Our finding that nearly one-third of ICU survivors died during the follow-up period aligns with previous work [6, 7, 28]. We found that a significant proportion of these deaths occurred among the elderly, with age being an independent strong predictor of mortality. While these results are not unexpected, that one in five survivors of criticalillness aged 85 years or older die within 6 months after hospital discharge suggests that there may be opportunities for informing patient and provider decisions regarding the increased risk of dying after an ICU stay in this subgroup. The observed negative associ- ation between days in the ICU and long-term mortality Table 2 Demographic and clinical characteristics and outcomes
To address this issue, there is a growing need to de- velop interventions that can improve patient outcomes. An essential part of this process is developing a patient- centered “core outcome set” of measures that should be evaluated and reported in all clinical trials evaluating post-discharge outcomes in ICU survivors . Core outcome sets allow more direct comparison of trial find- ings to draw more meaningful synthesis and conclusions on the effectiveness of interventions [13, 14]. However, the complex nature of outcomes after criticalillness necessitates having an in-depth understanding of the problems ICU survivors face following hospital dis- charge. The patients’ perspective is essential in gaining this understanding. Qualitative research is a well-known methodology to collect and analyze in-depth information from patients, particularly on their health status that may help inform development of core outcome sets . Recently, there has been an increase in qualitative re- search published on the patient perspective following criticalillness [16–20]. In addition, qualitative re- search is increasingly being recognized as an import- ant contribution to randomized controlled trials, with an important value in planning the trial, identifying important patient outcomes, and adding context to the trial findings [21, 22].
In the ICU, explicit interventions to prevent functional limitations typically rely on physical and occupational thera- py. Enacting such therapy broadly requires not only dedicated time with highly skilled therapists but also core nursing tasks, including sedation minimization, that allow patients to en- gage in as much self-care as possible, and frequent time out of bed. 68 Hospital variations in physical therapy practices may be marked. 69 Mobility-related activities have been called the most common “error of omission” by nursing care on general ﬂoors, 70,71 and there are few reasons to think this is better in the ICU. Although there are promising data about new interventions to improve cognition after criticalillness 72 and there is useful evidence from other related ﬁelds, 12,73–75 such interventions are not yet well integrated into ICU care. Other ICU interventions not directly targeted to improving functional status may also have critical “side-effects” in this step in the disablement process. 68 The interdependence of sedation, delirium, and patient activity has been increasingly evident since Kress et al’s ground-breaking study. 76 Sedation minimization makes possible active patient participation for many hours a day, from the crucial muscular activity of maintaining posture in a chair to playing video games. 77,78 Delirium prevention may improve the long-term outcomes of both mortality and cognition. 79–81 Conversely, other initia- tives intended to improve patient safety may have deleterious effects. Inouye and colleagues have pointed out that the labeling of in-hospital falls as never-events may lead instead to immobilization and unnecessary loss of functional capaci- ty. 68 As we consider the mobilization of hospitalized patients, we should remember that the mortality beneﬁts of paired spontaneous breathing and awakening trials 63 are compara- ble to those of low tidal volume ventilation. 82
response limiting deleterious inflammatory effects, modulation of the innate immune system, and enhancement of anti-microbial peptides. Vitamin D deficiency is frequently observed in critically ill patients and has been related to extrinsic causes (i.e., limited sunlight exposure), magnitude of injury/illness, or the treatment started by medical doctors including fluid resuscitation. Low levels of vitamin D in critically ill patients have been associated with sepsis, organ failure, and mortality. Despite this, there are subpopulations of criticalillness, such as burn patients, where the literature regarding vitamin D status and its influence on outcomes remain insufficient. Thermal injury results in damage to both burned and non-burned tissues, as well as induces an exaggerated and persistent immune-inflammatory and
The present study may have limitations. Postdischarge outcomes may be influenced by other unmeasured vari- ables independently of NRBCs, which could bias esti- mates. Ascertainment bias may be present because not all critically ill patients have NRBCs measured because it is included in the white blood cell differential. Reliance on ICD-9 codes to determine comorbidities will under- estimate the true incidence, which is likely higher . Despite adjustment for multiple potential confounders, residual confounding may be present contributing to ob- served differences in outcomes. We are unable to adjust for physiologic-based severity of illness scores which are strong predictors of criticalillness outcome . We have adjusted for an ICU risk prediction score validated against APACHE II  but it is conceivable that inclu- sion of a physiologic score in the analysis may materially alter the NRBC–postdischarge mortality association. However, despite multivariable adjustment, the absence of physiologic data is a potential limitation of our study. Further, our readmission data include only hospital read- missions from the two institutions under study, which may have underestimated the total readmission rates.
Establishing a ‘core outcome set’ (COS) is one strategy to address the requirement for outcome transparency in trials. A COS is an agreed, standardised collection of outcomes that would be measured and reported, as a minimum, in all clinical trials for a defined field of interest [25, 26]. Importantly a COS does not preclude researchers from measuring other outcomes of interest relevant to the specific intervention, including the pri- mary outcome. Rather, achieving consensus from key stakeholders on priority outcomes would increase the cumulative value of individual trials for informing evidence-based clinical decision-making. Recent COSs in the criticalillness population have focussed on long-term outcomes following hospital discharge in sur- vivors of acute respiratory failure [27, 28], mechanical ventilation , and delirium . Outcome selection in complex interventions, such as physical rehabilitation in criticalillness, is crucial . At present there is no COS for trials investigating physical rehabilitation interven- tions at any stage of the recovery pathway for this pa- tient population. The aim of the PRACTICE study, therefore, is to develop a COS for trials of physical re- habilitation interventions delivered across the con- tinuum of recovery from within the ICU to hospital discharge to the community.
A comprehensive, systematic and multi-disciplinary approach to assessing outcomes is necessary to support future plans for patient management. The extent to which this currently occurs prior to ICU discharge is unclear, but it is essential for assessment of outcome to begin at this time to provide a baseline for planning and ongoing intervention. Recovery following criticalillness extends beyond hospitalisation. In preparation for hospital discharge there is a need to reassess patient outcomes to determine the extent to which the patient has improved (or not) and to communicate this information to those responsible for patient care in the community. Comprehensive physical assessment is frequently undertaken, especially for those patients who are discharged into a subacute or rehabilitation setting. Determining psychological and cognitive compromise, or the need for social support, is more difficult.
However, these promising results were not replicated by Agus et al, who investigated the effect of tight glycemic control in 444 children and found that although normoglycemia was achieved sooner and was maintained for longer by using intensive insulin therapy (P,0.001), this had no effect on secondary outcomes, including infection, and did not benefit high-risk groups. 1
the effect of the duration of mechanical ventilation on the presence of dysphagia and the effect of dysphagia on patient outcomes. Because of the known strong effects of tracheostomy on swallowing function and a potential interaction between tracheostomy and duration of mechanical ventilation in the models we used to exam- ine the effect of the duration of mechanical ventilation on the presence of dysphagia, we prespecified that we would perform separate multivariate analyses for patients with or without tracheostomy. SAS version 9.1 software (SAS Institute Inc, Cary, NC, USA) was used for all analyses, and P < 0.05 was considered statistically significant. Confidence intervals (95%) for adjusted odds ratios (AORs) and 25th to 75th interquartile ranges [IQRs] for median values are recorded in square brack- ets. The Bonferroni correction for multiple comparisons was performed were appropriate.
Understanding the eff ects of ICU protocolization Many institutions, in an attempt to improve care, have adapted protocols without strong supporting evidence. More research about speciﬁ c protocols, and, more generally, about the role of protocols in patient care needs to be performed. We need to determine whether patient safety, outcomes and costs are reliably improved by protocols. As an initial step, the CriticalIllnessOutcomes Study (CIOS), organized through the US CriticalIllness and Injuries Trials (USCIIT) Group, is being conducted to examine organiza- tional and struc tural factors in adult ICUs, and to determine their asso ciation with patient-related treatments and outcomes . CIOS will enhance our understanding of the relation ship between ICU protocols, both availability and utiliza tion, and clinical outcomes.
ABSTRACT Criticalillness is hypothesized to associate with loss of “health- promoting” commensal microbes and overgrowth of pathogenic bacteria (dysbiosis). This dysbiosis is believed to increase susceptibility to nosocomial infections, sepsis, and organ failure. A trial with prospective monitoring of the intensive care unit (ICU) patient microbiome using culture-independent techniques to conﬁrm and character- ize this dysbiosis is thus urgently needed. Characterizing ICU patient microbiome changes may provide ﬁrst steps toward the development of diagnostic and thera- peutic interventions using microbiome signatures. To characterize the ICU patient microbiome, we collected fecal, oral, and skin samples from 115 mixed ICU patients across four centers in the United States and Canada. Samples were collected at two time points: within 48 h of ICU admission, and at ICU discharge or on ICU day 10. Sample collection and processing were performed according to Earth Microbiome Project protocols. We applied SourceTracker to assess the source composition of ICU patient samples by using Qiita, including samples from the American Gut Project (AGP), mammalian corpse decomposition samples, childhood (Global Gut study), and house surfaces. Our results demonstrate that criticalillness leads to signiﬁcant and rapid dysbiosis. Many taxons signiﬁcantly depleted from ICU patients versus AGP healthy controls are key “health-promoting” organisms, and overgrowth of known pathogens was frequent. Source compositions of ICU patient samples are largely un- characteristic of the expected community type. Between time points and within a patient, the source composition changed dramatically. Our initial results show great promise for microbiome signatures as diagnostic markers and guides to therapeutic interventions in the ICU to repopulate the normal, “health-promoting” microbiome and thereby improve patient outcomes.
There is considerable evidence linking sleep-related breathing disorders and poor sleep quality with cognitive impairment in many patient populations. Cognitive domains particularly associated with sleep disruption in- clude working memory, semantic memory, processing speed, and visuospatial abilities . Experimental studies support a number of potential neurobiological mechanisms including accumulation of beta-amyloid pathology, abnormalities of tau, synaptic abnormalities, changes in hippocampal long-term potentiation, im- paired hippocampal neurogenesis, and gene expression changes. Few studies have rigorously evaluated the prevalence of sleep disruption after criticalillness and its potential role in potentiating cognitive impairment. A recent systematic review by Altman and colleagues reported on 22 studies examining sleep after hospital discharge in survivors of criticalillness; however, none of these studies reported on cognitive outcomes . Despite sleep disturbances improving over time, up to two-thirds (61%) of patients reported persistently poor sleep at 6 months follow-up . Analyses of risk factors for sleep disturbances have had conflicting results, but persistent sleep disturbances were consistently associ- ated with post-discharge psychological comorbidities and impaired quality of life.
Our study has several limitations. First, a corticotropin test was not performed in our hospital. In this circumstance, group 2 patients (whose second serum cortisol level was between 34 μg/dl and 15 μg/dl) did not receive a corticotropin test. Second, the study population was small. We speculate that if larger numbers could be recruited, then differences in out- comes among the three groups, such as survival rate, might be significant. Third, the serum cortisol level measured in this study was total cortisol, rather than the free form of cortisol. However, there is no well documented evidence that free cor- tisol has superior diagnostic efficacy to total cortisol level . Fourth, the decision regarding whether to test the serum cor- tisol level depended on the ICU physicians, and so there may be a selection bias in the study population. This was a pilot study in which we aimed to analyze adrenal function in patients with prolonged criticalillness. Large trials are necessary to relate the outcomes of prolonged criticalillness to relative adrenal insufficiency. High-quality randomized control trials are necessary to evaluate the efficacy of corticosteroids at 'physiologic doses' in these patients.
Seasonal rhythms and ﬂ uctuations in innate and acquired immune responses have been documented in many species [52,53]. Profound but selective eﬀ ects on immune function are associated with the prevailing photoperiod [36,54]. T cell immunity is depressed in most species in the winter, even when natural light sources and exposure are kept constant [20,54]. Experimental data, however, show that immune cell numbers and immunoglobulin concentrations vary with respect to the season or day length [34,54] even during the winter. Higher leukocyte counts are noted with less hours of light [20,54], demonstrating that the photoperiod may also inﬂ uence the functional capabilities of immune cells. Short days selectively enhance natural killer (NK) basal proliferative capacity and cell activity . In contrast, in the same rodent model, phagocytic and granulocyte oxidative burst activity are reduced during short, by comparison to long, days [20,55]. Collectively, these results conﬁ rm reduced immune function in winter compared to summer, but with enhanced immune function in short winter-like photoperiods compared to long summer-like day lengths  (Table 1). Th e net elevated immune function in short days is thought to counteract the suppressive eﬀ ects of environmental stressors such as low ambient temperature on immune function . Th ese facts raise many questions for the management of critically ill patients. Is there a consistent seasonality on the outcomes of critically ill patients? Should we shorten the day length for the most seriously ill septic patients in the ICU to enhance their immunity? Th ese concepts await further investigation.
No studies reported our first primary outcome measure describing the risk of PTSD in patients recovering from admission to ICU using a structured clinical interview. We applied this definition a priori as it is supported by the American Psychiatric Association 2013 as the gold standard for the diagnosis of PTSD. Jones 2010, when attempting to reduce the risk of detection bias in the diag- nosis of PTSD, trained the interviewers in the administration, but not the meaning or scoring, of the items in the instrument. The use of an uninformed clinician makes the interview no longer di- agnostic, and limits its reliability as an assessment tool. Therefore, we did not include these results in the Cochrane Review. There is currently no general agreement on which outcomes should be measured in trials focusing on psychological recovery after criti- cal illness. Such agreement would be beneficial to aid consistency across relevant trials (Blackwood 2014).
Although this EVD outbreak narrowed some knowledge gaps, pathophysiology and the immunological response to acute infection and convalescence is still minimally char- acterized. Access to rapid point-of-care EVD diagnostic capacity to differentiate between other common febrile illnesses  is critical because the early presentation of EVD has a broad differential diagnosis [5, 7, 34]. Labora- tory testing to identify prognostic indicators could help guide clinical care. Evaluation of specific antiviral therap- ies is critical as is evaluation of commonly used treatments for which there is still very limited evidence (e.g., empiric antibiotics, anti-diarrheal agents, and fluid replacement composition and volume). The safety and functionality of PPE must be improved. Standardized, easy-to-use clinical charting and human resources for data entry should be made available to support cohort studies and clinical trials. While it seems intuitive that provision of advanced supportive and critical care improves patient outcomes, operationalizing and evaluating increased levels of care to resource-challenged environments is needed. Prepared research protocols that can be rapidly adapted to country- specific settings and quickly implemented could reduce research delays in future outbreaks. Following patients who survive EVD is important to better characterize immune correlates of virus clearance and host genetic factors that contribute to survival, and to better address morbidity of the post-Ebola syndrome.
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This study presents a subanalysis of 40 patients of a recent prospective observational study  that investi- gated the predictive value of certain electrophysiological measurements on the development of ICU-acquired weakness. Validating muscle membrane excitability at the onset of criticalillness turned out to be most valuable for an early prediction of ICU-acquired weakness in immo- bile, sedated patients adding important information to clinical estimation of the patients' motor function upon emergence from sedation. Mechanically ventilated ICU patients on an operative ICU who featured simplified acute physiology (SAPS-II) scores of 20 or higher on three successive days within one week after ICU admis- sion were included in the study. Sequential electrophysio- logical measurements including measurement of muscle membrane excitability had been performed at study enrollment and every three days until pathological find- ings were detected or clinical evaluation of muscle strength by Medical Research Council (MRC) score was possible.