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

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

A practice survey on vasopressor and inotropic drug therapy in Scandinavian intensive care units

BACKGROUND: This practice survey was performed to analyse the indications for use of vasopressor/inotropic drugs, preferred drugs and doses as well as concomitant monitoring and desired haemodynamic target values in Scandinavian ICUs. An internet-based reporting system was implemented. METHODS: A total of 223 ICUs were identified in the Scandinavian countries and invited to participate in a one-day point-prevalence study. An internet-based database was constructed and a practice survey protocol designed to identify haemodynamic monitoring, indications for vasopressor/inotropic drug-therapy, fluids used for volume loading, pretreatment circulatory state, actual and targeted haemodynamic variables. Patients were eligible for the study if on vasopressor/inotropic drug-therapy for more than 4 h. RESULTS: A total of 114 ICUs participated. A total of 114 adult patients matched the inclusion criteria. Sixty-seven per cent of the patients had received vasopressor/inotropic drug-treatment for >24 h and 32% received more than one drug. Arterial hypotension (92%) and oliguria (50%) were most common indications. Fluid loading prior to therapy was reported in 87% of patients. Dopamine (47%) and noradrenaline (44%) were the most commonly used drugs followed by dobutamine (24%). No other drug exceeded 6%. Non-catecholamine drugs were rarely used even in cardiac failure patients. Invasive arterial pressure was monitored in 95% of patients, pulmonary artery catheters were used in 19%. Other cardiac output monitoring techniques were used in 8.5% of the patients. CONCLUSION: Dopamine and noradrenaline seem to be the most commonly used inotropic/vasopressor drugs in Scandinavia. Traditional indications for inotropic/vasopressor support as hypotension and oliguria seem to be most common. Invasive monitoring was used in almost all patients, whereas a limited use of pulmonary artery catheters was noted. The internet-based reporting system proved to be an efficient tool for data collection