Tension between continuous and deep sedation and assistance in dying: a national survey of intensive care professionals' perceptions.

INTRODUCTION: The situation in France is unique, having a legal framework for continuous and deep sedation (CDS). However, its use in intensive care units (ICU), combined with the withdrawal of life-sustaining therapies, still raises ethical issues, particularly its potential to hasten death. The legalization of assistance in dying, i.e., assisted suicide or euthanasia at the patient's request, is currently under discussion in France. The objectives of this national survey were first, to assess whether ICU professionals perceive CDS administered to ICU patients as a practice that hastens death, in addition to relieving unbearable suffering, and second, to assess ICU professionals' perceptions of assistance in dying. METHODS: A national survey with online questionnaires for ICU physicians and nursesaddressed through the French Society of Anesthesiology and Critical Care Medicine. RESULTS: A total of 956 ICU professionals responded to the survey (38% physicians and 62% nurses). Of these, 22% of physicians and 12% of nurses (p < 0.001) felt that the purpose of CDS was to hasten death. For 20% of physicians, CDS combined with terminal extubation was considered an assistance in dying. For 52% of ICU professionals, the current framework did not sufficiently cover the range of situations that occur in the ICU. A favorable opinion on the potential legalization of assistance in dying was observed in 83% of nurses and 71% of physicians (p < 0.001), with no preference between assisted suicide and euthanasia. CONCLUSION: Our findings highlight the tension between CDS and assisted suicide/euthanasia in the specific context of intensive care and suggest that ICU professionals would be supportive of a legislative evolution.

Association of socioeconomic deprivation with outcomes in critically ill adult patients: an observational prospective multicenter cohort study.

BACKGROUND: The influence of socioeconomic deprivation on health inequalities is established, but its effect on critically ill patients remains unclear, due to inconsistent definitions in previous studies. METHODS: Prospective multicenter cohort study conducted from March to June 2018 in eight ICUs in the Greater Paris area. All admitted patients aged ≥ 18 years were enrolled. Socioeconomic phenotypes were identified using hierarchical clustering, based on education, health insurance, income, and housing. Association of phenotypes with 180-day mortality was assessed using Cox proportional hazards models. RESULTS: A total of 1,748 patients were included. Median age was 62.9 [47.4-74.5] years, 654 (37.4%) patients were female, and median SOFA score was 3 [1-6]. Study population was clustered in five phenotypes with increasing socioeconomic deprivation. Patients from phenotype A (n = 958/1,748, 54.8%) were without socioeconomic deprivation, patients from phenotype B (n = 273/1,748, 15.6%) had only lower education levels, phenotype C patients (n = 117/1,748, 6.7%) had a cumulative burden of 1[1-2] deprivations and all had housing deprivation, phenotype D patients had 2 [1-2] deprivations, all of them with income deprivation, and phenotype E patients (n = 93/1,748, 5.3%) included patients with 3 [2-4] deprivations and included all patients with health insurance deprivation. Patients from phenotypes D and E were younger, had fewer comorbidities, more alcohol and opiate use, and were more frequently admitted due to self-harm diagnoses. Patients from phenotype C (predominant housing deprivation), were more frequently admitted with diagnoses related to chronic respiratory diseases and received more non-invasive positive pressure ventilation. Following adjustment for age, sex, alcohol and opiate use, socioeconomic phenotypes were not associated with increased 180-day mortality: phenotype A (reference); phenotype B (hazard ratio [HR], 0.85; 95% confidence interval CI 0.65-1.12); phenotype C (HR, 0.56; 95% CI 0.34-0.93); phenotype D (HR, 1.09; 95% CI 0.78-1.51); phenotype E (HR, 1.20; 95% CI 0.73-1.96). CONCLUSIONS: In a universal health care system, the most deprived socioeconomic phenotypes were not associated with increased 180-day mortality. The most disadvantaged populations exhibit distinct characteristics and medical conditions that may be addressed through targeted public health interventions.

Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway?

Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system leading to neurodegeneration. It affects 2.3 million people worldwide, generally younger than 50. There is no known cure for the disease, and current treatment options - mainly immunotherapies to limit disease progression - are few and associated with serious side effects. In multiple sclerosis, disruption of the blood-brain barrier is an early event in the pathogenesis of lesions, predisposing to edema, excito-toxicity and inflammatory infiltration into the central nervous system. Recently, the vision of the blood brain barrier structure and integrity has changed and include contributions from all components of the neurovascular unit, among which astrocytes. During neuro-inflammation, astrocytes become reactive. They undergo morphological and molecular changes named "astrogliosis" driving the conversion from acute inflammatory injury to a chronic neurodegenerative state. Astrogliosis mechanisms are minimally explored despite their significance in regulating the autoimmune response during multiple sclerosis. Therefore, in this review, we take stock of the state of knowledge regarding astrogliosis in neuro-inflammation and highlight the central role of NOTCH signaling in the process of astrocyte reactivity. Indeed, a very detailed nomenclature published in nature neurosciences in 2021, listing all the reactive astrocyte markers fully identified in the literature, doesn't cover the NOTCH signaling. Hence, we discuss evidence supporting NOTCH1 receptor as a central regulator of astrogliosis in the pathophysiology of neuro-inflammation, notably multiple sclerosis, in human and experimental models.

Effectiveness of Surgeon-Performed Paravertebral Block Analgesia for Minimally Invasive Thoracic Surgery: A Randomized Clinical Trial.

Importance: In minimally invasive thoracic surgery, paravertebral block (PVB) using ultrasound (US)-guided technique is an efficient postoperative analgesia. However, it is an operator-dependent process depending on experience and local resources. Because pain-control failure is highly detrimental, surgeons may consider other locoregional analgesic options. Objective: To demonstrate the noninferiority of PVB performed by surgeons under video-assisted thoracoscopic surgery (VATS), hereafter referred to as PVB-VATS, as the experimental group compared with PVB performed by anesthesiologists using US-guided technique (PVB-US) as the control group. Design, Setting, and Participants: In this single-center, noninferiority, patient-blinded, randomized clinical trial conducted from September 8, 2020, to December 8, 2021, patients older than 18 years who were undergoing a scheduled minimally invasive thoracic surgery with lung resection including video-assisted or robotic approaches were included. Exclusion criteria included scheduled open surgery, any antalgic World Health Organization level greater than 2 before surgery, or a medical history of homolateral thoracic surgery. Patients were randomly assigned (1:1) to an intervention group after general anesthesia. They received single-injection PVB before the first incision was made in the control group (PVB-US) or after 1 incision was made under thoracoscopic vision in the experimental group (PVB-VATS). Interventions: PVB-VATS or PVB-US. Main Outcomes and Measures: The primary end point was mean 48-hour post-PVB opioid consumption considering a noninferiority range of less than 7.5 mg of opioid consumption between groups. Secondary outcomes included time of anesthesia, surgery, and operating room occupancy; 48-hour pain visual analog scale score at rest and while coughing; and 30-day postoperative complications. Results: A total of 196 patients were randomly assigned to intervention groups: 98 in the PVB-VATS group (mean [SD] age, 64.6 [9.5] years; 53 female [54.1%]) and 98 in the PVB-US group (mean [SD] age, 65.8 [11.5] years; 62 male [63.3%]). The mean (SD) of 48-hour opioid consumption in the PVB-VATS group (33.9 [19.8] mg; 95% CI, 30.0-37.9 mg) was noninferior to that measured in the PVB-US group (28.5 [18.2] mg; 95% CI, 24.8-32.2 mg; difference: -5.4 mg; 95% CI, -∞ to -0.93; noninferiority Welsh test, P ≤ .001). Pain score at rest and while coughing after surgery, overall time, and postoperative complications did not differ between groups. Conclusions and Relevance: PVB placed by a surgeon during thoracoscopy was noninferior to PVB placed by an anesthesiologist using ultrasonography before incision in terms of opioid consumption during the first 48 hours. Trial Registration: ClinicalTrials.gov Identifier: NCT04579276.

Fatal Fulminant Hepatitis E in a Diabetic Patient on Metformin.

Hepatitis E is mostly autochthonous in Western developed countries, eating pig-derived products being the most frequently documented source. Hepatitis E virus (HEV) infection is usually asymptomatic or self-limiting, but it can cause acute liver failure. HEV serological testing was performed using EUROIMMUN immunoenzymatic assays. HEV RNA in the serum was determined using an in-house real-time reverse transcriptase PCR procedure. The HEV genotype was determined through phylogenetic analysis after Sanger sequencing was performed using an in-house procedure. The case patient, an immunocompetent patient in his 60s with type 2 diabetes and no documented chronic liver disease, was hospitalized in February 2021 in an intensive care unit due to an initially unexplained coma. He presented metformin overdose and fulminant hepatitis E (HEV RNA in the serum was 4,140,000 copies/mL) that evolved toward death. The HEV genotype was 3f. We identified eight previous hepatitis E in diabetic patients, but with no metformin excessive plasma concentration, in the literature. Three patients were liver transplant recipients and three died. HEV infection can be severe and life-threatening in diabetic patients, which warrants HEV testing in this special population in the case of an altered general condition and/or liver cytolysis.

Does the ICU Requirement Score allow the poisoned patient to be safely managed without admission to the intensive care unit? - a validation cohort study.

BACKGROUND: The Intensive care unit (ICU) Requirement Score (IRS) has been defined as identifying poisoned patients on hospital admission who do not require ICU referral, in an effort to reduce health expenses. However, this score has been poorly validated. We aimed to evaluate the IRS in a large cohort of poisoned patients. METHODS: We performed a single-center retrospective cohort study. IRS was calculated using clinical parameters obtained on admission including age, systolic blood pressure, heart rate, Glasgow coma score, intoxication type, co-morbidities (i.e., arrhythmia, cirrhosis, and respiratory insufficiency), and the combination of the intoxication with another reason for ICU admission. We evaluated the ability of IRS < 6 determined on admission to predict the lack of need for ICU treatment, defined as the need for mechanical ventilation, vasopressors, and/or renal replacement therapy in the first 24 h post-admission and/or death during the hospital stay. This score was compared to the usual prognostic scores, i.e., SAPS II and III, SOFA score, and PSS. RESULTS: During the 10-year study period, 2,514 poisoned patients were admitted, 1,011 excluded as requiring ICU treatment on admission, and 1,503 included. Among these patients, 232 met the endpoint whereas only 23/510 patients with IRS < 6 (4.5%) presented the endpoint and one patient died. The area under the curve of the IRS ROC curve was 0.736 (95% confidence interval (CI), 0.702-0.770). The negative predictive value of IRS < 6 was 95% (95% CI, 93-97), sensitivity 89% (95% CI, 85-93), specificity 38% (95% CI, 36-41), and positive predictive value 21% (95% CI, 18-24). IRS performance was similar to those of the other tested scores, which are however not readily available on admission. CONCLUSION: Our data demonstrate the excellent negative predictive value of the IRS, allowing the exclusion of ICU requirements for poisoned patients with IRS < 6. IRS usefulness should be confirmed based on a prospective multicenter cohort study before extensive routine use.

Blood-brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans.

Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.

Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis.

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is spreading worldwide. To date, no specific treatment has convincingly demonstrated its efficacy. Hydroxychloroquine and lopinavir/ritonavir have potential interest, but virological and clinical data are scarce, especially in critically ill patients. METHODS: The present report took the opportunity of compassionate use and successive drug shortages to compare the effects of two therapeutic options, lopinavir/ritonavir and hydroxychloroquine, as compared to standard of care only. The primary outcomes were treatment escalation (intubation, extra-corporeal membrane oxygenation support, or renal replacement therapy) after day 1 until day 28. Secondary outcomes included ventilator-free days at day 28, mortality at day 14 and day 28, treatment safety issues and changes in respiratory tracts, and plasma viral load (as estimated by cycle threshold value) between admission and day 7. RESULTS: Eighty patients were treated during a 4-week period and included in the analysis: 22 (28%) received standard of care only, 20 (25%) patients received lopinavir/ritonavir associated to standard of care, and 38 (47%) patients received hydroxychloroquine and standard of care. Baseline characteristics were well balanced between the 3 groups. Treatment escalation occurred in 9 (41%), 10 (50%), and 15 (39%) patients who received standard of care only, standard of care and lopinavir/ritonavir, and standard of care and hydroxychloroquine, respectively (p = 0.567). There was no significant difference between groups regarding the number of ventilator-free days at day 28 and mortality at day 14 and day 28. Finally, there was no significant change between groups in viral respiratory or plasma load between admission and day 7. CONCLUSION: In critically ill patients admitted for SARS-CoV-2-related pneumonia, no difference was found between hydroxychloroquine or lopinavir/ritonavir as compared to standard of care only on the proportion of patients who needed treatment escalation at day 28. Further randomized controlled trials are required to demonstrate whether these drugs may be useful in this context.

Plastic bronchitis: An unusual complication of acute chest syndrome in adult.

Plastic bronchitis is used to designate endobronchial plugs of rubber-like consistency that form into bronchial trees. It has been described in several diseases like asthma, cystic fibrosis, pulmonary infection, cyanotic congenital heart disease and in few young children with homozygous sickle cell disease. We report the first sickle cell adult case of plastic bronchitis during acute chest syndrome. He developed severe acute respiratory distress syndrome. This unusual presentation related to obstruction by voluminous casts may alert physicians to focus more on the bronchi in sickle cell patients. Realization of fiberoptic bronchoscopy to diagnose endobronchial injury and preventive measures such as fluidification of sputum at the early stage of thoracic vaso-occlusive crisis are essential.

Effects of oxidative stress on red blood cell rheology in sickle cell patients.

Sickle cell anaemia (SS) and sickle cell-haemoglobin C disease (SC) patients exhibit severe red blood cell (RBC) rheological alterations involved in the development of several complications. The contribution of oxidative stress in these haemorheological abnormalities is still unknown. We compared RBC reactive oxygen species (ROS) and glutathione (GSH) content, and the haemorheological profile of SS (n = 11), SC (n = 11) and healthy subjects (n = 12) at baseline and after in-vitro treatment with t-butyl hydroperoxide (TBHP). We showed: (i) higher RBC ROS content in SS and SC patients, with the highest level observed in SS patients; (ii) lower RBC GSH content in sickle syndrome patients, especially in SS patients; (iii) TBHP increased RBC ROS production and decreased RBC GSH content in all groups; (iv) TBHP decreased RBC aggregation and increased the strength of RBC aggregates in all groups but the increase in RBC aggregates strength was greater in sickle cell patients; (v) TBHP decreased RBC deformability in the three groups but with a higher magnitude in sickle cell patients. These data suggest that RBCs from sickle cell patients have an exaggerated response to oxidative stress, which is accompanied by a profound abnormal haemorheological profile, with greater alterations in SS than in SC patients.