Nicole Zytaruk

To review the effect of alendronate on bone density and fractures in postmenopausal women. We searched MEDLINE, EMBASE, Current Contents, and the Cochrane Controlled trials registry from 1980 to 1999, and we examined citations of relevant articles and proceedings of international meetings. We included 11 trials that randomized women to alendronate or placebo and measured bone density for at least 1 yr. For each trial, three independent reviewers assessed the methodological quality and abstracted data. The pooled relative risk (RR) for vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% confidence interval (CI), 0.43-0.65]. The RR of nonvertebral fractures in patients given 10 mg or more of alendronate was 0.51 (95% CI 0.38-0.69), an appreciably greater effect than for the 5 mg dose. We found a similar reduction in RR across nonvertebral fracture types; in particular, RR reductions for fractures traditionally thought to be "osteoporotic," such as hip and forearm, were very similar to RR reductions for "nonosteoporotic" fractures. Individual studies showed similar results, reflected in the P values of the test of heterogeneity (P = 0.99 for vertebral and 0.88 for nonvertebral fractures). Alendronate produced positive effects on the percentage change in bone density, which increased with both dose and time. After 3 yr of treatment with 10 mg of alendronate or more, the pooled estimate of the difference in percentage change between alendronate and placebo was 7.48% (95% CI 6.12-8.85) for the lumbar spine (2-3 yr), 5.60% (95% CI 4.80-6.39) for the hip (3-4 yr), 2.08% (95% CI 1.53-2.63) for the forearm (2-4 yr), and 2.73% (95% CI 2.27-3.20) for the total body (3 yr). Heterogeneity of the treatment effect of alendronate was not consistently explained by any of our a priori hypotheses; in particular, the effect was very similar in prevention and treatment studies. The pooled RR for discontinuing medication due to adverse effects for 5 mg or greater of alendronate was 1.15 (95% CI 0.93-1.42). The pooled RR for discontinuing medication due to gastro-intestinal (GI) side effects for 5 mg or greater was 1.03 (0.81-1.30, P = 0.83), and the pooled RR for GI adverse effects with continuation of medication was 1.03 (0.98 to 1.07) P = 0.23. Alendronate increases bone density in both early postmenopausal women and those with established osteoporosis while reducing the rate of vertebral fracture over 2-3 yr of treatment. Reductions in nonvertebral fractures are evident among postmenopausal women without prevalent fractures and have bone mineral density (BMD) levels below the World Health Organization threshold for osteoporosis. The impact on fractures appears consistent across all fracture types, casting doubt on traditional distinctions between osteoporotic and nonosteoporotic fractures.

Postmenopausal osteoporosis results in an increased susceptibility to low-trauma fractures due to reduced bone volume and microarchitectural deterioration. Risedronate, a third generation bisphosphonate, has been shown in multiple clinical trials to reduce fracture risk and improve bone mineral density in postmenopausal women with osteoporosis. First and second generation bisphosphonates are known to have gastrointestinal side-effects and risedronate may be better tolerated. To systematically review the efficacy of risedronate on bone density, and fracture reduction in postmenopausal women. The Cochrane Controlled Trials Registry Medline, and Current Contents were searched from 1990 - 2001. The electronic search was supplemented by handsearching four osteoporosis journals and their conference proceedings, as well as contacting content experts and industry sources for unpublished data. We included eight trials that randomised women to risedronate or an alternative (placebo or calcium and /or vitamin D) and measured bone mineral density for at least one year. For each trial three independent reviewers assessed the methodological quality and abstracted data. Data was extracted for outcomes of fracture, bone mineral density and adverse events. The more conservative random effects model was used to pool data. The quality of trials was assessed according to the Jadad five-point scale. Both vertebral and non-vertebral fractures were statistically and clinically reduced with risedronate. Eleven out of one hundred women who received risedronate had a vertebral fracture compared to 17 out of one hundred of those who received an alternative treatment (pooled relative risk for vertebral fractures of 0.64 (95% CI 0.52 - 0.77). Three percent of participants who received risedronate had a non-vertebral fracture compared to 4.6% of those who received an alternative treatment (pooled relative risk for nonvertebral fractures of 0.73 (95% CI 0.61 - 0.87). The weighted mean difference for the percent change from baseline for bone mineral density with 5 mg daily for lumbar spine, femoral neck and trochanter was 4.54% (95%CI 4.12 - 4.97), p<0.01; 2.75% (95% CI 2.32 - 3.17), p<0.01; and 4.38% (95% CI 3.51 - 5.25), p<0.01 respectively. There is good evidence for the efficacy of risedronate in the reduction of both vertebral and non-vertebral fractures. In addition, there is evidence from randomized trials that risedronate is able to achieve this without increasing risk for overall withdrawals due to adverse effects.

McMaster University, Hamilton, Canada, Connecticut Children's Medical Center, Hartford, CT, United States of America, Sainte Justine 1 2 ... Hospital, Montreal, Canada, Ottawa Hospital Research Institute, Ottawa, Canada, McMaster University Medical Center, Hamilton, ON, 4

Abstract 198FN2 Introduction: Many critically ill patients are frequently suspected of having HIT because heparin exposure is nearly universal and up to 45% of medical-surgical ICU patients have a platelet count of less than 150 × 109. Methods: Our objectives were: (1) To estimate the incidence of suspected and objectively confirmed HIT; and (2) To evaluate whether a published clinical prediction rule (the…

Abstract 2471 Poster Board II-448 Background: Adjudication in clinical trials can confirm or refute eligibility, describe cointerventions, judge appropriateness of care, or assess the severity of morbidity outcomes. Objective: To refine the adjudication process, calibrate 4 adjudicators, and measure agreement on bleeding severity in an international trial of heparin thromboprophylaxis (PROTECT). Methods: Independently and blinded to each others' ratings and study drug, 4 adjudicators used web-based methods to examine 40 charts of patients assessed by local research coordinators to have either major (20 patients) or minor (20 patients) bleeding. We discussed reasons for disagreement after the first 20 charts to remediate and recalibrate. We calculated crude agreement, chance-corrected agreement (kappa), and chance-independent agreement (phi). Results: For 45 events in 40 patients, pair-wise crude agreement ranged from 86.7-93.3% (average 82.2%). Overall kappa was 0.81. Phi (which can only analyze pair-wise values) ranged from 0.75-0.87. We resolved all disagreements. During adjudication discussions, we 1) addressed methodological issues (e.g., handling recurrent bleeds), 2) added a category (e.g., no bleed), 3) expanded a category (e.g., a major bleed did not have to be overt if other criteria were fulfilled), and 4) divorced procedure-grounded definitions (such as the need for transfusion or therapeutic interventions) from bleeding severity criteria (e.g., the patient could still be classified as having no bleed or a minor bleed if 2 units of PRBCs were transfused for anemia). Conclusions: After independent quadruplicate review of 45 bleeding events, we documented satisfactory agreement for bleeding outcomes, refined the adjudication process, and calibrated adjudicators for the remainder of the trial. Henceforth, charts will be randomly allocated to pairs of adjudicators for blinded review. Disclosures: No relevant conflicts of interest to declare.

Although calcium is one the simplest and least expensive strategies for preventing osteoporotic fractures calcium supplementation is nevertheless not without controversy (Kanis 1989; Nordin 1990). The Food and Drug Administration in the US has permitted a bone health claim for calcium-rich foods, and the NIH in its Consensus Development Process approved a statement that high calcium intake reduces the risk of osteoporosis. To assess the effects of calcium on bone density and fractures in postmenopausal women. We searched Cochrane Controlled Register, MEDLINE and EMBASE up to 2001, and examined citations of relevant articles and proceedings of international meetings. Trials that randomized postmenopausal women to calcium supplementation or usual calcium intake in the diet and reported bone mineral density of the total body, vertebral spine, hip, or forearm or recorded the number of fractures, and followed patients for at least one year were considered for inclusion. Three independent reviewers assessed the methodologic quality and extracted data for each trial. For each bone density site (lumbar spine, total body, combined hip and combined forearm), we calculated the weighted mean difference in bone density between treatment and control groups using the percentage change from baseline. We constructed regression models in which the independent variables were year and dose, and the dependent variable was the effect size. This regression was used to determine the years across which pooling was appropriate. Heterogeneity was assessed. For each fracture analysis we calculated a risk ratio. Fifteen trials, representing 1806 participants, were included. Calcium was more effective than placebo in reducing rates of bone loss after two or more years of treatment. The pooled difference in percentage change from baseline was 2.05% (95% CI 0.24 to 3.86) for total body bone density, 1.66% (95% CI 0.92 to 2.39) for the lumbar spine at 2 years, 1.60% (95% CI 0.78 to 2.41) for the hip, and 1.91% (95% CI 0.33 to 3.50) for the distal radius. The relative risk of fractures of the vertebrae was 0.79 (95% CI 0.54 to 1.09); the relative risk for non-vertebral fractures was 0.86 (95% CI 0.43 to 1.72). Calcium supplementation alone has a small positive effect on bone density. The data show a trend toward reduction in vertebral fractures, but it is unclear if calcium reduces the incidence of non vertebral fractures.

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.

198FN2 Introduction: Many critically ill patients are frequently suspected of having HIT because heparin exposure is nearly universal and up to 45% of medical-surgical ICU patients have a platelet count of less than 150 × 109. Methods: Our objectives were: (1) To estimate the incidence of suspected and objectively confirmed HIT; and (2) To evaluate whether a published clinical prediction rule (the…

Background Critical care research coordinators implement study protocols in intensive care units, yet little is known about their experiences. Objective To identify the responsibilities, stressors, motivators, and job satisfaction of critical care research coordinators in Canada. Methods Responses to a self-administered survey were collected in order to identify and understand factors that motivate and stress research coordinators and enhance their job satisfaction. Items were generated in 5 domains (demographics, job responsibilities, stressors, motivators, and satisfaction). Face validity pretesting was conducted and clinical sensibility was evaluated. Items were rated on 5-point Likert scales. Descriptive analyses were used to report results. Results The response rate was 78% (66 of 85). Most critical care research coordinators (71%) were employed full time; they were engaged in 9 studies (7 academic, 2 industry); and 49% were nurses. Of 30 work responsibilities, the most frequen...

4669 Background: Thrombocytopenia occurs in 20–45% of critically-ill medical-surgical patients. The ‘4Ts’ HIT score (with 4 domains: Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and oTher reason for thrombocytopenia) might reliably identify patients at low risk of HIT. Agreement on 4Ts scoring is uncertain in this setting. Objective: To compare 4Ts HIT scores among research coordinators (who scored real-time), and 2 adjudicators (who scored retrospectively, independently) during an international heparin thromboprophylaxis trial. Methods: 763 of 3746 medical-surgical ICU patients in PROTECT met enrolment criteria in this HIT substudy, if any of the following occurred: platelets <50×109/L, platelets decreased to 50% of ICU admission value, venous thrombosis, or if HIT was otherwise clinically suspected. Persons independently completed 4Ts scores blinded to all laboratory HIT results and each…

Supplementary methodology and results. Table S1. ICU samples collected and additional information concerning the patients included in the study. Table S2. Samples collected from healthy donors. Table S3. OTUs significantly different in the lower respiratory tract between healthy donors and ICU patients. Table S4. OTUs that are significantly different in stool between healthy donors and ICU patients. Table S5. Correlation matrix results using Spearman rank coefficient correlation between metadata and α-diversity metrics of ETAs. Figure S1. Greater heterogeneity within anatomical site in the ICU cohort in comparison to a healthy cohort. Figure S2. Gastric microbial diversity is not associated with illness severity in critical ill patients. Figure S3. Microbial profiles of the ETA specimens collected from critically ill patients. Figure S4. Lack of association between hospital mortality and bacterial load in lower respiratory tract samples. Figure S5. Absence of detectable difference w...

Background: Scaling-up and sustaining healthcare interventions can be challenging. Our objective was to describe how the 3 Wishes Project (3WP), a personalized end-of-life intervention, was scaled-up and sustained in an intensive care unit (ICU).Methods: In a longitudinal mixed-methods study from January 1,2013 - December 31, 2018, dying patients and families were invited to participate if the probability of patient death was >95% or after a decision to withdraw life support. A research team member or bedside clinician learned more about each of the patients and their family, then elicited and implemented <3 personalized wishes for patients and/or family members. We used a qualitative descriptive approach to analyze interviews and focus groups conducted with 25 clinicians who cared for patients enrolled in the project. We used descriptive statistics to summarize patient, wish, and clinician characteristics, and analyzed outcome data in quarters using Statistical Process Contro...

PURPOSE Alterations in bowel habits are common during critical illness, and bowel protocols are gaining acceptance. Our objective was to characterize bowel protocols in a cross-sectional analysis of ICUs. MATERIALS AND METHODS We engaged 44 adult ICUs and performed content analysis of bowel protocols, addressing initiation criteria, medications incorporated, medication escalation, discontinuation criteria, stool assessment methods, and protocol contraindications. RESULTS Bowel protocols operated in 33/44 ICUs (79.5%). The commonest medications were senna (81.0%) and bisacodyl (75.6%). Less common agents were sodium phosphate (45.9%), glycerin (43.2%), docusate sodium (43.2%), polyethylene glycol 3350 (37.8%), lactulose (29.7%), sodium citrate (16.2%), milk of magnesia (13.5%) and mineral oil (16.2%). Bowel protocols were activated by nurses (62.8%) based on initiation criteria [no bowel movement for 24-96 h (35.1%), opioid use (18.9%), "at risk for constipation" (13.5%), stool on digital rectal exam (10.8%), feeding initiation (10.8%), and ICU admission (8.1%)]. Laxative escalation criteria included time from last bowel movement (59.4%), opioid use (18.9%) and no stool on digital rectal exam (10.8%), while 15 (40.5%) included diarrhea as a discontinuation criterion. CONCLUSIONS Bowel protocols have variable initiation, escalation, and discontinuation criteria incorporating different classes of laxatives, reflecting unclear evidence about optimal bowel management strategies in ICU.

2471 Poster Board II-448 Background: Adjudication in clinical trials can confirm or refute eligibility, describe cointerventions, judge appropriateness of care, or assess the severity of morbidity outcomes. Objective: To refine the adjudication process, calibrate 4 adjudicators, and measure agreement on bleeding severity in an international trial of heparin thromboprophylaxis (PROTECT). Methods: Independently and blinded to each others' ratings and study drug, 4 adjudicators used web-based methods to examine 40 charts of patients assessed by local research coordinators to have either major (20 patients) or minor (20 patients) bleeding. We discussed reasons for disagreement after the first 20 charts to remediate and recalibrate. We calculated crude agreement, chance-corrected agreement (kappa), and chance-independent agreement (phi). Results: For 45 events in 40 patients, pair-wise crude agreement ranged from 86.7-93.3% (average 82.2%). Overall kappa was 0.81. Phi (which can only...

IntroductionVentilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probiotic Lactobacillus rhamnosus GG on VAP and other clinically important outcomes in critically ill adults.MethodsPROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×1010 colony forming units of L. rhamnosus GG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. S...

Purpose: To estimate the incidence, severity, duration and consequences of bleeding during critical illness, and to test the performance characteristics of a new bleeding assessment tool. Methods: Clinical bleeding assessments were performed prospectively on 100 consecutive patients admitted to a medical-surgical intensive care unit (ICU) using a novel bleeding measurement tool called HEmorrhage MEasurement (HEME). Bleeding assessments were done daily in duplicate and independently by blinded, trained assessors. Inter-rater agreement and construct validity of the HEME tool were calculated using φ. Risk factors for major bleeding were identified using a multivariable Cox proportional hazards model. Results: Overall, 90% of patients experienced a total of 480 bleeds of which 94.8% were minor and 5.2% were major. Inter-rater reliability of the HEME tool was excellent (φ = 0.98, 95% CI: 0.96 to 0.99). A decrease in platelet count and a prolongation of partial thromboplastin time were in...