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We read with interest the letter by Twycross and al on our article recently published in BMC Palliative Care. The authors suggest that the term palliative sedation has been used inappropriately and they consider that in the situation described the sedation was a procedural one rather than a continuous deep sedation. We strongly disagree with this point of view. In an end-of-life situation, the priorities are the patient’s comfort, pain and anxiety. This type of sedation does not have the characteristics of procedural sedation described in anaesthesia. The French Clayes Leonetti law makes it possible to clarify the intention of the sedation in end-of-life situations.

Background Deciding to withdraw non-invasive ventilation (NIV) at end-of-life (EOL) in patients with chronic respiratory failure is a challenge. The European Association for Palliative Care recommends not maintaining artificial therapies that could prolong life during palliative sedation (PS) at EOL. The aim of this survey was to assess palliative care physicians’ and pulmonologists’ opinion on withdrawing or maintaining NIV in patients with chronic respiratory failure during PS at EOL. Methods From April to May 2019, we performed a prospective survey among pulmonologists ( n  = 1545) and palliative care physicians ( n  = 631) in France to determine the prevalence of opinion in favour of maintaining NIV and identify the factors associated with opinion in favour of withdrawing or maintaining NIV with multiple logistic regression. Results A total of 457 participants were enrolled comprising 202 pulmonologists and 255 palliative care physicians. An opinion in favour of maintaining NIV was found in 88 (19.3 95%CI [15.7; 23.2]) physicians comprising 57 (28.2%) pulmonologists and 31 (12.2%) palliative care physicians ( p  < 0.001). The factors associated with an opinion in favour of maintaining NIV were spending time looking for advanced directives (AD) in the patient’s file (odds ratio (OR): 6.54, 95%CI [2.00; 21.32], p  = 0.002 ) and personal ethics of physicians (OR: 17.97, 95%CI [9.52; 33.89], p  < 0.001 ). The factor associated with an opinion in favour of withdrawing NIV was palliative care training (OR: 0.31, 95%CI [0.16; 0.60], p  < 0.001) . The three main reasons in favour of maintaining NIV among the nine identified were emotional comfort for close relatives, reducing discomfort of dyspneoa and anticipation of suffocation. Conclusion In France, around 20% of pulmonologists and palliative care physicians declared an opinion in favour of maintaining NIV during PS at EOL because of their personal ethics and spending time looking for AD, if any, in the patient’s file. Palliative care training can stimulate reflection help foster a change of opinion about practices, especially in the case of patients with NIV during PS at EOL.

This multicenter randomized trial compared strategies of early and delayed renal-replacement therapy in patients with severe acute kidney injury. There was no significant difference in mortality, the primary outcome, between the study groups. Acute kidney injury is a common condition among patients in the intensive care unit 1 – 4 and is associated with high morbidity and mortality. 2 , 5 – 8 Renal-replacement therapy is the cornerstone of the management of severe acute kidney injury. Many studies have focused on methods of renal-replacement therapy, 5 , 6 , 8 , 9 but the issue of when to initiate the therapy in the absence of a potentially life-threatening complication directly related to renal failure remains a subject of debate. Indirect evidence has suggested that early renal-replacement therapy could confer a survival benefit. 10 – 12 However, two observational studies reported high survival rates among . . .

The optimal strategy for initiation of renal replacement therapy (RRT) in patients with severe acute kidney injury in the context of septic shock and acute respiratory distress syndrome (ARDS) is unknown. To examine the effect of an early compared with a delayed RRT initiation strategy on 60-day mortality according to baseline sepsis status, ARDS status, and severity. Post hoc analysis of the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial. Subgroups were defined according to baseline characteristics: sepsis status (Sepsis-3 definition), ARDS status (Berlin definition), Simplified Acute Physiology Score 3 (SAPS 3), and Sepsis-related Organ Failure Assessment (SOFA). Of 619 patients, 348 (56%) had septic shock and 207 (33%) had ARDS. We found no significant influence of the baseline sepsis status (P = 0.28), baseline ARDS status (P = 0.94), and baseline severity scores (P = 0.77 and P = 0.46 for SAPS 3 and SOFA, respectively) on the comparison of 60-day mortality according to RRT initiation strategy. A delayed RRT initiation strategy allowed 45% of patients with septic shock and 46% of patients with ARDS to escape RRT. Urine output was higher in the delayed group. Renal function recovery occurred earlier with the delayed RRT strategy in patients with septic shock or ARDS (P < 0.001 and P = 0.003, respectively). Time to successful extubation in patients with ARDS was not affected by RRT strategy (P = 0.43). Early RRT initiation strategy was not associated with any improvement of 60-day mortality in patients with severe acute kidney injury and septic shock or ARDS. Unnecessary and potentially risky procedures might often be avoided in these fragile populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01932190).

Background Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious complication in the ICU that results in increased mortality and risk of chronic kidney disease (CKD). Some studies suggest RRT modality may have an impact on long-term renal recovery after AKI. However, other predictive factors of severe long-term CKD in ICU patients with AKI requiring RRT are unknown. Methods We performed an ancillary study of the multicenter ELVIS trial in the population with AKI requiring RRT. Patients alive 3 months after RRT initiation were eligible. Serum creatinine levels available at 3, 6 and 12 months and 3 and 5 years were recorded. CKD stage was determined according to the glomerular filtration rate as estimated by the CKD-EPI formula. At each timepoint, two groups of patients were compared, a no/mild CKD group with normal or mildly to moderately decreased renal function (stages 1, 2 and 3 of the international classification) and a severe CKD group (stages 4 and 5). Our objective was to identify predictive factors of severe long-term CKD. Results Of the 287 eligible patients, 183 had follow-up at 3 months, 136 (74.3%) from the no/mild CKD group and 47 (25.7%) from the severe CKD group, and 122 patients at 5 years comprising 96 (78.7%) from the no/mild CKD group and 26 (21.3%) from the severe CKD group. Multivariate analysis showed that a long RRT period was associated with severe CKD up to 12 months (OR M12  = 1.03 95% CI [1.02–1.05] per day) and that a high SOFA score at the initiation of RRT was not associated with severe CKD up to 5 years (OR M60  = 0.85 95% CI [0.77–0.93] per point). Conclusion Severe long-term CKD was found in 21% of ICU survivors who underwent RRT for AKI. The duration of the RRT in AKI patients was identified as a new predictive factor for severe long-term CKD. This finding should be taken into consideration in future studies on the prognosis of ICU patients with AKI requiring RRT. Trial registration ELVIS trial was registered with ClinicalTrials.gov, number: NCT00875069 (June 16, 2014), and this ancillary study was registered with ClinicalTrials.gov, number: NCT03302624 (October 6, 2017).

Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-α (TGF-α) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-α or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-α and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.

Data on aminoglycoside stewardship in critically ill septic patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT) are scarce. The objectives of the study were to determine, during CRRT, the time window with low likelihood for safe reinjection and the proportion of inappropriate reinjection. A post hoc observational analysis of a multicenter randomized trial comparing the risk of hemodialysis catheter infection with ethanol lock vs placebo in critically ill patients with AKI was conducted. Eligible patients were adults in intensive care units from 6 French hospitals. Any patient with AKI needing CRRT and receiving an antimicrobial therapy for a septic episode occurring before (≤24 hours) or during CRRT was included. The aminoglycoside orders were left to the physicians’ discretion, but high dose once daily was the schedule of aminoglycoside administration. A total of 145 septic episodes treated by aminoglycosides were analyzed in patients receiving CRRT. A mean (SD) of 1.6 (0.8) amikacin and 1.8 (1.2) gentamicin administrations per patient were observed. During CRRT, Cmax was 17.3 mg/L (interquartile range, 13.2-22.5 mg/L) for gentamicin and 50 mg/L (interquartile range, 43.7-76.6 mg/L) for amikacin. The plasma drug concentration at 24 hours (CH24) was 2.3 mg/L (interquartile range, 1.6-3.2 mg/L) for gentamicin and 9.3 (interquartile range, 6.6-12.0 mg/L) for amikacin. Sixty-five Cmin dosages remained above the reinjection threshold. Inappropriate reinjection was observed in 11 of 65 episodes (17%). Inappropriate reinjection (defined by, at the reinjection time, Cmin dosages above the threshold; ie, Cmin >2 mg/L for gentamicin and >5 mg/L for amikacin) was observed in 17% of analyzed episodes. Most patients did not need reinjection until approximately ≥30 hours after their initial administration. During CRRT, as indicated by the CH24 value, which was higher than the recommended threshold, the interval to obtain a Cmin low enough to allow for redosing aminoglycosides is significantly longer than 24 hours. This interval is not always respected and leads to an of inappropriate reinjection rate of 17%. ClinicalTrials.gov identifier: ISRCTNCT00875069.

IntroductionFirst-line oxygenation strategy in patients with acute hypoxaemic respiratory failure consists in standard oxygen or high-flow nasal oxygen therapy. Clinical practice guidelines suggest the use of high-flow nasal oxygen rather than standard oxygen. However, findings remain contradictory with a low level of certainty. We hypothesise that compared with standard oxygen, high-flow nasal oxygen may reduce mortality in patients with acute hypoxaemic respiratory failure.Method and analysisThe Standard Oxygen versus High-flow nasal Oxygen-trial is an investigator-initiated, multicentre, open-label, randomised controlled trial comparing high-flow nasal oxygen versus standard oxygen in patients admitted to an intensive care unit (ICU) for acute respiratory failure with moderate-to-severe hypoxaemia. 1110 patients will be randomly assigned to one of the two groups with a ratio of 1:1. The primary outcome is the number of patients who died 28 days after randomisation. Secondary outcomes include comfort, dyspnoea and oxygenation 1 hour after treatment initiation, the number of patients intubated at day 28, mortality in ICU, in hospital and until day 90, and complications during ICU stay.Ethics and disseminationThe study has been approved by the central Ethics Committee ‘Sud Méditerranée III’ (2020-07-05) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04468126.

Data on aminoglycoside stewardship in critically ill septic patients with acute kidney injury (AKI) needing intermittent hemodialysis (IH) are scarce. The first objective of the study was to evaluate whether aminoglycoside administration occurs before vs after IH in the real-life management of critically ill septic patients with AKI needing IH. The second objective was to assess the delay in achieving a potential reinjection window for a second dose of aminoglycoside, which should be obtained with a postdialysis vs predialysis regimen. A post hoc observational analysis of a multicenter randomized trial of critically ill patients with AKI needing renal replacement therapy was conducted. Inclusion criteria consisted of any patients receiving IH for AKI during an antimicrobial therapy for a septic episode. Among 206 of 341 septic patients (60%) receiving aminoglycosides, 90 underwent IH (46 with previous continuous renal replacement therapy and 44 without). Amikacin and gentamicin were administered for a mean (SD) of 2.2 (1.5) and 2.5 (2.1) days with mean (SD) doses of 20.6 (6.6) and 5.4 (2.5) mg/kg, respectively. In the 44 patients undergoing exclusive IH, aminoglycosides were administered in a predialysis in 53% of episodes versus 35% in a postdialysis schedule. The first Cmin target was obtained earlier with a predialysis vs postdialysis schedule (33.9 [14.2] hours vs 50.9 [12.2] hours, P = 0.009). Despite being less frequently used than a predialysis schedule, the postdialysis administration of aminoglycosides remains a regular practice in the intensive care unit. A predialysis schedule of administration in IH reduces the interval time to tolerable aminoglycoside redosing.

Background Stress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments. Methods This is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5. Results A total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54–76) years. Median values for SAPS II and HbA1C were 50 (37.5–64) and 5.7 (5.4–6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group ( p  < 0.01). IPTW analysis showed that PRI on Day 5 was not associated with Day 90 mortality ( IPTW HR = 1.22; CI 95% 0.84–1.75; p  = 0.29), whereas PRI without glycemic control was associated with an increased risk of death at Day 90 ( IPTW HR = 3.34; CI 95% 1.26–8.83; p  < 0.01). Conclusion In ICU patients without previous diabetic treatments, only PRI without glycemic control on Day 5 was associated with an increased risk of death. Additional studies are required to determine the factors contributing to these results.