Impact of sleep disturbances on outcomes in intensive care units.

BACKGROUND: Sleep deprivation is common in intensive care units (ICUs) and may alter respiratory performance. Few studies have assessed the role of sleep disturbances on outcomes in critically ill patients. OBJECTIVES: We hypothesized that sleep disturbances may be associated with poor outcomes in ICUs. METHODS: Post-hoc analysis pooling three observational studies assessing sleep by complete polysomnography in 131 conscious and non-sedated patients included at different times of their ICU stay. Sleep was assessed early in a group of patients admitted for acute respiratory failure while breathing spontaneously (n = 34), or under mechanical ventilation in patients with weaning difficulties (n = 45), or immediately after extubation (n = 52). Patients admitted for acute respiratory failure who required intubation, those under mechanical ventilation who had prolonged weaning, and those who required reintubation after extubation were considered as having poor clinical outcomes. Durations of deep sleep, rapid eye movement (REM) sleep, and atypical sleep were compared according to the timing of polysomnography and the clinical outcomes. RESULTS: Whereas deep sleep remained preserved in patients admitted for acute respiratory failure, it was markedly reduced under mechanical ventilation and after extubation (p < 0.01). Atypical sleep was significantly more frequent in patients under mechanical ventilation than in those breathing spontaneously (p < 0.01). REM sleep was uncommon at any time of their ICU stay. Patients with complete disappearance of REM sleep (50% of patients) were more likely to have poor clinical outcomes than those with persistent REM sleep (24% vs. 9%, p = 0.03). CONCLUSION: Complete disappearance of REM sleep was significantly associated with poor clinical outcomes in critically ill patients.

High Throughput Proteomic Exploration of Hypothermic Preservation Reveals Active Processes within the Cell Associated with Cold Ischemia Kinetic.

The demand for organs to be transplanted increases pressure on procurement centers, to the detriment of organ quality, increasing complications. New preservation protocols are urgently needed, requiring an in-depth understanding of ischemia-reperfusion mechanisms. We performed a proteomic analysis using LC-MS/MS-TOF data analyzed through R software and Cytoscape's ClueGO application, comparing the proteome of kidney endothelial cells, key cell type, subjected to 3, 6, 12, 19, and 24 h of cold ischemia and 6 h reperfusion. Critical pathways such as energy metabolism, cytoskeleton structure/transport system, and gene transcription/translation were modulated. Important time windows were revealed: a-during the first 3 h, central proteins were upregulated within these pathways; b-the majority of these upregulations were maintained until 12 h cold ischemia time (CIT); c-after that time, the overall decrease in protein expression was observed; d-at reperfusion, proteins expressed in response to cold ischemia were all downregulated. This shows that cold ischemia is not a simple slowing down of metabolism, as deep changes take place within the proteome on major pathways. Time-sensitive expression of key protein reveals possible quality biomarkers as well as potential targets for new strategies to maintain or optimize organ quality.

Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation.

BACKGROUND: Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms. STUDY DESIGN: We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage. RESULTS: Serum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals. CONCLUSIONS: In this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term.

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation.

In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.

Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model.

BACKGROUND: In kidney transplantation, the prevalence of hypercholesterolemia as a co-morbidity factor known to affect graft function, is rising due to the increased number of older donors in response to organ shortage as well as to the hyperlipidemic effects of immunosuppressors in recipient. This study aimed to characterize the effects of hypercholesterolemia on renal graft outcome, investigating the role of oxidized low-density lipoprotein (OxLDL). METHODS: In vivo, we used a porcine preclinical model of renal auto-transplantation modulated by two experimental diets: a normal (n = 6) or a hyperlipidemic diet (n = 5) maintained during the 3 month follow-up after the surgical procedure. Kidney function and OxLDL levels were monitored as well as fibrosis, LOX-1 and TGF beta signaling pathways. In vitro, we used human artery endothelial cells subjected to OxLDL to investigate the TGF beta profibrotic pathway and the role of the scavenger receptor LOX-1. RESULTS: Hyperlipidemic diet-induced increase in plasma OxLDL levels at the time of surgery correlated with an increase in proteinuria 3 months after transplantation, associated with an early graft fibrosis combined with an activation of renal TGF beta signaling. These data suggest a direct involvement of OxLDL in the hyperlipidemic diet-induced activation of the pro-fibrotic TGF beta pathway which seems to be activated by LOX-1 signaling. These results were supported by studies with endothelial cells incubated in culture medium containing OxLDL promoting TGF beta expression inhibited by LOX-1 antibody. CONCLUSIONS: These results implicate OxLDL in the hyperlipidemic diet-promoted fibrosis in transplanted kidneys, suggesting LOX-1 as a potential therapeutic target and reinforce the need to control cholesterol levels in kidney transplant recipients.

Factors associated with decreased compliance after on-site extracorporeal membrane oxygenation cannulation for acute respiratory distress syndrome: A retrospective, observational cohort study.

Background: Extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) is systematically associated with decreased respiratory system compliance (CRS). It remains unclear whether transportation to the referral ECMO center, changes in ventilatory mode or settings to achieve ultra-protective ventilation, or the natural evolution of ARDS drives this change in respiratory mechanics. Herein, we assessed the precise moment when CRS decreases after ECMO cannulation and identified factors associated with decreased CRS. Methods: To rule out the effect of transportation and the different modes of ventilation on CRS, we conducted a retrospective, single-center, observational cohort study from January 2013 to May 2020, on 22 patients with severe ARDS requiring on-site ECMO and ventilated in pressure-controlled mode to achieve ultra-protective ventilation. CRS was assessed at different time points ranging from 12 h before ECMO cannulation to 72 h after ECMO cannulation. The primary outcome was the relative change in CRS between 3 h before and 3 h after ECMO cannulation. The secondary outcomes included variables associated with the relative changes in CRS within the first 3 h after ECMO cannulation and the relative changes in CRS at each time point. Results: CRS decreased within the first 3 h after ECMO cannulation (-28.3%, 95% confidence interval [CI]: -38.8 to -17.9, P<0.001), while the decrease was mild before and after these first 3 h after ECMO cannulation. To achieve ultra-protective ventilation, respiratory rate decreased in the mean by -13 breaths/min (95% CI: -15 to -11) and driving pressure by -8.3 cmH2O (95% CI: -11.2 to -5.3), resulting in decreased tidal volume by -3.3 mL/kg of predicted body weight (95% CI: -3.9 to -2.6) as compared to before ECMO cannulation (P <0.001 for all). Plateau pressure reduction, driving pressure reduction, and tidal volume reduction were significantly associated with decreased CRS after ECMO cannulation, whereas neither respiratory rate, positive end-expiratory pressure, inspired fraction of oxygen, fluid balance, nor mean airway pressure was associated with decreased CRS. Conclusions: Decreased driving pressure resulting in lower tidal volume to achieve ultra-protective ventilation after ECMO cannulation was associated with a marked decrease in CRS in ARDS patients with on-site ECMO cannulation.

Physiologic Effects of Reconnection to the Ventilator for 1 Hour Following a Successful Spontaneous Breathing Trial.

BACKGROUND: Reconnection to the ventilator for 1 h following a successful spontaneous breathing trial (SBT) may reduce reintubation rates compared with direct extubation. However, the physiologic mechanisms leading to this effect are unclear. RESEARCH QUESTION: Does reconnection to the ventilator for 1 h reverse alveolar derecruitment induced by SBT, and is alveolar derecruitment more pronounced with a T-piece than with pressure-support ventilation (PSV)? STUDY DESIGN AND METHODS: This is an ancillary study of a randomized clinical trial comparing SBT performed with a T-piece or with PSV. Alveolar recruitment was assessed by using measurement of end-expiratory lung volume (EELV). RESULTS: Of the 25 patients analyzed following successful SBT, 11 underwent SBT with a T-piece and 14 with PSV. At the end of the SBT, EELV decreased by -30% (95% CI, -37 to -23) compared with baseline prior to the SBT. This reduction was greater with a T-piece than with PSV: -43% (95% CI, -51 to -35) vs -20% (95% CI, -26 to -13); P < .001. Following reconnection to the ventilator for 1 h, EELV accounted for 96% (95% CI, 92 to 101) of baseline EELV and did not significantly differ from prior to the SBT (P = .104). Following 10 min of reconnection to the ventilator, EELV wasted at the end of the SBT was completely recovered using PSV (P = .574), whereas it remained lower than prior to the SBT using a T-piece (P = .010). INTERPRETATION: Significant alveolar derecruitment was observed at the end of an SBT and was markedly more pronounced with a T-piece than with PSV. Reconnection to the ventilator for 1 h allowed complete recovery of alveolar derecruitment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04227639; URL: www. CLINICALTRIALS: gov.

Role of warm ischemia on innate and adaptive responses in a preclinical renal auto-transplanted porcine model.

BACKGROUND: Deceased after cardiac arrest donor are an additional source of kidney graft to overcome graft shortage. Deciphering the respective role of renal warm and cold ischemia is of pivotal interest in the transplantation process. METHODS: Using a preclinical pig model of renal auto-transplantation, we investigated the consequences of warm and cold ischemia on early innate and adaptive responses as well as graft outcome. Kidneys were subjected to either 60 min-warm ischemia (WI) or auto-transplanted after cold storage for 24 h at 4°C (CS), or both conditions combined (WI+CS). Renal function, immune response and cytokine expression, oxidative stress and cell death were investigated at 3 h, 3 and 7 days (H3, D3 and D7) after reperfusion. At 3 months, we focused on cell infiltration and tissue remodelling. RESULTS: WI + CS induced a delayed graft function linked to higher tubular damage. Innate response occurred at D3 associated to a pro-oxidative milieu with a level dependent on the severity of ischemic injury whereas adaptive immune response occurred only at D7 mainly due to CS injuries and aggravated by WI. Graft cellular death was an early event detected at H3 and seems to be one of the first ischemia reperfusion injuries. These early injuries affect graft outcome on renal function, cells infiltration and fibrosis development. CONCLUSIONS: The results indicate that the severe ischemic insult found in kidneys from deceased after cardiac arrest donor affects kidney outcome and promotes an uncontrolled deleterious innate and adaptive response not inhibited 3 months after reperfusion.

High-flow nasal cannula oxygen versus conventional oxygen therapy for acute respiratory failure due to COVID-19: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of high-flow nasal cannula oxygen therapy (HFNC) in patients with acute respiratory failure due to COVID-19 remains uncertain. We aimed at assessing whether HFNC is associated with reduced risk of intubation or mortality in patients with acute respiratory failure due to COVID-19 compared with conventional oxygen therapy (COT). METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Science, and CENTRAL databases for randomized controlled trials (RCTs) and observational studies comparing HFNC vs. COT in patients with acute respiratory failure due to COVID-19, published in English from inception to December 2022. Pediatric studies, studies that compared HFNC with a noninvasive respiratory support other than COT and those in which intubation or mortality were not reported were excluded. Two authors independently screened and selected articles for inclusion, extracted data, and assessed the risk of bias. Fixed-effects or random-effects meta-analysis were performed according to statistical heterogeneity. Primary outcomes were risk of intubation and mortality across RCTs. Effect estimates were calculated as risk ratios and 95% confidence interval (RR; 95% CI). Observational studies were used for sensitivity analyses. RESULTS: Twenty studies were analyzed, accounting for 8383 patients, including 6 RCTs (2509 patients) and 14 observational studies (5874 patients). By pooling the 6 RCTs, HFNC compared with COT significantly reduced the risk of intubation (RR 0.89, 95% CI 0.80 to 0.98; p = 0.02) and reduced length of stay in hospital. HFNC did not significantly reduce the risk of mortality (RR 0.93, 95% CI 0.77 to 1.11; p = 0.40). CONCLUSIONS: In patients with acute respiratory failure due to COVID-19, HFNC reduced the need for intubation and shortened length of stay in hospital without significant decreased risk of mortality. Trial registration The study was registered on the International prospective register of systematic reviews (PROSPERO) at https://www.crd.york.ac.uk/prospero/ with the trial registration number CRD42022340035 (06/20/2022).

Sex difference in the risk of extubation failure in ICUs.

BACKGROUND: Little attention has been paid to potential differences in prognosis between mechanically ventilated males and females in intensive care units (ICUs). We hypothesized that a sex gap in the risk of extubation failure in ICUs may exist. METHODS: Post hoc analysis of a large-scale clinical trial including patients at high risk of extubation failure in ICUs, with the aim of assessing the risk of extubation failure according to sex. The primary outcome was reintubation within the 7 days following extubation. RESULTS: Out of 641 patients, 425 (66%) were males and 216 (34%) were females. Males were more likely to be admitted for cardiac arrest and to have underlying ischemic heart disease whereas females were more likely to be admitted for coma and to have obesity. Whereas the rate of reintubation at 48 h was significantly higher in males than in females (11.0% vs. 6.0%; difference, + 5.0 [95% CI, 0.2 to 9.2]; P = 0.038), the rate of reintubation at day 7 did not significantly differ between males and females (16.7% vs. 11.1%; difference, + 5.6% [95%CI, - 0.3 to 10.8], P = 0.059). Using multivariable logistic regression analysis, male sex was independently associated with reintubation within the 7 days following extubation (adjusted OR 1.70 [95% CI, 1.01 to 2.89]; P = 0.048), even after adjustment on reason for admission, body-mass index, severity score, respiratory rate before extubation, and noninvasive ventilation after extubation. CONCLUSION: In this post hoc analysis of a clinical trial including a homogeneous subset of patients at high risk of extubation failure, sex was independently associated with reintubation. The role of sex on outcomes should be systematically examined in future studies of critically ill patients.

Noninvasive Oxygenation in Patients with Acute Respiratory Failure: Current Perspectives.

Purpose of Review: High-flow nasal oxygen and noninvasive ventilation are two alternative strategies to standard oxygen in the management of acute respiratory failure. Discussion: Although high-flow nasal oxygen has gained major popularity in ICUs due to its simplicity of application, good comfort for patients, efficiency in improving oxygenation and promising results in patients with acute hypoxemic respiratory failure, further large clinical trials are needed to confirm its superiority over standard oxygen. Non-invasive ventilation may have deleterious effects, especially in patients exerting strong inspiratory efforts, and no current recommendations support its use in this setting. Protective non-invasive ventilation using higher levels of positive-end expiratory pressure, more prolonged sessions and other interfaces such as the helmet may have beneficial physiological effects leading to it being proposed as alternative to high-flow nasal oxygen in acute hypoxemic respiratory failure. By contrast, non-invasive ventilation is the first-line strategy of oxygenation in patients with acute exacerbation of chronic lung disease, while high-flow nasal oxygen could be an alternative to non-invasive ventilation after partial reversal of respiratory acidosis. Questions remain about the target populations and non-invasive oxygen strategy representing the best alternative to standard oxygen in acute hypoxemic respiratory failure. As concerns acute on-chronic-respiratory failure, the place of high-flow nasal oxygen remains to be evaluated.

Predictors of successful separation from high-flow nasal oxygen therapy in patients with acute respiratory failure: a retrospective monocenter study.

BACKGROUND: High-flow nasal oxygen therapy (HFOT) is a promising first-line therapy for acute respiratory failure. However, its weaning has never been investigated and could lead to unnecessary prolonged intensive-care unit (ICU) stay. The aim of this study is to assess predictors of successful separation from HFOT in critically ill patients. We performed a retrospective monocenter observational study over a 2-year period including all patients treated with HFOT for acute respiratory failure in the ICU. Those who died or were intubated without prior HFOT separation attempt, who were treated with non-invasive ventilation at the time of HFOT separation, or who received HFOT as a preventive treatment during the post-extubation period were excluded. RESULTS: From the 190 patients analyzed, 168 (88%) were successfully separated from HFOT at the first attempt. Patients who failed separation from HFOT at the first attempt had longer ICU length of stay than those who succeeded: 10 days (7-12) vs. 5 (4-8), p < 0.0001. Fraction of inspired oxygen (FiO2) ≤ 40% and a respiratory rate-oxygenation (ROX) index (calculated as the ratio of SpO2/FiO2 to the respiratory rate) ≥ 9.2 predicted successful separation from HFOT with sensitivity of 85% and 84%, respectively. CONCLUSIONS: FiO2 ≤ 40% and ROX index ≥ 9.2 were two predictors of successful separation from HFOT at the bedside. Prospective multicenter studies are needed to confirm these results.

Postoperative fasting after general anaesthesia: A survey of French anaesthesiology practices.

BACKGROUND: Preoperative fasting is well codified worldwide. In contrast, the literature on the postoperative fasting (POF) is scarce, leading to potentially wide discrepancies among anaesthesiology practices. This survey assessed French POF practices. METHODS: From March 2013 to January 2014, a survey was conducted among anaesthesiologists, members of the French Society of Anaesthesiology and Intensive Care Medicine (SFAR). The POF durations of either fluid or solid food intake was assessed according to airway management procedures (endotracheal intubation [EI] or laryngeal mask [LMA]) and age of the patients (adult or paediatric). RESULTS: Seven hundred and fifty-four surveys were returned (67% from public hospital practitioners and 33% from private hospital and clinic practitioners). The majority of anaesthesiologists allowed fluid intake 2h after EI and immediately after discharge from PACU following LMA. For solid food resumption, it was 2h for children and 4h for adults after EI and 2h for both children and adults after LMA. Regardless of the airway management procedures, fasting was permitted immediately after PACU discharge more frequently in public than in private hospitals (36% vs. 33%, P<0.05). Four hours after the end of surgery, the rate was significantly higher in private than in public hospitals (93% vs. 89 %, P<0.001). CONCLUSIONS: All in all, POF lasted less than 4hours after surgery regardless of airway management. They were shorter with regard to fluid intake, paediatric patients and LMA in comparison with solid food, adult patients and EI respectively.

Decoding cold ischaemia time impact on kidney graft: the kinetics of the unfolded protein response pathways.

The relationship between cold ischaemia time (CIT) and adverse outcome is now acknowledged. However, the underlying mechanisms remain to be defined, which slows the development of adapted therapeutics and diagnostics. We explored the impact of CIT in both preclinical and in vitro models of preservation. We determined that the endoplasmic reticulum (ER) and its stress response (unfolded protein response, UPR) were regulated in close association with CIT; the eIF2α-ATF4 pathway was inhibited early (1-8 h) at the detriment of cell survival, while the ATF6 pathway was activated late (12-24 h) and associated with cell death. The IRE1α-XBP1 branch was activated at reperfusion only if CIT extended beyond 8 h, and had a dual role on cell fate - deleterious through IRE1's RNase activity and beneficial through IRE1α other roles. Finally, the pro-apoptotic factor CHOP was a common target of both ATF6 and IRE1α pathways and was associated with elongated CIT and increased cell death. Microarray analysis of human transplanted kidney confirmed that UPR markers were regulated by CIT and that CHOP was associated with adverse outcome. We show that UPR could be a critical pathway explaining the relationship between CIT and graft outcome, highlighting the potential for UPR-based therapeutics and diagnostics to improve transplantation.

Polynomial algebra reveals diverging roles of the unfolded protein response in endothelial cells during ischemia-reperfusion injury.

The unfolded protein response (UPR)--the endoplasmic reticulum stress response--is found in various pathologies including ischemia-reperfusion injury (IRI). However, its role during IRI is still unclear. Here, by combining two different bioinformatical methods--a method based on ordinary differential equations (Time Series Network Inference) and an algebraic method (probabilistic polynomial dynamical systems)--we identified the IRE1α-XBP1 and the ATF6 pathways as the main UPR effectors involved in cell's adaptation to IRI. We validated these findings experimentally by assessing the impact of their knock-out and knock-down on cell survival during IRI.