factor-1 (HIF-1) allows for adaptation of cellular physiology in hypoxia and may permit the enhanced 34 release of EVs under such conditions. Nitric oxide (NO) plays a pivotal role in vascular homeostasis, 35 and can modulate the cellular response to hypoxia by preventing HIF-1 accumulation. We aimed to 36 selectively target HIF-1 via sodium nitrite (NaNO2) addition, and examine the effect on endothelial 37 EV, size, concentration and function, and delineate the role of HIF-1 in EV biogenesis. 38Methods: Endothelial (HECV) cells were exposed to hypoxic conditions (1% O2, 24 hours) and 39 compared to endothelial cells exposed to normoxia (21% O2) with and without the presence of sodium 40 nitrite (NaNO2) (30 µM). Allopurinol (100 µM), an inhibitor of xanthine oxidoreductase, was added 41 both alone and in combination with NaNO2 to cells exposed to hypoxia. EV and cell preparations 42 were quantified by nanoparticle tracking analysis and confirmed by electron microscopy. Western 43 blotting and siRNA were used to confirm the role of HIF-1α and HIF-2α in EV biogenesis. Flow 44 cytometry and time-resolved fluorescence were used to assess the surface and intravesicular protein 45 content. 46Results: Endothelial (HECV) cells exposed to hypoxia (1% O2) produced higher levels of EVs 47 compared to cells exposed to normoxia. This increase was confirmed using the hypoxia-mimetic 48 agent desferrioxamine. Treatment of cells with sodium nitrite (NaNO2) reduced the hypoxic 49 enhancement of EV production. Treatment of cells with the xanthine oxidoreductase inhibitor 50 allopurinol, in addition to NaNO2 attenuated the NaNO2-attributed suppression of hypoxia-mediated 51 EV release. Transfection of cells with HIF-1α siRNA, but not HIF-2α siRNA, prior to hypoxic 52 exposure prevented the enhancement of EV release. 53Conclusion: These data provide evidence that hypoxia enhances the release of EVs in endothelial 54 cells, and that this is mediated by HIF-1α, but not HIF-2α. Furthermore, the reduction of NO2 -to NO 55 via xanthine oxidoreductase during hypoxia appears to inhibit HIF-1α-mediated EV production. 56

ObjectiveSepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments.Results839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%).Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3819-2) contains supplementary material, which is available to authorized users.

Although the true incidence of postoperative dysphagia after cardiac surgery is unknown, it has been reported to occur in 3 to 21.6 per cent of patients. Historically, dysphagia has been associated with increased surgical complications and prolonged hospital stay. This study aimed to evaluate the costs and outcomes associated with dysphagia after cardiac surgery. Patients undergoing nonemergent, nontransplant cardiac operations between June 2013 and June 2014 were eligible for inclusion. Independent predictors of cost were identified through a multivariate linear regression model. Of the 354 patients (35% female) included for analysis, 56 (16%) were diagnosed with postoperative dysphagia. On univariate analysis, patients with dysphagia had increased intensive care unit and total hospital lengths of stay (11.8 vs 5.2 days, P < 0.001 and 18.2 vs 9.7 days, P < 0.001, respectively), and a 57 ± 15 per cent increase in cost of care ( P < 0.001). Dysphagia was not associated with higher rates of in-hospital mortality (3.6% vs 3.0%, P = 0.83). On multivariate linear regression, the development of dysphagia was independently associated with a 45.1 per cent increase in total hospital costs [95% confidence interval (31% and 59%), P < 0.001]. Dysphagia is an independent and major contributor to health care costs after cardiac operations, suggesting that postoperative dysphagia represents a highly suitable target for quality improvement and cost containment efforts.

We would like to comment on, and correct some misunderstandings in, the paper by Foy et al., which suggests that there are major gaps in optimal airway management in neonatal intensive care units (NICUs) in the UK, particularly lack of continuous waveform capnography and/or videolarygoscopy [1]. We are in full agreement with the NHS Improvement recommendation that undetected oesophageal intubation should be a 'Never Event', but note that detection of this event relates mostly to the use of capnography at intubation, rather than during ongoing ventilatory support.It is well recognised that detection of exhaled CO 2 using a colorimetric device facilitates confirmation of tracheal tube placement in newborn babies, despite being subject to both false-positive and false-negative results, and this is recommended by international guidelines [2]. A recent survey of UK neonatal units reported routine use of CO 2 monitoring in 84-88% of neonatal intubations in the labour ward [3], considerably at odds with the reported availability of 'capnography' of between 18% and 48% in Foy et al.'s paper. The phrase 'continuous waveform capnography' may not be one with which most staff working in a UK NICU will be familiar, and it is not clear from the paper whether the question regarding capnography was, or could have been, interpreted as including single use colorimetric CO 2 detector devices at neonatal intubation. Based on a single personal communication, Foy et al. state that capnography is 'routinely' used in 'many' neonatal transfers. This contradicts data presented in Fig. 2, but accords with a recent informal survey of 15 UK transport services, of which 13 routinely use capnography (personal communication -Dr A. Jackson). The transport neonatal population differs in several regards from the NICU population and continuous waveform capnography may be more useful in sedated babies, and when the environment means that the ventilator may not reliably produce flowgraphs. As acknowledged by Foy et al., there is no evidence of reduction in harm from intubation with the use of continuous waveform capnography in the NICU. Interpretation of continuous waveform capnography is likely to be complicated by the fast ventilator rates and short expiry time used in neonates, routine use of uncuffed tracheal tubes and the relatively large dead space in the smallest preterm infants. Most neonatal ventilators now incorporate flow graphs, with which neonatal nursing and medical staff are familiar, and which provide an opportunity to recognise accidental extubation. There has been no direct comparison of continuous waveform capnography and ventilator flow graphs in terms of efficacy and safety in ventilated preterm infants. Videolaryngoscopy has potential to facilitate teaching and practice of neonatal intubation [4] and videolaryngoscopes suitable for very preterm infants are now available. We anticipate therefore that availability of and (just as importantly) familiarity with videolaryngoscopy within UK neonatal units will continue to increase alt...

Background Delirium is a common complication of critical illness with a significant impact on patient morbidity and mortality. The Greater Manchester Critical Care Network established the Delirium Reduction Working Group in 2015. This article describes a region-wide delirium improvement project launched by that group. Methods Multiple Plan-Do-Study-Act cycles were undertaken. Cycle 1: April 2015 demonstrated only 48% of patients had a formal delirium screen. Following this a network-wide event took place and the Delirium Standards for the Greater Manchester Critical Care Network were produced. Cycle 2: May 2016 quarterly audits across the network monitored compliance against the agreed standards. Group events involved implementation of a delirium care bundle, sharing best practice, educating staff and providing guidance on the management of delirium. Cycle 3: November 2016 quarterly audit continued and a regional delirium study day was rolled out across the region. Results We have 14 different units across our network, all of which have participated in the audit. The first audit showed a delirium point prevalence of 28%, subsequent point prevalence audits demonstrated rates as low as 13%. There has also been an improvement in the use of delirium screening tools. In the first audit 37% of patients had two delirium screens in 24 h, this has increased to 60% in the latest audit. Improvements were also made in availability of sensory aids and pain assessments. Conclusion The project has demonstrated the feasibility of delivering a coordinated delirium improvement project across multiple critical care units.