Problems in care and avoidability of death after discharge from intensive care: a multi-centre retrospective case record review study.

BACKGROUND: Over 138,000 patients are discharged to hospital wards from intensive care units (ICUs) in England, Wales and Northern Ireland annually. More than 8000 die before leaving hospital. In hospital-wide populations, 6.7-18% of deaths have some degree of avoidability. For patients discharged from ICU, neither the proportion of avoidable deaths nor the reasons underlying avoidability have been determined. We undertook a retrospective case record review within the REFLECT study, examining how post-ICU ward care might be improved. METHODS: A multi-centre retrospective case record review of 300 consecutive post-ICU in-hospital deaths, between January 2015 and March 2018, in 3 English hospitals. Trained multi-professional researchers assessed the degree to which each death was avoidable and determined care problems using the established Structured Judgement Review method. RESULTS: Agreement between reviewers was good (weighted Kappa 0.77, 95% CI 0.64-0.88). Discharge from an ICU for end-of-life care occurred in 50/300 patients. Of the remaining 250 patients, death was probably avoidable in 20 (8%, 95% CI 5.0-12.1) and had some degree of avoidability in 65 (26%, 95% CI 20.7-31.9). Common problems included out-of-hours discharge from ICU (168/250, 67.2%), suboptimal rehabilitation (167/241, 69.3%), absent nutritional planning (76/185, 41.1%) and incomplete sepsis management (50/150, 33.3%). CONCLUSIONS: The proportion of deaths in hospital with some degree of avoidability is higher in patients discharged from an ICU than reported in hospital-wide populations. Extrapolating our findings suggests around 550 probably avoidable deaths occur annually in hospital following ICU discharge in England, Wales and Northern Ireland. This avoidability occurs in an elderly frail population with complex needs that current strategies struggle to meet. Problems in post-ICU care are rectifiable but multi-disciplinary. TRIAL REGISTRATION: ISRCTN14658054.

Neuropsin cleaves EphB2 in the amygdala to control anxiety.

A minority of individuals experiencing traumatic events develop anxiety disorders. The reason for the lack of correspondence between the prevalence of exposure to psychological trauma and the development of anxiety is unknown. Extracellular proteolysis contributes to fear-associated responses by facilitating neuronal plasticity at the neuron-matrix interface. Here we show in mice that the serine protease neuropsin is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2-NMDA-receptor interaction, the expression of Fkbp5 and anxiety-like behaviour. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkbp5 gene expression and enhances behavioural signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1 resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene and low anxiety. The behavioural response to stress can be restored by intra-amygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wild-type mice. Our findings establish a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.

Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation.

Psychological stress causes adaptive changes in the nervous system directed toward maintaining homoeostasis. These biochemical and structural mechanisms regulate animal behavior, and their malfunction may result in various forms of affective disorders. Here we found that the lipocalin-2 (Lcn2) gene, encoding a secreted protein of unknown neuronal function, was up-regulated in mouse hippocampus following psychological stress. Addition of lipocalin-2 to cultured hippocampal neurons reduced dendritic spine actin's mobility, caused retraction of mushroom spines, and inhibited spine maturation. These effects were further enhanced by inactivating iron-binding residues of Lcn-2, suggesting that they were facilitated by the iron-free form of Lcn-2. Concurrently, disruption of the Lcn2 gene in mice promoted stress-induced increase in spine density and caused an increase in the proportion of mushroom spines. The above changes correlated with higher excitability of CA1 principal neurons and with elevated stress-induced anxiety in Lcn-2(-/-) mice. Our study demonstrates that lipocalin-2 promotes stress-induced changes in spine morphology and function to regulate neuronal excitability and anxiety.

Clinical review: the role of ultrasound in estimating extra-vascular lung water.

The estimation of extra-vascular lung water (EVLW) is an essential component in the assessment of critically ill patients. EVLW is independently associated with mortality and its manipulation has been shown to improve outcome. Accurate assessment of lung water is possible with CT and MR imaging but these are impractical for real-time measurement in sick patients and have been superseded by single thermal dilution techniques. While useful, single thermo-dilution requires repeated calibration and is prone to error, suggesting a need for other monitoring methods. Traditionally the lung was not thought amenable to ultrasound examination owing to the high acoustic impedance of air; however, the identification of artefacts in diseased lung has led to increased use of ultrasound as a point of care investigation for both diagnosis and to monitor response to interventions. Following the initial description of B-lines in association with increased lung water, accumulating evidence has shown that they are a useful and responsive measure of the presence and dynamic changes in EVLW. Animal models have confirmed a correlation with lung gravimetry and the utility of B-lines has been demonstrated in many clinical situations and correlated against other established measures of EVLW. With increasing availability and expertise the role of ultrasound in estimating EVLW should be embedded in clinical practice and incorporated into clinical algorithms to aid decision making. This review looks at the evidence for ultrasound as a valid, easy to use, non-invasive point of care investigation to assess EVLW.

Ephs and ephrins: emerging therapeutic targets in neuropathology.

Eph receptors have been the subject of intense research since their discovery. Their widespread pattern of expression, involvement in a variety of important cellular phenomena and unique mode of action have stimulated interest in their role in health and disease across biological and medical domains. However, the function of Ephs in nervous system development and plasticity remains the best characterised. Recent advances suggest that Ephs play an important role in the development of brain pathologies. This review focuses on their basic structure and function and discusses the latest research on their role in neurological diseases.