Many continuous variables should be analyzed using the relative scale: a case study of β2-agonists for preventing exercise-induced bronchoconstriction

BACKGROUND: The relative scale adjusts for baseline variability and therefore may lead to findings that can be generalized more widely. It is routinely used for the analysis of binary outcomes but only rarely for continuous outcomes. Our objective was to compare relative vs absolute scale pooled outcomes using data from a recently published Cochrane systematic review that reported only absolute effects of inhaled β2-agonists on exercise-induced decline in forced-expiratory volumes in 1 s (FEV1). METHODS: From the Cochrane review, we selected placebo-controlled cross-over studies that reported individual participant data (IPD). Reversal in FEV1 decline after exercise was modeled as a mean uniform percentage point (pp) change (absolute effect) or average percent change (relative effect) using either intercept-only or slope-only, respectively, linear mixed-effect models. We also calculated the pooled relative effect estimates using standard random-effects, inverse-variance-weighting meta-analysis using study-level mean effects. RESULTS: Fourteen studies with 187 participants were identified for the IPD analysis. On the absolute scale, β2-agonists decreased the exercise-induced FEV1 decline by 28 pp., and on the relative scale, they decreased the FEV1 decline by 90%. The fit of the statistical model was significantly better with the relative 90% estimate compared with the absolute 28 pp. estimate. Furthermore, the median residuals (5.8 vs. 10.8 pp) were substantially smaller in the relative effect model than in the absolute effect model. Using standard study-level meta-analysis of the same 14 studies, β2-agonists reduced exercise-induced FEV1 decline on the relative scale by a similar amount: 83% or 90%, depending on the method of calculating the relative effect. CONCLUSIONS: Compared with the absolute scale, the relative scale captures more effectively the variation in the effects of β2-agonists on exercise-induced FEV1-declines. The absolute scale has been used in the analysis of FEV1 changes and may have led to sub-optimal statistical analysis in some cases. The choice between the absolute and relative scale should be determined based on biological reasoning and empirical testing to identify the scale that leads to lower heterogeneity.Peer reviewe

Long-term outcomes and clinical predictors of hospital mortality in very long stay intensive care unit patients: a cohort study

INTRODUCTION: Little information is available on prognosis and outcomes of very long stay intensive care unit (ICU) patients. The purpose of this study was to identify long-term outcomes after hospital discharge and readily available clinical predictors of hospital mortality for patients requiring prolonged care in the ICU. METHOD: Clinical data were collected from consecutive patients requiring at least 30 days of ICU care admitted over 3 calendar years (2001 to 2003) to a medical/surgical ICU in a university-affiliated tertiary care centre. RESULTS: A total of 182 patients met the inclusion criteria, with a mean age of 63 years, median ICU stay of 48.5 days (interquartile range 36–78 days) and ICU mortality of 32%. They accounted for 8% of total admissions and 48% of total occupied beds. Of these patients, 42% died in hospital, 44% returned to their previous place of residence, and 14% were transferred to long-term care institutions. By 6 months after hospital discharge a further 8% of the patients had died, 40% remained at their previous place of residence, and 10% were in long-term care. Predictors of hospital mortality, identified using multivariate logistic regression, included age (odds ratio [OR] 1.45 per additional decade, 95% confidence interval [CI] 1.10–1.91), any immunosuppression (OR 5.2, 95% CI 1.7–15.5), mechanical ventilation for longer than 90 days (OR 4.0, 95% CI 1.3–12.0), treatment with inotropes or vasopressors for more than 3 days at or after day 30 in the ICU (OR 7.1, 95% CI 2.6–19.3), and acute renal failure requiring dialysis at or after day 30 in the ICU (OR 6.3, 95% CI 2.0–19.7). CONCLUSION: Patients with very long stays in the ICU appear to have a reasonable chance of survival, with most survivors in our cohort residing at their previous place of residence 6 months after hospital discharge. Prolonged requirement for life support therapies (ventilation, vasoactive agents, or acute dialysis) and a limited number of pre-existing co-morbidities (immunosuppression and, to a lesser extent, patient age) were predictors of increased hospital mortality. These predictors may assist in clinical decision making for this resource intensive patient population, and their reproducibility in other very long stay patient populations should be explored

Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged ICU length of stay: a cohort study

INTRODUCTION: Anemia among the critically ill has been described in patients with short to medium length of stay (LOS) in the intensive care unit (ICU), but it has not been described in long-stay ICU patients. This study was performed to characterize anemia, transfusion, and phlebotomy practices in patients with prolonged ICU LOS. METHODS: We conducted a retrospective chart review of consecutive patients admitted to a medical-surgical ICU in a tertiary care university hospital over three years; patients included had a continuous LOS in the ICU of 30 days or longer. Information on transfusion, phlebotomy, and outcomes were collected daily from days 22 to 112 of the ICU stay. RESULTS: A total of 155 patients were enrolled. The mean age, admission Acute Physiology and Chronic Health Evaluation II score, and median ICU LOS were 62.3 ± 16.3 years, 23 ± 8, and 49 days (interquartile range 36–70 days), respectively. Mean hemoglobin remained stable at 9.4 ± 1.4 g/dl from day 7 onward. Mean daily phlebotomy volume was 13.3 ± 7.3 ml, and 62% of patients received a mean of 3.4 ± 5.3 units of packed red blood cells at a mean hemoglobin trigger of 7.7 ± 0.9 g/dl after day 21. Transfused patients had significantly greater acuity of illness, phlebotomy volumes, ICU LOS and mortality, and had a lower hemoglobin than did those who were not transfused. Multivariate logistic regression analysis identified the following as independently associated with the likelihood of requiring transfusion in nonbleeding patients: baseline hemoglobin, daily phlebotomy volume, ICU LOS, and erythropoietin therapy (used almost exclusively in dialysis dependent renal failure in this cohort of patients). Small increases in average phlebotomy (3.5 ml/day, 95% confidence interval 2.4–6.8 ml/day) were associated with a doubling in the odds of being transfused after day 21. CONCLUSION: Anemia, phlebotomy, and transfusions, despite low hemoglobin triggers, are common in ICU patients long after admission. Small decreases in phlebotomy volume are associated with significantly reduced transfusion requirements in patients with prolonged ICU LOS

Does intensive insulin therapy really reduce mortality in critically ill surgical patients? A reanalysis of meta-analytic data

Two recent systematic reviews evaluating intensive insulin therapy (IIT) in critically ill patients grouped randomized controlled trials (RCTs) by type of intensive care unit (ICU). The more recent review found that IIT reduced mortality in patients admitted to a surgical ICU, but not in those admitted to medical ICUs or mixed medical-surgical ICUs, or in all patients combined. Our objective was to determine whether IIT saves lives in critically ill surgical patients regardless of the type of ICU. Pooling mortality data from surgical and medical subgroups in mixed-ICU RCTs (16 trials) with RCTs conducted exclusively in surgical ICUs (five trials) and in medical ICUs (five trials), respectively, showed no effect of IIT in the subgroups of surgical patients (risk ratio = 0.85, 95% confidence interval (CI) = 0.69 to 1.04, P = 0.11; I2 = 51%, 95% CI = 1 to 75%) or of medical patients (risk ratio = 1.02, 95% CI = 0.95 to 1.09, P = 0.61; I2 = 0%, 95% CI = 0 to 41%). There was no differential effect between subgroups (interaction P = 0.10). There was statistical heterogeneity in the surgical subgroup, with some trials demonstrating significant benefit and others demonstrating significant harm, but no surgical subgroup consistently benefited from IIT. Such a reanalysis suggests that IIT does not reduce mortality in critically ill surgical patients or medical patients. Further insights may come from individual patient data meta-analyses or from future large multicenter RCTs in more narrowly defined subgroups of surgical patients

Rosiglitazone: can meta-analysis accurately estimate excess cardiovascular risk given the available data? Re-analysis of randomized trials using various methodologic approaches

<p>Abstract</p> <p>Background</p> <p>A recent and provocative meta-analysis, based on few outcome events, suggested that rosiglitazone increased cardiovascular mortality and myocardial infarction. However, results of meta-analyses of trials with sparse events, often performed when examining uncommon adverse effects due to common therapies, can vary substantially depending on methodologic decisions. The objective of this study was to assess the robustness of the rosiglitazone results by using alternative reasonable methodologic approaches and by analyzing additional related outcomes.</p> <p>Findings</p> <p>In duplicate and independently, we abstracted all myocardial and cerebrovascular ischemic events from all randomized controlled trials listed on the manufacturer's web site meeting inclusion criteria of the original meta-analysis (at least 24 weeks of rosiglitazone exposure in the intervention group and any control group without rosiglitazone). We performed meta-analyses of these data under different methodologic conditions. An unconfounded comparison that includes only trials (or arms of trials) in which medications apart from rosiglitazone are identical suggests higher risks than previously reported, making even the risk of cardiovascular death statistically significant. Alternatively, meta-analysis that includes all trials comparing a treatment arm receiving rosiglitazone to any control arm without rosiglitazone (as in the original meta-analysis) but also including trials with no events in both the rosiglitazone and control arms (not incorporated in the original meta-analysis), shows adverse but non-statistically significant effects of rosiglitazone on myocardial infarction and cardiovascular mortality. Rosiglitazone appears to have inconsistent effects on a wider range of cardiovascular outcomes. It increases the risk of a broad range of myocardial ischemic events (not just myocardial infarction). However, its effect on cerebrovascular ischemic events suggests benefit, although far from statistically significant.</p> <p>Conclusion</p> <p>We have shown that alternative reasonable methodological approaches to the rosiglitazone meta-analysis can yield increased or decreased risks that are either statistically significant or not significant at the p = 0.05 level for both myocardial infarction and cardiovascular death. Completion of ongoing trials may help to generate more accurate estimates of rosiglitazone's effect on cardiovascular outcomes. However, given that almost all point estimates suggest harm rather than benefit and the availability of alternative agents, the use of rosiglitazone may greatly decline prior to more definitive safety data being generated.</p

Discontinuous Galerkin method for the spherically reduced BSSN system with second-order operators

We present a high-order accurate discontinuous Galerkin method for evolving the spherically-reduced Baumgarte-Shapiro-Shibata-Nakamura (BSSN) system expressed in terms of second-order spatial operators. Our multi-domain method achieves global spectral accuracy and long-time stability on short computational domains. We discuss in detail both our scheme for the BSSN system and its implementation. After a theoretical and computational verification of the proposed scheme, we conclude with a brief discussion of issues likely to arise when one considers the full BSSN system.Comment: 35 pages, 6 figures, 1 table, uses revtex4. Revised in response to referee's repor