BACKGROUNDDe-escalation of empirical antimicrobial therapy, a key component of antibiotic stewardship, is considered difficult in ICUs with high rates of antimicrobial resistance.OBJECTIVESTo assess the feasibility and the impact of antimicrobial de-escalation in ICUs with high rates of antimicrobial resistance.METHODSMulticentre, prospective, observational study in septic patients with documented infections. Patients in whom de-escalation was applied were compared with patients without de-escalation by the use of a propensity score matching by SOFA score on the day of de-escalation initiation.RESULTSA total of 262 patients (mean age 62.2 ± 15.1 years) were included. Antibiotic-resistant pathogens comprised 62.9%, classified as MDR (12.5%), extensively drug-resistant (49%) and pandrug-resistant (1.2%). In 97 (37%) patients de-escalation was judged not feasible in view of the antibiotic susceptibility results. Of the remaining 165 patients, judged as patients with de-escalation possibility, de-escalation was applied in 60 (22.9%). These were matched to an equal number of patients without de-escalation. In this subset of 120 patients, de-escalation compared with no de-escalation was associated with lower all-cause 28 day mortality (13.3% versus 36.7%, OR 0.27, 95% CI 0.11-0.66, P = 0.006); ICU and hospital mortality were also lower. De-escalation was associated with a subsequent collateral decrease in the SOFA score. Cox multivariate regression analysis revealed de-escalation as a significant factor for 28 day survival (HR 0.31, 95% CI 0.14-0.70, P = 0.005).CONCLUSIONSIn ICUs with high levels of antimicrobial resistance, feasibility of antimicrobial de-escalation was limited because of the multi-resistant pathogens isolated. However, when de-escalation was feasible and applied, it was associated with lower mortality.

Key PointsQuestionHave end-of-life practices in European intensive care units (ICUs) changed from 1999-2000 to 2015-2016? FindingsIn this prospective observational study of 1785 patients who had limitations in life-prolonging therapies or died in 22 European ICUs in 2015-2016, compared with data previously reported from the same ICUs in 1999-2000 (2807 patients), treatment limitations (withholding or withdrawing life-sustaining treatment or active shortening of the dying process) occurred significantly more frequently (89.7% vs 68.3%), whereas death without any limitations in life-prolonging therapies occurred significantly less frequently (10.3% vs 31.7%). MeaningThese findings suggest that end-of-life care practices in European ICUs changed from 1999-2000 to 2015-2016 with more limitations in life-prolonging therapies and fewer deaths without treatment limitations. ImportanceEnd-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time. ObjectiveTo determine the changes in end-of-life practices in European ICUs after 16 years. Design, Setting, and ParticipantsEthicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision. ExposuresComparison between the 1999-2000 cohort vs 2015-2016 cohort. Main Outcomes and MeasuresEnd-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation [CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists. ResultsOf 13625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n=2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years [interquartile range {IQR}, 59-79] vs 67 years [IQR, 54-75]; P<.001) and the proportion of female patients was similar (39.6% vs 38.7%; P=.58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 [89.7%] vs 1918 [68.3%]; difference, 21.4% [95% CI, 19.2% to 23.6%]; P<.001), with more withholding of life-prolonging therapy (892 [50.0%] vs 1143 [40.7%]; difference, 9.3% [95% CI, 6.4% to 12.3%]; P<.001), more withdrawing of life-prolonging therapy (692 [38.8%] vs 695 [24.8%]; difference, 14.0% [95% CI, 11.2% to 16.8%]; P<.001), less failed CPR (110 [6.2%] vs 628 [22.4%]; difference, -16.2% [95% CI, -18.1% to -14.3%]; P<.001), less brain death (74 [4.1%] vs 261 [9.3%]; difference, -5.2% [95% CI, -6.6% to -3.8%]; P<.001) and less active shortening of the dying process (17 [1.0%] vs 80 [2.9%]; difference, -1.9% [95% CI, -2.7% to -1.1%]; P<.001). Conclusions and RelevanceAmong patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitations. This study compares changes in end-of-life practices (withholding or withdrawing of life-prolonging therapy, active shortening of the dying process, failed CPR, documentation of brain death) in 22 European ICUs between 1999-2000 and 2015-2016.

Mechanical stress exerts a substantial role on skeletal-cell renewal systems, whereas accumulating evidence suggests that epigenetic mechanisms induce changes and differential gene expression. Although the underlying mechanisms remain to be fully elucidated, our study suggests that the influence of the long term mechanical stimulation elicits epigenetic modifications controlling osteogenic differentiation of human adipose tissue multipotential stromal cells (hAT-MSCs) and contributes to an accelerating in vitro osteogenesis. GNAS imprinting gene acts as a critical regulator of osteoblast differentiation and is implicated in human genetic disorders with pathological formation of ectopic-skeletal bone. Investigating a wide variety of stimuli, we showed that daily mechanical stretch on hAT-MSCs of 7th and 15th days' intervals induced a significant down-regulation in DNA methylation status of critical CpG sites of NESP and GNASXL isoforms, accompanied by up-regulation of the corresponding gene transcripts, and osteogenic differentiation earlier in culture. Importantly, methylation analysis of differentiating bone marrow-derived MSCs revealed similar methylation patterns. Bioinformatic analysis further showed that all CpG islands exhibiting significant methylation alterations encompassed transcriptional repressor CTCF binding sites. We hereby emphasize the need to investigate the epigenetic alterations on hAT-MSCs during environmental mechanical forces and to consider how the knowledge gained through these studies may foster new means of symptoms prevention and management of ectopic bone formation in the clinic.

Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes.It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality.The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment.Prone positioning is a supplementary strategy available in managing patients with ARDS.It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the "sponge lung" -and the "shape matching" -model.Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle.The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized.Although patients' response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS.This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort.

Background Studies have shown an association between intensive care unit environments and symptoms of psychological distress in family members of critically ill patients.Objective To investigate levels of cardiac anxiety in family members of intensive care unit patients.Methods From March 2012 to July 2013, on the third day after the patient's admission, 223 family members of 147 patients completed the Cardiac Anxiety Questionnaire. A total score was calculated from 3 subscales: fear and worry about heart sensations, avoidance of activities reproducing cardiac symptoms, and heart-focused attention and monitoring of cardiac activity.Results Among the family members, 142 were women (63.7%) and 81 (36.3%) were men, 150 (67.3%) were married, and 37 (16.6%) were unemployed. Their mean score for overall cardiac anxiety was 1.11 (SD, 0.64), significantly higher (P <.001) than for the general Greek population. Although all 3 subscales scores were significantly higher than for the general population, the highest score was recorded for the avoidance subscale (mean, 1.77; SD, 0.68). The relationship to the patient had a significant effect on heart-focused attention (F-5 = 3.51; P =.03). The mean score for patients' siblings (2.0; SD, 0.01) differed significantly (P =.02) from the mean for other family member groups. Older adults (P =.02) and married participants (P =.05) reported higher levels of fear and worry related to cardiac stimuli, and women further reported higher levels of cardioprotective avoidance behavior (P =.02).Conclusions A noticeable number of family members of critical care patients had moderate to severe cardiac anxiety during the hospitalization of their relatives.

Percutaneous endoscopic gastrostomy (PEG) is considered a safe technique for providing enteral access and nutrition support in patients incapable of oral feeding. The fixation between the stomach wall and abdominal wall requires time and is essential for the formation of the PEG tract. However, there is no evidence in the literature that endoscopy should not be attempted in patients with an immature PEG tract. Here, we report a complication of pneumoperitoneum and peritonitis in a patient with a recently performed PEG as a result of upper gastrointestinal endoscopy.