically treated for open tibial shaft fractures.Moderate confidence evidence showed that unreamed nailing may reduce the likelihood of reoperation compared with external fixation (network odds ratio [OR], 0.38; 95% CI, 0.23-0.62; p 0.05), although not necessarily compared with reamed nailing (direct OR, 0.74; 95% CI, 0.45-1.24; p = 0.25). Only low- or very low-quality evidence informed the primary outcome for other treatment comparisons, such as those involving internal plate fixation, Ilizarov external fixation, and Ender nailing. Method ranking based on reoperation data showed that unreamed nailing had the highest probability of being the best treatment, followed by reamed nailing, external fixation, and plate fixation. CIs around pooled estimates of malunion and infection risk were very wide, and therefore no conclusive results could be made based on these data.Current evidence suggests that intramedullary nailing may be superior to other fixation strategies for open tibial shaft fractures. Use of unreamed nails over reamed nails also may be advantageous in the setting of open fractures, but this remains to be confirmed. Unfortunately, these conclusions are based on trials that have had high risk of bias and poor precision. Larger and higher-quality head-to-head randomized controlled trials are required to confirm these conclusions and better inform clinical decision-making.Level I, therapeutic study.

Fluid resuscitation, along with the early administration of antibiotics, is the cornerstone of treatment for patients with sepsis. However, whether differences in resuscitation fluids impact on the requirements for renal replacement therapy (RRT) remains unclear. To examine this issue, we performed a network meta-analysis (NMA), including direct and indirect comparisons, that addressed the effect of different resuscitation fluids on the use of RRT in patients with sepsis. The data sources MEDLINE, EMBASE, ACPJC, CINAHL and Cochrane Central Register were searched up to March 2014. Eligible studies included randomized trials reported in any language that enrolled adult patients with sepsis or septic shock and addressed the use of RRT associated with alternative resuscitation fluids. The risk of bias for individual studies and the overall certainty of the evidence were assessed. Ten studies (6664 patients) that included a total of nine direct comparisons were assessed. NMA at the four-node level showed that an increased risk of receiving RRT was associated with fluid resuscitation with starch versus crystalloid [odds ratio (OR) 1.39, 95% credibility interval (CrI) 1.17-1.66, high certainty]. The data suggested no difference between fluid resuscitation with albumin and crystalloid (OR 1.04, 95% CrI 0.78-1.38, moderate certainty) or starch (OR 0.74, 95% CrI 0.53-1.04, low certainty). NMA at the six-node level showed a decreased risk of receiving RRT with balanced crystalloid compared to heavy starch (OR 0.50, 95% CrI 0.34-0.74, moderate certainty) or light starch (OR 0.70, 95% CrI 0.49-0.99, high certainty). There was no significant difference between balanced crystalloid and saline (OR 0.85, 95% CrI 0.56-1.30, low certainty) or albumin (OR 0.82, 95% CrI 0.49-1.37, low certainty). Of note, these trials vary in terms of case mix, fluids evaluated, duration of fluid exposure and risk of bias. Imprecise estimates contributed to low confidence in most estimates of effect. Among the patients with sepsis, fluid resuscitation with crystalloids compared to starch resulted in reduced use of RRT; the same may be true for albumin versus starch.

To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU.Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial.Sixty-seven medical-surgical ICUs in six countries.Three thousand seven hundred forty-six medical-surgical critically ill patients.All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses.Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004).Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

Objectives To analyze FLOW data to identify baseline patient, injury, fracture, and treatment factors associated with lower health-related quality of life (HRQoL) at 12-month postfracture. Design Prognostic study using data from a prospective randomized controlled trial. Setting Thirty-one clinical centers in the United States, Canada, Australia, and India. Patients/participants One thousand four hundred twenty-seven patients with open fracture from the FLOW trial with complete 12-month Short Form-12 (SF-12) follow-up assessment and no missing data for selected baseline factors. Intervention Not applicable. Main outcome measurement Physical Component Score (PCS) and the Mental Component Score (MCS) of the SF-12 at 12-month postfracture. Results One thousand four hundred twenty-seven patients were included in the SF-12 PCS and MCS linear regression models. Smoking, lower preinjury SF-12 PCS and MCS, and work-related injuries were significantly associated with lower SF-12 PCS and MCS at 12-month postfracture. A lower extremity fracture and a wound that was not closed at initial irrigation and debridement were significantly associated with lower 12-month SF-12 PCS but not MCS. Only the adjusted mean difference for lower extremity fractures approached the minimally important difference for the SF-12 PCS. Conclusions We identified a number of statistically significant baseline factors associated with lower HRQoL; however, only the presence of a lower extremity fracture approached clinical significance. More research is needed to quantify the impact of these factors on patients and to determine whether changes to modifiable factors at baseline will lead to clinically significant improvements in HRQoL after open fractures. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Purpose: Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers. Results: Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies. Conclusions: Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question.

Background Platelet transfusions are commonly used to treat critically ill patients with thrombocytopenia. Whether platelet transfusions are associated with a reduction in the risk of major bleeding is unknown. Patients/Methods Observational cohort study nested in a previous multicenter, randomized thromboprophylaxis trial in the intensive care unit (ICU). The objective was to evaluate the association between platelet transfusions and adjudicated major bleeding events. Platelet transfusion episodes were reviewed for timing of administration, product type, and dose. Major bleeding with and without platelet transfusions was adjusted for severity of thrombocytopenia, use of anti‐platelet agents, surgery and other covariates. Secondary outcomes were thrombosis, death in ICU and platelet count increment. Results Among 2,256 patients, 71 (3.1%) received 190 platelet transfusions. Of those, 121 (63.7%) were administered to 54 non‐bleeding, thrombocytopenic patients. Adjusted rates of major bleeding were not statistically different with or without the administration of platelet transfusions (hazard ratio for transfused patients 0.85; 95% confidence interval, 0.42‐1.72). We did not find a significant association between platelet transfusion use and thrombosis or death in ICU in adjusted analyses. Thrombocytopenia, anemia, major or minor bleeding and use of anticoagulants were associated with platelet transfusion administration. The median post‐transfusion platelet count increment was 20×109/L at 3.5 hours post‐transfusion. Conclusions Rates of major bleeding were not different for patients who did and did not receive platelet transfusions. Inferences were limited by the small number of transfused patients. Clinical trials are needed to better investigate the potential hemostatic benefit and potential harms of platelet transfusions for this high‐risk population.

© 2017 Elsevier Ltd Background Reoperation rates are high after surgery for hip fractures. We investigated the effect of a sliding hip screw versus cancellous screws on the risk of reoperation and other key outcomes. Methods For this international, multicentre, allocation concealed randomised controlled trial, we enrolled patients aged 50 years or older with a low-energy hip fracture requiring fracture fixation from 81 clinical centres in eight countries. Patients were assigned by minimisation with a centralised computer system to receive a single large-diameter screw with a side-plate (sliding hip screw) or the present standard of care, multiple small-diameter cancellous screws. Surgeons and patients were not blinded but the data analyst, while doing the analyses, remained blinded to treatment groups. The primary outcome was hip reoperation within 24 months after initial surgery to promote fracture healing, relieve pain, treat infection, or improve function. Analyses followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT00761813. Findings Between March 3, 2008, and March 31, 2014, we randomly assigned 1108 patients to receive a sliding hip screw (n=557) or cancellous screws (n=551). Reoperations within 24 months did not differ by type of surgical fixation in those included in the primary analysis: 107 (20%) of 542 patients in the sliding hip screw group versus 117 (22%) of 537 patients in the cancellous screws group (hazard ratio [HR] 0·83, 95% CI 0·63–1·09; p=0·18). Avascular necrosis was more common in the sliding hip screw group than in the cancellous screws group (50 patients [9%] vs 28 patients [5%]; HR 1·91, 1·06–3·44; p=0·0319). However, no significant difference was found between the number of medically related adverse events between groups (p=0·82; appendix); these events included pulmonary embolism (two patients [

The purpose of this study was to determine whether the SPRINT definition of a "critical-sized defect" (fracture gap at least 1 cm in length and involving over 50% of the cortical diameter) was accurate, to discern which factors predict reoperation in patients with these defects, and to compare the patient-based outcomes of these patients with patients without a critical defect.Therapeutic Cohort Study.Level 1 and level 2 trauma centers.Thirty-seven patients in the SPRINT trial with a critical-sized defect participated. We evaluated these patients for planned and unplanned secondary intervention to gain union. Additionally, we evaluated which other factors predicted the need for reoperation. Finally, the 37 patients with a critical defect were compared with the larger cohort of patients without a defect with respect to demographics, mechanism of injury, fracture characteristics, and patient-based outcome.Revision surgery for tibial nonunion.Of the 37 patients with a large fracture gap, 7 patients had a planned secondary procedure. Of the remaining 30 patients in whom the attending surgeon adopted a "watch and wait" strategy, 14 patients (47%) never required additional surgery to gain union. Additional surgery to gain union was less likely in patients treated with a reamed nail (P = 0.04) and in female patients (P = 0.04). Patients with a critical-sized defect were more likely to have a high-energy mechanism of injury (P = 0.001), AO-OTA fracture type 42 B or C (P0.001), and location involving the middle third of the tibia (P = 0.02). The 12-month SF-36 physical component summary score in patients with a critical-sized defect was 38.2 ± 10.5 (mean ± SD) compared with 43.3 ± 10.7 in those without a critical defect (P = 0.02, difference = 5.2, 95% confidence interval = 0.8-9.6).Tibial diaphyseal defects of1 cm and50% cortical circumference healed without additional surgery in 47% of cases. This definition of a critical-sized defect is not "critical." However, as compared with the overall cohort of tibial fractures, patients with these bone defects had a higher rate of reoperation and worse patient-based outcomes. Further investigation is required to determine which factors predict union in this challenging fracture to avoid unnecessary secondary surgery.Prognostic level I. See instructions for authors for a complete description of levels of evidence.

The 3 Wishes Project (3WP) is an end-of-life program that aims to honor the dignity of dying patients by creating meaningful patient- and family-centered memories while promoting humanistic interprofessional care.To determine whether this palliative intervention could be successfully implemented-defined as demonstrating value, transferability, affordability, and sustainability-beyond the intensive care unit in which it was created.Mixed-methods formative program evaluation. (ClinicalTrials.gov: NCT04147169).4 North American intensive care units.Dying patients, their families, clinicians, hospital managers, and administrators.Wishes from dying patients, family members, and clinicians were elicited and implemented.Patient characteristics and processes of care; the number, type, and cost of each wish; and semistructured interviews and focus groups with family members, clinicians, and managers.A total of 730 patients were enrolled, and 3407 wishes were elicited. Qualitative data were gathered from 75 family members, 72 clinicians, and 20 managers or hospital administrators. Value included intentional comforting of families as they honored the lives and legacies of their loved ones while inspiring compassionate clinical care. Factors promoting transferability included family appreciation and a collaborative intensive care unit culture committed to dignity-conserving end-of-life care. Staff participation evolved from passive support to professional agency. Program initiation required minimal investment for reusable materials; thereafter, the mean cost was $5.19 (SD, $17.14) per wish. Sustainability was demonstrated by the continuation of 3WP at each site after study completion.This descriptive formative evaluation describes tertiary care center-specific experiences rather than aiming for generalizability to all jurisdictions.The 3WP is a transferrable, affordable, and sustainable program that provides value to dying patients, their families, clinicians, and institutions.Greenwall Foundation.

IntroductionAcute rehabilitation in critically ill patients can improve post-intensive care unit (post-ICU) physical function. In-bed cycling early in a patient’s ICU stay is a promising intervention. The objective of this study was to determine the feasibility of recruitment, intervention delivery and retention in a multi centre randomised clinical trial (RCT) of early in-bed cycling with mechanically ventilated (MV) patients.MethodsWe conducted a pilot RCT conducted in seven Canadian medical-surgical ICUs. We enrolled adults who could ambulate independently before ICU admission, within the first 4 days of invasive MV and first 7 days of ICU admission. Following informed consent, patients underwent concealed randomisation to either 30 min/day of in-bed cycling and routine physiotherapy (Cycling) or routine physiotherapy alone (Routine) for 5 days/week, until ICU discharge. Our feasibility outcome targets included: accrual of 1–2 patients/month/site; >80% cycling protocol delivery; >80% outcomes measured and >80% blinded outcome measures at hospital discharge. We report ascertainment rates for our primary outcome for the main trial (Physical Function ICU Test-scored (PFIT-s) at hospital discharge).ResultsBetween 3/2015 and 6/2016, we randomised 66 patients (36 Cycling, 30 Routine). Our consent rate was 84.6 % (66/78). Patient accrual was (mean (SD)) 1.1 (0.3) patients/month/site. Cycling occurred in 79.3% (146/184) of eligible sessions, with a median (IQR) session duration of 30.5 (30.0, 30.7) min. We recorded 43 (97.7%) PFIT-s scores at hospital discharge and 37 (86.0%) of these assessments were blinded.DiscussionOur pilot RCT suggests that a future multicentre RCT of early in-bed cycling for MV patients in the ICU is feasible.Trial registration numberNCT02377830.

Purpose Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients. Methods We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers. Results Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies. Conclusions Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question. Electronic supplementary material The online version of this article (10.1007/s00134-017-5005-8) contains supplementary material, which is available to authorized users.

Background Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical ICUs. Methods Three thousand seven hundred forty-six patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared with low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts 9 /L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149 × 10 9 /L), moderate (50-99 × 10 9 /L), and severe ( 9 /L) thrombocytopenia during an ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death. Results The incidences of mild, moderate, and severe thrombocytopenia were 15.3%, 5.1%, and 1.6%, respectively. The predictors of each category of thrombocytopenia were APACHE (Acute Physiology and Chronic Health Evaluation) II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality. Conclusion A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in the ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions, and die. Trial registry ClinicalTrials.gov; No.: NCT00182143; URL: www.clinicaltrials.gov

To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with >10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19–50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61–4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27–14.34). Refusals decreased each year of enrollment compared to the pilot phase. Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians’ concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.

Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials.The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143).Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily.The trial was conducted in 67 centers in 6 countries.A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P.001 for those with10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs,0.5; P.001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P.001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P.001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P.001).Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial.

Objective To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures. Design A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year. Setting 43 North American academic trauma centers. Participants Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient’s tibial fracture, and tibial fractures that showed 1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled. Interventions Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation. Main outcome measures Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to ≥80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device. Results SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval −0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered ≥50% of all recommended treatments. Conclusions Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery. Study registration ClinicalTrialGov Identifier: [NCT00667849][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00667849&atom=%2Fbmj%2F355%2Fbmj.i5351.atom

Background Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). Methods In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. Results Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7–18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14–44 days); 23 patients (15.3 %) died in the ICU. Conclusions The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. Trial registration Clinicaltrials.gov NCT01782755. Registered on 29 January 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1495-x) contains supplementary material, which is available to authorized users.

© Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. Objectives: To determine the extent to which knowledge from clinical trial protocols is transferred to nonparticipating patients. Design: Retrospective review of prospectively collected data from a large clinical trial. Setting: Six level-1 international trauma centers. Methods: We compared rates and timing of reoperation in a subset of patients enrolled in the Study to Prospectively evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) to concurrent patients who were eligible but not enrolled. This was a retrospective review of prospectively collected trial data. The records of 6 of the original SPRINT centers were searched for non-SPRINT patients who underwent intramedullary nailing of a closed tibial fracture. The rate and timing of reoperation were compared. A P < 0.05 was considered significant. Results: One hundred fourteen non-SPRINT patients were compared with 328 patients enrolled in SPRINT from those same sites. There were 7 reoperations (6.1%) in non-SPRINT patients versus 18 (5.2%) in SPRINT patients [odds ratio (OR) 1.19, 95% confidence interval (CI) 0.41 to 3.13; P 0.811]. There was no difference in the time to reoperation between the SPRINT and non-SPRINT patients (6.2 vs. 6.8 months, 95% CI of the difference -3.8 to 2.6; P 0.685) or in the proportion of patients who underwent reoperation before 6 months (29% vs. 43%; OR 1.75; 95% CI 0.18 to 15.41; P 0.647). Conclusions: Patients not enrolled in SPRINT had similarly low rates of reoperation for nonunion, and the average time to reoperation for both groups was longer than 6 months. A 6-month waiting period may have allowed slow-to-heal fractures adequate time to heal, thereby reducing the rate of diagnosis of nonunion. As such, this waiting period could contribute to lower-than-expected reoperation rates for nonunion. It is possible that clinical trials may beneficially influence the care of nonenrolled patients.

Objective The objectives of this study were to describe residents9 experiences with end-of-life (EOL) education during a rotation in the intensive care unit (ICU), and to understand the possible influence of the 3 Wishes Project. Design We enrolled dying patients, their families and 1–3 of their clinicians in the 3 Wishes Project, eliciting and honouring a set of 3 wishes to bring peace to the final days of a critically ill patient9s life, and ease the grieving process for families. We conducted semistructured interviews with 33 residents who had cared for 50 dying patients to understand their experiences with the project. Interviews were recorded, transcribed verbatim, then analysed using a qualitative descriptive approach. Setting 21-bed medical surgical ICU in a tertiary care, university-affiliated hospital. Results 33 residents participated from internal medicine (24, 72.7%), anaesthesia (8, 24.2%) and laboratory medicine (1, 3.0%) programmes in postgraduate years 1–3. 3 categories and associated themes emerged. (1) EOL care is a challenging component of training in that (a) death in the ICU can invoke helplessness, (b) EOL education is inadequate, (c) personal connections with dying patients is difficult in the ICU and (d) EOL skills are valued by residents. (2) The project reframes the dying process for residents by (a) humanising this aspect of practice, (b) identifying that family engagement is central to the dying process, (c) increasing emotional responsiveness and (d) showing that care shifts, not stops. (3) The project offers experiential education by (a) intentional role modelling, (b) facilitating EOL dialogue, (c) empowering residents to care in a tangible way and (d) encouraging reflection. Conclusions For residents, the 3 Wishes Project integrated many forms of active learning for residents. Practice-based rather than classroom-based programmes may engage trainees to develop EOL skills transferable to other settings.

Background Research ethics board (REB) review of scientific protocols is essential, ensuring participants' dignity, safety, and rights. The objectives of this study were to examine the time from submission to approval, to analyze predictors of approval time, and to describe the scope of conditions from REBs evaluating an international thromboprophylaxis trial. Methods We generated survey items through literature review and investigators' discussions, creating 4 domains: respondent and institutional demographics, the REB application process, and alternate consent models. We conducted a document analysis that involved duplicate assessment of themes from REB critique of the protocol and informed consent forms (ICF). Results Approval was granted from 65 REB institutions, requiring 58 unique applications. We analyzed 44 (75.9%) of 58 documents and surveys. Survey respondents completing the applications had 8 (5-12) years of experience; 77% completed 4 or more REB applications in previous 5 years. Critical care personnel were represented on 54% of REBs. The time to approval was a median (interquartile range) of 75 (42, 150) days, taking longer for sites with national research consortium membership (89.1 vs 31.0 days, P = .03). Document analysis of the application process and ICF yielded 5 themes: methodology, data management, consent procedures, cataloguing, and miscellaneous. Protocol-specific themes focused on trial implementation, external critiques, and budget. The only theme specific to the ICF was risks and benefits. The most frequent comments on the protocol and ICF were about methodology and miscellaneous issues; ICF comments also addressed study risks and benefits. Conclusions More studies on methods to enhance efficiency and consistency of the REB approval processes for clinical trials are needed while still maintaining high ethical standards.

Copyright © 2015 Massachusetts Medical Society. BACKGROUND The management of open fractures requires wound irrigation and dridement to remove contaminants, but the effectiveness of various pressures and solutions for irrigation remains controversial. We investigated the effects of castile soap versus normal saline irrigation delivered by means of high, low, or very low irrigation pressure. METHODS In this study with a 2-by-3 factorial design, conducted at 41 clinical centers, we randomly assigned patients who had an open fracture of an extremity to undergo irrigation with one of three irrigation pressures (high pressure [>20 psi], low pressure [5 to 10 psi], or very low pressure [1 to 2 psi]) and one of two irrigation solutions (castile soap or normal saline). The primary end point was reoperation within 12 months after the index surgery for promotion of wound or bone healing or treatment of a wound infection. RESULTS A total of 2551 patients underwent randomization, of whom 2447 were deemed eligible and included in the final analyses. Reoperation occurred in 109 of 826 patients (13.2%) in the high-pressure group, 103 of 809 (12.7%) in the low-pressure group, and 111 of 812 (13.7%) in the very-low-pressure group. Hazard ratios for the three pairwise comparisons were as follows: for low versus high pressure, 0.92 (95% confidence interval [CI], 0.70 to 1.20; P = 0.53), for high versus very low pressure, 1.02 (95% CI, 0.78 to 1.33; P = 0.89), and for low versus very low pressure, 0.93 (95% CI, 0.71 to 1.23; P = 0.62). Reoperation occurred in 182 of 1229 patients (14.8%) in the soap group and in 141 of 1218 (11.6%) in the saline group (hazard ratio, 1.32, 95% CI, 1.06 to 1.66; P = 0.01). CONCLUSIONS The rates of reoperation were similar regardless of irrigation pressure, a finding that indicates that very low pressure is an acceptable, low-cost alternative for the irrigation of open fractures. The reoperation rate was higher in the soap group than in the saline group. (Funded by the Canadian Institutes of Health Research and others; FLOW ClinicalTrials.gov number, NCT00788398.

Introduction Recently, results from the large, randomized study to prospectively evaluate reamed intramedullary nails in patients with tibial fractures (SPRINT) trial suggested a benefit for reamed intramedullary nail insertion in patients with closed tibial shaft fractures largely based on cost-neutral autodynamizations and a potential advantage for unreamed intramedullary nailing in open fractures. We performed an economic evaluation to compare resource use and effectiveness of reamed and unreamed intramedullary nailing using a cost-utility analysis. Methods We calculated quality-adjusted life years (QALYs) for each patient from a self-administered health utility index 3 questionnaire for the first 12 months following the intramedullary nailing. A convenience sample of 235 SPRINT patients provided data on costs associated with health care resource utilization. All costs are reported in Canadian dollars for the 2008 financial year. Results We found incremental effects of −0.017 (95% confidence interval [CI] −0.021–0.058) and −0.002 (95% CI −0.060–0.062) QALYs for patients treated with reamed compared with unreamed intramedullary nails in closed and open fractures, respectively. The incremental costs for reamed compared with unreamed intramedullary nailing were $51 Canadian dollars (95% CI −$2298–$2400) in closed tibial fractures and $2546 Canadian dollars (95%CI −$1773–$6864) in open tibial fractures. Unreamed nailing dominated reamed nailing for both closed and open tibial fractures; however, the cost and the utility results had high variability. Conclusion Our economic analysis from a governmental perspective suggests small differences in both cost and effectiveness with large uncertainty between reamed and unreamed intramedullary nailing.

Background The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients. Methods In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle. Results There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046). Conclusions Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

To examine the effect of brief disease-specific education delivered in primary care on objective measures of knowledge in individuals recently diagnosed with chronic obstructive pulmonary disease (COPD).A randomized control trial was undertaken during which an experimental group received 2h of education delivered by a certified COPD educator and a control group received usual care. The Bristol COPD Knowledge Questionnaire (BCKQ) was self-administered at the time of randomization and approximately three months later.Of the 93 individuals that completed the study, 50 (forced expiratory volume in 1s [FEV(1)]=60.0+/-14.3% predicted; 22 males) and 43 (FEV(1)=58.2+/-14.4% predicted; 20 males) participants were randomized to the experimental and control groups, respectively. The BCKQ increased from 27.6+/-8.7 to 36.5+/-7.7 points (p0.001) in the experimental group, which was greater than any seen in the control group (between-group difference 8.3, 95% confidence interval 5.5-11.2 points).As little as 2h of education delivered in primary care was effective at increasing objective measures of disease-specific knowledge.A program of brief education delivered in the primary care setting, represents an important approach for many individuals with COPD who are unlikely to access pulmonary rehabilitation.

Purpose The aim of this study was to assess the etiology of cardiac troponin elevation among patients admitted to the intensive care unit (ICU) and to examine whether etiology affects mortality and length of stay. Methods All patients admitted over 2 months underwent screening with troponin measurements and were included if 1 or more measurements were elevated. Two adjudicators retrospectively reviewed patient charts to determine the likely cause of troponin elevation. Results Of 103 patient admissions, 52 (50.5%) had 1 or more elevated troponin measurements, and 49 (94.2%) had medical charts available for review. Troponin elevation was adjudicated as myocardial infarction (MI) in 53.1% of patients, sepsis in 18.4%, renal failure in 12.2%, and other causes in 16.3%. Overall ICU mortality was 16.0%; 2.0% for patients with no troponin elevation, 23.1% in patients with MI, and 39.1% in patients with troponin elevation not due to MI. Having an elevated troponin level not due to MI was significantly associated with increased hospital mortality compared with having no troponin elevation. Conclusions The most common cause of troponin elevation among critically ill patients was MI. Patients with elevated troponin had worse outcomes compared with patients without troponin elevation, and troponin elevation not due to MI was predictive of increased hospital mortality.

Introduction Adherence to hand hygiene recommendations in the intensive care unit (ICU) is variable and moderate, at best. Objectives To measure adherence to hand hygiene recommendations among ICU clinicians in a prospective observational study in 6 multidisciplinary ICUs among 4 hospitals. Patients and methods We observed 115 clinicians (64 nurses, 21 respiratory therapists, 18 residents and 12 physicians) during 1 patient encounter, each. Clinicians were unaware that they were under observation. We documented use of gloves, soap, and alcohol solution before and after patient encounters for purposes of physical examination or patient care. Results The rate of adherence to current recommendations was 20% (95% CI 13.7-28.2). All 23 clinicians adhering to recommendations used gloves followed by washing with soap or alcohol solution. 57.4% (95% CI 48.3-66.0) of clinicians used some form of hand hygiene without fully adhering to recommendations, whereas 42.6% did not appear to attend to hand hygiene at all during observation. By univariate analysis, with nurses as the reference group, we found trends suggesting lowest adherence rates among residents (odds ratio [OR] 0.32, 95% CI 0.11-0.96) and intensivists (OR 0.46, 95% CI, 0.13-1.60), and highest adherence among respiratory therapists (OR 2.05, 95% CI 0.67-6.30). We also observed a center effect (p = 0.04). However, multivariate analysis showed no relationship of hand hygiene to clinician group (p = 0.06) nor ICU (p = 0.05). Conclusions Multidisciplinary, multimethod approaches to improving hand hygiene are likely necessary to improve the modest adherence to hand hygiene that we observed.

As critical care practice increases in scope, size, and complexity, enrollment of critically ill patients into clinical studies is increasing.To understand the experiences, beliefs, and practices of the Canadian Critical Care Trials Group and Australian and New Zealand Intensive Care Society Clinical Trials Group regarding enrollment of critically ill children and adults into clinical studies.Survey items generated by the research team were formatted in four domains: experiences, beliefs, practices, and demographics. Five research coordinators and five physicians pretested the survey, providing feedback on clarity and completeness. Intrarater reliability (16 participants, 2 wks apart) was very good.The response rate was 284 of 322 (88.2%). Respondents worked in intensive care units with a mean of 20.5 (SD 10) beds, caring for adults (72.2%), pediatric (18.8%), and both groups (9%) of critically ill patients. Clinical research was considered key to the future of improved clinical care. To enhance recruitment efficiency, respondents widely endorsed the effectiveness of increasing participating centers, after-hours, and weekend enrollment (all 3 scores 7 [6-7[sqb], reflecting median [interquartile range] on 1-7 scale). Overall, the effectiveness (6 [4-7]), feasibility (5 [4-6]) and ethics (5 [4-7]) of coenrollment into more than one randomized trial was endorsed. Half of respondents have adopted coenrollment with scientific and psychosocial provisos. Alternative designs, such as factorial and cluster randomized trials, were considered when suitable. Modifications to consent approaches (deferred consent (7 [6-7]), waived consent (7 [6-7]), or consent from two physicians in the absence of a substitute decision maker (6 [5-7])) were considered effective, but beliefs about the feasibility and ethics of some of these approaches varied.Clinical research is highly valued by these intensive care unit communities. Strategies to increase capacity involve enhancing recruitment efficiencies, considering alternative study designs and expanding consent procedures. Thoughtfully implementing these strategies may advance the care of critically ill adults and children.

Objective To examine how authors of systematic reviews that include randomized clinical trials (RCTs) that are stopped early for benefit (truncated RCTs—tRCTs) address the potential for overestimation of treatment effects and to determine the weight of the tRCTs on pooled results. Study Design and Setting We searched the Cochrane Library and MEDLINE and evaluated systematic reviews that include at least one tRCT. We documented approaches that authors used to address potential overestimates of treatment effect introduced by including tRCTs. We assessed the impact of tRCTs in meta-analyses on the outcomes that led to their early termination. Results Of 96 systematic reviews that included at least one tRCT, 44 (46%) included >1 tRCT, 68 (71%) did not mention truncation at all, and 2 (2%) documented early stopping for benefit as a criterion for methodological quality. Of 47 meta-analyses in which authors reported, or we could calculate the contribution of the tRCTs to the pooled result, the tRCTs contributed more than 40% of the weight in 16/47 (34%). Conclusion Most systematic reviews and meta-analyses including tRCTs fail to consider the possible overestimates of effect that may result from early stopping for benefit. We recommend safeguards that address this possibility.

Background Previous studies have suggested that prediction models for mortality should be adjusted for additional risk factors beyond the Acute Physiology and Chronic Health Evaluation (APACHE) score. Our objective was to identify risk factors independent of APACHE II score and construct a prediction model to improve the predictive accuracy for hospital and intensive care unit (ICU) mortality. Methods We used data from a multicenter randomized controlled trial (PROTECT, Prophylaxis for Thromboembolism in Critical Care Trial) to build a new prediction model for hospital and ICU mortality. Our primary outcome was all-cause 60-day hospital mortality, and the secondary outcome was all-cause 60-day ICU mortality. Results We included 3746 critically ill non-trauma medical–surgical patients receiving heparin thromboprophylaxis (43.3 % females) in this study. The new model predicting 60-day hospital mortality incorporated APACHE II score (main effect: hazard ratio (HR) = 0.97 for per-point increase), body mass index (BMI) (main effect: HR = 0.92 for per-point increase), medical admission versus surgical (HR = 1.67), use of inotropes or vasopressors (HR = 1.34), acetylsalicylic acid or clopidogrel (HR = 1.27) and the interaction term between APACHE II score and BMI (HR = 1.002 for per-point increase). This model had a good fit to the data and was well calibrated and internally validated. However, the discriminative ability of the prediction model was unsatisfactory (C index

Background The aim of the study was to evaluate the impact of flavonoids on those symptoms important to patients with symptomatic haemorrhoids. Methods A comprehensive search strategy was used. All published and unpublished randomized controlled trials comparing any type of flavonoid to placebo or no therapy in patients with symptomatic haemorrhoids were included. Two reviewers independently screened studies for inclusion, retrieved all potentially relevant studies and extracted data. Results Fourteen eligible trials randomized 1514 patients. Studies were of moderate quality and showed variability in the results with potential publication bias. Meta-analyses using random-effects models suggested that flavonoids decrease the risk of not improving or persisting symptoms by 58 per cent (relative risk (RR) 0·42 (95 per cent confidence interval (c.i.) 0·28 to 0·61)) and showed an apparent reduction in the risk of bleeding (RR 0·33 (95 per cent c.i. 0·19 to 0·57)), persistent pain (RR 0·35 (95 per cent c.i. 0·18 to 0·69)), itching (RR 0·65 (95 per cent c.i. 0·44 to 0·97)) and recurrence (RR 0·53 (95 per cent c.i. 0·41 to 0·69)). Conclusion Limitations in methodological quality, heterogeneity and potential publication bias raise questions about the apparent beneficial effects of flavonoids in the treatment of haemorrhoids.

Background: A number of studies compared the quality, efficacy and tolerability of oral sodium phosphate (NaP) and polyethylene glycol (PEG)-based solutions in preparation for colonoscopy. The primary aim of this study was to explore whether endoscopists can be effectively blinded to the type of bowel preparation. Methods: We recruited 3 experienced endoscopists and 57 outpatients (18–65 years old) undergoing colonoscopy. We randomized eligible patients to receive one of the two bowel preparations. Endoscopists who performed the tests were blinded to the type of preparation, and made their best judgment on the type and quality of the bowel preparation. Results: Forty-five patients completed the study. The overall correct estimation of the type of bowel preparation was 60.0% (95% CI; 45.5%, 73.0%). The cleansing quality did not differ between the two preparations. Patients found oral NaP solution much easier to take (81.8% versus 36.4%; P =0.005) and the PEG-based group tended to have more nausea or vomiting. 47.6% of patients in the PEG group indicated they would prefer to try another bowel preparation in the future compared to 4.5% in the oral NaP group ( P =0.002). We stopped the study after an interim analysis indicating that more than 600 patients would be required to detect statistically significant differences in the primary aim. Conclusion: Our findings suggest that blinding of endoscopists in clinical trials comparing oral NaP to PEG had a relatively low likelihood of bias. The study also suggests that oral NaP is easier to take and more tolerable than PEG without impairing cleansing quality.

Background Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial. Methods/Design The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping. Discussion This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication. Trial registration Clinicaltrials.gov Identifier: NCT00182143. Date of registration: 10 September 2005. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-15-502) contains supplementary material, which is available to authorized users.

Objective This systematic review summarizes the evidence from randomized clinical trials of bright light therapy for treatment of premenstrual dysphoric disorder. Study design The authors performed a systematic review and meta-analysis of randomized clinical trials. They searched MEDLINE, AMED, CINAHL, Digital Dissertations, EMBASE, and the Cochrane Central Register of Controlled Trials. The main outcome measure was the change in depressive symptom scores as measured by the Hamilton Depression Rating Scale and the Beck Depression Inventory. Results Four crossover trials studying a total of 55 participants met inclusion criteria. Three trials showed similar results; one fully unblinded trial showed a much larger effect. The pooled effect size from the random-effects model of the 3 higher quality trials was −0.20 (95% CI −0.48 to 0.07). Conclusion The small size of trials and correspondingly wide confidence limits, and methodologic limitations of the trials, leaves the impact of bright light therapy for relief of premenstrual depressive symptoms uncertain. The current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality.