Mortality of Older Patients Admitted to an ICU: A Systematic Review.

OBJECTIVES: To conduct a systematic review of mortality and factors independently associated with mortality in older patients admitted to ICU. DATA SOURCES: MEDLINE via PubMed, EMBASE, the Cochrane Library, and references of included studies. STUDY SELECTION: Two reviewers independently selected studies conducted after 2000 evaluating mortality of older patients (≥ 75 yr old) admitted to ICU. DATA EXTRACTION: General characteristics, mortality rate, and factors independently associated with mortality were extracted independently by two reviewers. Disagreements were solved by discussion within the study team. DATA SYNTHESIS: Because of expected heterogeneity, no meta-analysis was performed. We selected 129 studies (median year of publication, 2015; interquartile range, 2012-2017) including 17 based on a national registry. Most were conducted in Europe and North America. The median number of included patients was 278 (interquartile range, 124-1,068). ICU and in-hospital mortality were most frequently reported with considerable heterogeneity observed across studies that was not explained by study design or location. ICU mortality ranged from 1% to 51%, in-hospital mortality from 10% to 76%, 6-month mortality from 21% to 58%, and 1-year mortality from 33% to 72%. Factors addressed in multivariate analyses were also heterogeneous across studies. Severity score, diagnosis at admission, and use of mechanical ventilation were the independent factors most frequently associated with ICU mortality, whereas age, comorbidities, functional status, and severity score at admission were the independent factors most frequently associated with 3- 6 and 12 months mortality. CONCLUSIONS: In this systematic review of older patients admitted to intensive care, we have documented substantial variation in short- and long-term mortality as well as in prognostic factors evaluated. To better understand this variation, we need consistent, high-quality data on pre-ICU conditions, ICU physiology and treatments, structure and system factors, and post-ICU trajectories. These data could inform geriatric care bundles as well as a core data set of prognostic factors to inform patient-centered decision-making.

Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the ADAMON cluster-randomised study.

Background According to Good Clinical Practice, clinical trials must protect rights and safety of patients and make sure that the trial results are valid and interpretable. Monitoring on-site has an important role in achieving these objectives; it controls trial conduct at trial sites and informs the sponsor on systematic problems. In the past, extensive on-site monitoring with a particular focus on formal source data verification often lost sight of systematic problems in study procedures that endanger Good Clinical Practice objectives. ADAMON is a prospective, stratified, cluster-randomised, controlled study comparing extensive on-site monitoring with risk-adapted monitoring according to a previously published approach. Methods In all, 213 sites from 11 academic trials were cluster-randomised between extensive on-site monitoring (104) and risk-adapted monitoring (109). Independent post-trial audits using structured manuals were performed to determine the frequency of major Good Clinical Practice findings at the patient level. The primary outcome measure is the proportion of audited patients with at least one major audit finding. Analysis relies on logistic regression incorporating trial and monitoring arm as fixed effects and site as random effect. The hypothesis was that risk-adapted monitoring is non-inferior to extensive on-site monitoring with a non-inferiority margin of 0.60 (logit scale). Results Average number of monitoring visits and time spent on-site was 2.1 and 2.7 times higher in extensive on-site monitoring than in risk-adapted monitoring, respectively. A total of 156 (extensive on-site monitoring: 76; risk-adapted monitoring: 80) sites were audited. In 996 of 1618 audited patients, a total of 2456 major audit findings were documented. Depending on the trial, findings were identified in 18%-99% of the audited patients, with no marked monitoring effect in any of the trials. The estimated monitoring effect is -0.04 on the logit scale with two-sided 95% confidence interval (-0.40; 0.33), demonstrating that risk-adapted monitoring is non-inferior to extensive on-site monitoring. At most, extensive on-site monitoring could reduce the frequency of major Good Clinical Practice findings by 8.2% compared with risk-adapted monitoring. Conclusion Compared with risk-adapted monitoring, the potential benefit of extensive on-site monitoring is small relative to overall finding rates, although risk-adapted monitoring requires less than 50% of extensive on-site monitoring resources. Clusters of findings within trials suggest that complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings. Risk-adapted monitoring in only a sample of patients appears sufficient to identify systematic problems in the conduct of clinical trials. Risk-adapted monitoring has a part to play in quality control. However, no monitoring strategy can remedy defects in quality of design. Monitoring should be embedded in a comprehensive quality management approach covering the entire trial lifecycle.

Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials.

BACKGROUND: The concept of risk assessment for clinical trials has been discussed before, but no comprehensive structured procedure leading to risk-adapted quality management has been published so far. Such a procedure is of particular interest for noncommercial trials in order to optimally use the sparse resources. PURPOSE: To provide a structured procedure for risk analysis in clinical trials. To propose strategies for on-site monitoring adapted to the risks identified. RESULTS: The risk analysis refers to the risk of noncompliance with the main objectives of Good Clinical Practice. It takes into account risks of the study intervention compared to the risks a patient would run if treated outside a protocol as well as further potential risks regarding patient safety, patient rights, or the credibility of results. The risk analysis is based on detailed questionnaires, which are used to draw up (a) an on-site monitoring strategy recommendation, (b) a list of trial-specific tasks to be covered by on-site monitoring, and (c) a specification of further quality management measures e.g., central monitoring measures. The resulting risk-adapted monitoring strategies focus on the trial's critical aspects, and differ in terms of the recommended extent of on-site activities. LIMITATIONS: The effectiveness of the proposed risk analysis and risk-adapted monitoring has not yet been confirmed. However, the ADAMON project (prospective cluster-randomised study of trial-specific adapted strategies for on-site monitoring in combination with additional quality management measures) has been started in Germany to investigate whether a trial-specific, risk-adapted, reduced on-site monitoring strategy is as effective as an intensive monitoring strategy with regard to the occurrence of serious or critical audit findings. Twelve clinical trials planning to recruit more than 3200 patients participate in this investigation. CONCLUSIONS: Our proposal will provide sponsor-investigators and other noncommercial sponsors with an instrument that may facilitate risk analysis and the implementation of targeted quality management measures.

The connexin31 F137L mutant mouse as a model for the human skin disease erythrokeratodermia variabilis (EKV).

Erythrokeratodermia variabilis (EKV) is a rare autosomal dominant human genodermatosis. Its clinical appearance varies from transient, fast moving erythemas to persistent brown hyperkeratoses. So far, several mutations in the Cx31 or Cx30.3 gene have been reported to cause EKV in humans. We have generated a conditional mouse mutant that carries the human F137L mutation in the Cx31 gene which was described to act in a transdominant negative manner. The phenylalanine residue at position 137 is highly conserved in several human and mouse connexin genes. Mouse embryonic stem (ES) cells expressing one allele of the Cx31F137L mutation were stable but showed approximately 30% decreased transfer of neurobiotin. This is probably due to dominant negative effects of the Cx31F137L protein on wild type Cx31 and Cx43 protein expressed in ES cells. Surprisingly, the healing process of tail incision wounds in Cx31(+/F137L) mice was shortened by 1 day, i.e. very similar as previously reported for mice with decreased expression of Cx43 in the epidermis. This suggests again that Cx31 and Cx43 proteins functionally interact, possibly by forming heteromeric channels in the epidermis. Heterozygous Cx31(+/F137L) mice are viable and fertile, in contrast to homozygous Cx31(F137L/F137L) mice that die around ED 7.5. In Cx31(+/F137L) mice, the epidermal expression pattern and level of Cx26, Cx30, Cx30.3 and Cx43 proteins were not altered compared with wild-type mice. No erythemas were detected in young C31(+/F137L) mice before 2 weeks of age. In contrast to human EKV patients, hyperproliferation of the stratum germinativum was found in only 5% of the analyzed skin area.