Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Dynamic flow synthesis of porous organic cages

The dynamic covalent synthesis of two imine-based porous organic cages was successfully transferred from batch to continuous flow. The same flow reactor was then used to scramble the constituents of these two cages in differing ratios to form cage mixtures. Preparative HPLC purification of one of these mixtures allowed rapid access to a desymmetrised cage molecule.We thank the Engineering and Physical Sciences Research Council (EPSRC) for financial support under the Grants EP/H000925/1 (AIC), EP/K009494/1 (SVL) and EP/M004120/1 (SVL), and Pfizer Worldwide Research & Development (CB). The authors would like to thank EPSRC Dial-a-Molecule Grand Challenge Network (EP/K004840/1) for funding a placement with SVL via the Interdisciplinary Mobility Funding scheme (AGS).This is the author accepted manuscript. The final version is available from RSC via http://dx.doi.org/10.1039/C5CC07447

Measurement of the 2νββ decay half-life of 150Nd and a search for 0νββ decay processes with the full exposure from the NEMO-3 detector

We present results from a search for neutrinoless double-β (0νββ) decay using 36.6 g of the isotope 150Nd with data corresponding to a live time of 5.25 y recorded with the NEMO-3 detector. We construct a complete background model for this isotope, including a measurement of the two-neutrino double-β decay half-life of T2ν 1=2 ¼ ½9.34 0.22ðstatÞ þ0.62 −0.60 ðsystÞ × 1018 y for the ground state transition, which represents the most precise result to date for this isotope. We perform a multivariate analysis to search for 0νββ decays in order to improve the sensitivity and, in the case of observation, disentangle the possible underlying decay mechanisms. As no evidence for 0νββ decay is observed, we derive lower limits on half-lives for several mechanisms involving physics beyond the standard model. The observed lower limit, assuming light Majorana neutrino exchange mediates the decay, is T0ν 1=2 > 2.0 × 1022 y at the 90% C.L., corresponding to an upper limit on the effective neutrino mass of hmνi < 1.6–5.3 eV

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3&nbsp;days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3&nbsp;days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60\u20131.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14\u20131.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Splanchnic organ homeostasis in experimental endotoxin shock : with special reference to the endothelin and renin-angiotensin systems

Splanchnic organ homeostasis may become severely deteriorated in states of sepsis and endotoxaemia. Gut tissue hypoxia with subsequent increases in intestinal mucosal permeability has been proposed to contribute to the development of multiple organ failure. The main aims of the present study were: to assess local metabolic endotoxin-induced deterioration in the ileum and liver as well as changes in splanchnic haemodynamic parameters in relation to other tissues and systemic variables; to evaluate the role of the endothelin (ET) and renin-angiotensin systems (RAS) in the endotoxin-induced metabolic and haemodynamic changes in the splanchnic region and systemically. All experiments were conducted in anaesthetised, mechanically ventilated pigs. Catheters, ultrasonic flow probes, intestinal tonometry and in some cases microdialysis probes were used to measure systemic and regional haemodynamics and metabolic changes in response to endotoxin infusion. All interventive drugs were administered after two hours of endotoxaemia when a state of shock was established. Endotoxin induced a hypodynamic shock characterised by reductions in regional and systemic perfusion. Signs of splanchnic metabolic deterioration were seen in the ileum and liver as increased tissue levels of hypoxanthine and lactate as well as ileal mucosal acidosis obtained by tonometry. In addition, endotoxaemia induced a notable mucosal injury as evident by microscopical examination. A more limited increase was seen in tissue hypoxanthine levels in the lung and only moderate changes were evident in subcutaneous fat and arterial blood. Moreover, the endotoxin- induced hypoperfusion was more pronounced in the splanchnic region than at the systemic level. Furthermore, ileal mucosal acidosis was more prominent than pH changes in arterial blood. Thus, systemic variables did not fully reflect changes seen in the splanchnic region in response to endotoxin, suggesting obvious limitations in relying on systemic monitoring only. Plasma levels of endothelin-1-like immunoreactivity (ET-1-LI) and plasma renin activity were both markedly increased in response to endotoxin, indicating strong activation of the ET- and RAS. Intervention with non-selective ET receptor antagonists (RA) effectively counteracted endotoxin-induced reductions in systemic and gut oxygen delivery as well as ileal mucosal acidosis. Selective ETA RA did not result in any beneficial effects in the splanchnic region whereas selective ETB RA proved to be fatal. In contrast, simultaneous administration of the selective ETA and ETB RA improved systemic and gut oxygen delivery as well as systemic metabolic acidosis, but not ileal mucosal acidosis, indicating that antagonism of both ETA and ETB receptors is necessary to counteract endotoxin-induced perfusion disturbances. Only treatments involving ETB RA increased the already high arterial plasma levels of ET-1-LI suggesting an important role for this receptor in plasma clearance of ET-1. The fatal effect of separate ETB RA may be explained by increased ETA receptor activity from increased levels of ET-1. Antagonism of the angiotensin II type 1 (AT1) receptor improved gut oxygen delivery and reduced pulmonary hypertension whereas no beneficial effects were seen on systemic oxygen delivery, systemic metabolic acidosis or ileal mucosal acidosis, suggesting a limited contribution of AT1 receptor activity to endotoxin-induced perfusion disturbances. AT1 RA did not affect plasma renin activity or plasma levels of ET- I -LI, suggesting that activation of the AT1 receptor was of minor importance for ET- 1 release in this endotoxaemic model. In conclusion: Endotoxin- induced metabolic and haemodynamic changes in the splanchnic region were not fully reflected at the systemic level. The ET system seems to play an important role in the endotoxin- induced disturbances in splanchnic homeostasis as well as regional and systemic haemodynamics in the current model. AT1 receptor activity seems to be of limited importance for these disturbances

Snabb behandling vid septisk chock räddar liv - Även om »early goal-directed therapy«-protokoll inte ger effekt i nya studier. : Fast treatment of septic shock saves lives. Although "early goal-directed therapy"-protocol does not show any effect in new studies

Three recent randomised trials have shown a lack of effect of EGDT for the treatment of severe sepsis and septic shock. Notably, control group care was excellent in all trials, including early recognition, early and aggressive fluid resuscitation and prompt administration of antibiotics, and was reflected in a lower than expected mortality.The discussion emphasizes the need for continued vigilance and early aggressive management