Claudia Schmoor

Noninvasive Ventilation in COPD: Impact of Inspiratory Pressure Levels on Sleep Quality

BACKGROUNDnAlthough high-intensity noninvasive positive pressure ventilation (HI-NPPV) is superior to low-intensity noninvasive positive pressure ventilation (LI-NPPV) in controlling nocturnal hypoventilation in stable hypercapnic patients with COPD, it produces higher amounts of air leakage, which, in turn, could impair sleep quality. Therefore, the present study assessed the difference in sleep quality during HI-NPPV and LI-NPPV.nnnMETHODSnA randomized, controlled, crossover trial comparing sleep quality during HI-NPPV (mean inspiratory positive airway pressure 29 ± 4 mbar) and LI-NPPV (mean inspiratory positive airway pressure 14 mbar) was performed in 17 stable hypercapnic patients with COPD who were already familiar with HI-NPPV.nnnRESULTSnThirteen patients (mean FEV(1) 27% ± 11% predicted) completed the trial; four patients refused to sleep under LI-NPPV. There was no significant difference in sleep quality between the treatment groups (all P > .05), with a mean difference of -3.0% (95% CI, -10.0 to 3.9; P = .36) in the primary outcome, namely non-rapid eye movement sleep stages 3 and 4. However, nocturnal Paco(2) was lower during HI-NPPV compared with LI-NPPV, with a mean difference of -6.4 mm Hg (95% CI, -10.9 to -1.8; P = .01).nnnCONCLUSIONSnIn patients with COPD, high inspiratory pressures used with long-term HI-NPPV produce acceptable sleep quality that is no worse than that produced by lower inspiratory pressures, which are more traditionally applied in conjunction with LI-NPPV. In addition, higher pressures are more successful in maintaining sufficient alveolar ventilation compared with low pressures. Thus, HI-NPPV is a very promising new approach, but still requires large, longer-term trials to determine the impact on outcomes such as exacerbation rates and longevity.nnnTRIAL REGISTRYnGerman Clinical Trials Register (DRKS); No.: DRKS00000520; URL: www.drks.de.

Skin disinfection with octenidine dihydrochloride for central venous catheter site care: a double-blind, randomized, controlled trial.

To compare the efficacy of two commercially available, alcohol-based antiseptic solutions for preparation and care of central venous catheter (CVC) insertion sites, with and without octenidine dihydrochloride, a double-blind, randomized, controlled trial was undertaken in the haematology units and in one surgical unit of two university hospitals. Adult patients with a non-tunnelled CVC were randomly assigned to two different skin disinfection regimens at the insertion site: 0.1% octenidine with 30% 1-propanol and 45% 2-propanol, and as control 74% ethanol with 10% 2-propanol. Endpoints were (i) skin colonization at the insertion site; (ii) positive culture from the catheter tip (> or = 15 CFU); and (iii) occurrence of CVC-associated bloodstream infection (defined according to criteria set by the CDC). Four hundred patients with inserted CVC were enrolled from May 2002 through April 2005. Both groups were similar in respect of patient characteristics and co-morbidities. Skin colonization at the CVC insertion site during the first 10 days was significantly reduced by octenidine treatment (relative difference octenidine vs. control: 0.21; 95%CI: 0.11-0.39, p <0.0001). Positive culture of the catheter tip was significantly less frequent in the octenidine group (7.9%) than in the control group (17.8%): OR = 0.39 (95%CI: 0.20-0.80, p 0.009). Patients treated with octenidine had a non-significant reduction in catheter-associated bloodstream infections (4.1% vs. 8.3%; OR = 0.44; 95%CI: 0.18-1.08, p 0.081). Side effects were similar in both groups. This randomized controlled trial supports the results of two observational studies demonstrating octenidine in alcoholic solution to be a better option than alcohol alone for the prevention of CVC-associated infections.

Evidence from Nonrandomized Studies: A Case Study on the Estimation of Causal Effects

Although randomized controlled trials are regarded as the gold standard for comparison of treatments, evidence from observational studies is still relevant. To cope with the problem of possible confounding in these studies, investigators need methods for analyzing their results which adjust for confounders and lead to unbiased estimation of the treatment effect. In this paper, the authors describe the main principles of three statistical methods for doing this. The first method is the classical approach of a multiple regression model including the effects of treatment and covariates. This considers the relation between prognostic factors and the outcome variable as a relevant criterion for adjustment. The second method is based on the propensity score, focusing on the relation between prognostic factors and treatment assignment. The third method is an ecologic approach using a grouped treatment variable, which may aid in avoiding confounding by indication. These approaches are applied to a partially randomized trial conducted in 720 German breast cancer patients between 1984 and 1997. The study had a comprehensive cohort study design that included recruitment of patients who had consented to participation but not to randomization because of a preference for one of the treatments. This design offers a unique opportunity to contrast results from the nonrandomized portion of a study with those for a randomized subcohort as a reference.

Competing Risks and Multistate Models

Complex clinical endpoints are present in studies in cancer. Especially in studies on hematopoietic stem-cell transplantation (HSCT), various risks exist after HSCT. Patients can experience acute and chronic graft versus host disease (GVHD) or need to undergo immunosuppressive therapy (IST), a relapse can occur, or patients can die after relapse or without former relapse (nonrelapse mortality, NRM). Sometimes, endpoints can be reasonably combined in a composite endpoint, as, for example, relapse and NRM are combined into disease-free survival (DFS). In this case, standard survival techniques, as Kaplan–Meier estimation of the DFS probability, can be applied. Often, interest focuses on endpoints for which competing risks are present, as, for example, GVHD, with death without prior GVHD as competing risk. This results in a competing risks model, a special case of a multistate model. A more complex multistate model is required when the effects of events occurring in the course of the study on further disease process shall be investigated, as, for example, the effect of GVHD on relapse and NRM. Another endpoint of interest is time under IST. As patients usually experience multiple episodes of IST, thus switching back and forth between “IST” and “no IST” during follow-up, the multistate model used for analysis must be adapted for this event structure. The aim of this nontechnical report is to explain use and interpretation of Cox-type regression models suitable for the different situations in a randomized trial on the effects of anti-T-cell globulin as GVHD prophylaxis. Clin Cancer Res; 19(1); 12–21. ©2012 AACR.

Statistical issues in the analysis of adverse events in time-to-event data

The aim of this work is to shed some light on common issues in the statistical analysis of adverse events (AEs) in clinical trials, when the main outcome is a time-to-event endpoint. To begin, we show that AEs are always subject to competing risks. That is, the occurrence of a certain AE may be precluded by occurrence of the main time-to-event outcome or by occurrence of another (fatal) AE. This has raised concerns on informative censoring. We show that, in general, neither simple proportions nor Kaplan-Meier estimates of AE occurrence should be used, but common survival techniques for hazards that censor the competing event are still valid, but incomplete analyses. They must be complemented by an analogous analysis of the competing event for inference on the cumulative AE probability. The commonly used incidence rate (or incidence density) is a valid estimator of the AE hazard assuming it to be time constant. An estimator of the cumulative AE probability can be derived if the incidence rate of AE is combined with an estimator of the competing hazard. We discuss less restrictive analyses using non-parametric and semi-parametric approaches. We first consider time-to-first-AE analyses and then briefly discuss how they can be extended to the analysis of recurrent AEs. We will give a practical presentation with illustration of the methods by a simple example. Copyright

Home Mechanical Ventilation for COPD: High-Intensity Versus Target Volume Noninvasive Ventilation

BACKGROUND: High-intensity noninvasive ventilation (HI-NIV) is the most effective means of improving several physiological and clinical parameters in subjects with chronic hypercapnic COPD. Whether the newer hybrid mode using target tidal volume noninvasive ventilation (target VT NIV) provides additional benefits remains unclear. METHODS: Subjects with COPD successfully established on long-term HI-NIV were switched to target VT NIV. Optimal target VT settings according to nocturnal transcutaneous PCO2 measurements were achieved following a randomized crossover trial using 8 mL/kg ideal body weight and 110% of individual VT during HI-NIV, respectively. The following parameters were compared at the beginning of the trial while subjects were on HI-NIV, and after 3 months on optimal target VT NIV: sleep quality by polysomnography, overnight gas exchange, subjects tolerance, overnight pneumotachygraphic measurements during NIV, health-related quality of life (severe respiratory insufficiency questionnaire), exercise capacity (6-min walk test), and lung function. RESULTS: Ten of 14 subjects completed the study. There were no differences between HI-NIV and target VT NIV in any of the above-mentioned parameters. Specifically, the mean overnight transcutaneous PCO2 was equivalent under each form of ventilation (both 45 ± 5 mm Hg, P = .75). CONCLUSIONS: Switching subjects from well-established HI-NIV to target VT NIV shows no clinical benefits in chronic hypercapnic COPD. In particular, sleep quality, the control of nocturnal hypoventilation, daytime hypercapnia, overnight ventilation patterns, subjects tolerance, health-related quality of life, lung function, and exercise capability were all similar in subjects who underwent HI-NIV and target VT NIV. Nevertheless, target VT NIV might offer some physiological advantages in breathing pattern and might be beneficial in some individual patients. (German Clinical Trials Register [www.drks.de] Registration DRKS00000450.)

Central venous catheter-associated bloodstream infection and colonisation of insertion site and catheter tip. What are the rates and risk factors in haematology patients?

Skin colonisation is an important source for central venous catheter (CVC) colonisation and infection. This study intended to identify risk factors for skin colonisation prior to CVC placement (baseline colonisation) and within 10xa0days after CVC insertion (subsequent colonisation), for CVC-tip colonisation and for bloodstream infection (BSI). Within a randomised clinical trial, data of 219 patients with haematological malignancies and inserted CVC (with a total of 5,501 CVC-days and 4,275xa0days at risk) in two university hospitals were analysed. Quantitative skin cultures were obtained from the insertion site before CVC placement and at regular intervals afterwards. CVC-tip cultures were taken on CVC removal and data collection was performed. Statistical analysis included linear and logistic regression models. Age was an independent risk factor for colonisation prior to CVC placement (baseline colonisation). Independent risk factors for subsequent colonisation were baseline colonisation and male gender. High level of subsequent skin colonisation at the insertion site was a predictor of CVC-tip colonisation, and a predictor of BSI. High level of skin colonisation predicts catheter tip colonisation and possibly subsequent infection. Sustained reduction of bacterial growth at the CVC insertion site is therefore indispensable. Male patients are at particular risk for skin colonisation and may be a target population for additional insertion-site care before and during catheterisation.

Correction of confounding bias in non-randomized studies by appropriate weighting.

In non-randomized studies, the assessment of a causal effect of treatment or exposure on outcome is hampered by possible confounding. Applying multiple regression models including the effects of treatment and covariates on outcome is the well-known classical approach to adjust for confounding. In recent years other approaches have been promoted. One of them is based on the propensity score and considers the effect of possible confounders on treatment as a relevant criterion for adjustment. Another proposal is based on using an instrumental variable. Here inference relies on a factor, the instrument, which affects treatment but is thought to be otherwise unrelated to outcome, so that it mimics randomization. Each of these approaches can basically be interpreted as a simple reweighting scheme, designed to address confounding. The procedures will be compared with respect to their fundamental properties, namely, which bias they aim to eliminate, which effect they aim to estimate, and which parameter is modelled. We will expand our overview of methods for analysis of non-randomized studies to methods for analysis of randomized controlled trials and show that analyses of both study types may target different effects and different parameters. The considerations will be illustrated using a breast cancer study with a so-called Comprehensive Cohort Study design, including a randomized controlled trial and a non-randomized study in the same patient population as sub-cohorts. This design offers ideal opportunities to discuss and illustrate the properties of the different approaches.

Minute Ventilation During Spontaneous Breathing, High-Intensity Noninvasive Positive Pressure Ventilation and Intelligent Volume Assured Pressure Support in Hypercapnic COPD

Abstract Background: High-intensity noninvasive positive pressure ventilation (HI-NPPV) is an effective treatment option in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). However, the effect of HI-NPPV compared with spontaneous breathing (SB) on minute ventilation (MV) in patients receiving long-term treatment remains to be determined. This study compared MV during HI-NPPV and SB. In addition, the ability of intelligent volume assured pressure support (iVAPS) to increase MV to the same extent as HI-NPPV was determined. Methods: Daytime pneumotachographic measurements were performed during SB, HI-NPPV and iVAPS. Results: Twenty-seven stable hypercapnic COPD patients (mean FEV1 34 ± 15% predicted) who had been treated with HI-NPPV for a median of 22 months (interquartile range 8.5–84 months) were enrolled. Mean MV was 9.5 ± 1.7 L/min during SB and 12.1 ± 2.8 L/min during HI-NPPV, an increase of 2.5 L/min (95%u2009CI [1.5–3.6] p < 0.001), or 26%. MV during iVAPS was 11.7 ± 3.6 L/min, an increase of 1.8 L/min (95%CI [0.7–3.0], p = 0.003) compared with SB. There was no difference in MV between HI-NPPV and iVAPS (p = 0.25). Conclusion: Long-term HI-NPPV increased MV by an average of 26% compared with SB in stable hypercapnic COPD patients. A similar increase in MV was observed during use of iVAPS.

Predictors of prognosis and treatment outcome in central retinal artery occlusion: local intra-arterial fibrinolysis vs. conservative treatment

IntroductionThe study analyses patients’ risk factors to determine prognostic and predictive factors in patients with acute central retinal artery occlusion (CRAO) treated in the randomized European Assessment Group for Lysis in the Eye (EAGLE) Study with local intra-arterial fibrinolysis (LIF) or conservative standard treatment (CST). These data could improve patient selection for either method.MethodsPost hoc statistical analysis of effects of risk factors on overall best corrected visual acuity (BCVA [logarithm of the minimum angle of resolution (logMAR)]) at baseline and month 1 (prognostic effect) and on the difference between outcome of CST and LIF (predictive effect) was conducted.ResultsSeventy two of 84 EAGLE datasets were included. Prognostic effect: Patients with coronary heart disease (CHD) presented worse BCVA at baseline (0.39 logMAR, pu2009=u20090.0097). Patients with time from occlusion to treatment <12xa0h showed a trend to better vision gain at month 1 (−0.23 logMAR, pu2009=u20090.086), similarly smoking (−0.24 logMAR, pu2009=u20090.077). Predictive effect: Age (<60xa0years favours LIF −0.54 logMAR; >70xa0years favours CST 0.28 logMAR; interaction pu2009=u20090.070) and CHD (favours CST 0.44 logMAR; interaction pu2009=u20090.073) might be predictors of therapeutic outcome. There were no strong effects in multivariate analysis.ConclusionCHD, time from occlusion to treatment and smoking influence BCVA at baseline and at month 1 (prognostic effect). Patients treated within 12xa0h are more likely to profit from treatment. In multivariate analysis, there is no clear trend to benefit from LIF even in patients with young age, no CHD and early treatment. Based on this preliminary report on a rather small sample size, we do not recommend LIF in CRAO patients.