Continuous and deep sedation until death after a decision to withdraw life-sustaining therapies in intensive care units: A national survey.

BACKGROUND: Continuous and deep sedation until death is a much highly debated end-of-life practice. France is unique in having a regulatory framework for it. However, there are no data on its practice in intensive care units (ICUs). AIM: The aim is to describe continuous and deep sedation in relation to the framework in the specific context of withdrawal of life-sustaining therapies in ICUs, that is, its decision-making process and its practice compared to other end-of-life practices in this setting. DESIGN AND SETTING: French multicenter observational study. Consecutive ICU patients who died after a decision to withdraw life-sustaining therapies. RESULTS: A total of 343 patients in 57 ICUs, 208 (60%) with continuous and deep sedation. A formalized procedure for continuous and deep sedation was available in 32% of the ICUs. Continuous and deep sedation was not the result of a collegial decision-making process in 17% of cases, and did not involve consultation with an external physician in 29% of cases. The most commonly used sedative medicines were midazolam (10 [5-18] mg h-1) and propofol (200 [120-250] mg h -1). The Richmond Agitation Sedation Scale (RASS) was -5 in 60% of cases. Analgesia was associated with sedation in 94% of cases. Compared with other end-of-life sedative practices (n = 98), medicines doses were higher with no difference in the depth of sedation. CONCLUSIONS: This study shows a poor compliance with the framework for continuous and deep sedation. It highlights the need to formalize it to improve the decision-making process and the match between the intent, the practice and the actual effect.

Impact of Strategy on Clinical Outcome in Large Vessel Occlusion Stroke Successfully Reperfused: ETIS Registry Results.

BACKGROUND AND PURPOSE: Approximately half of the patients with acute ischemic stroke due to anterior circulation large vessel occlusion do not achieve functional independence despite successful reperfusion. We aimed to determine influence of reperfusion strategy (bridging therapy, intravenous thrombolysis alone, or mechanical thrombectomy alone) on clinical outcomes in this population. METHODS: From ongoing, prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke registry in France, all patients with anterior circulation large vessel occlusion who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3) following reperfusion therapy were included. Primary end point was favorable outcome, defined as 90-day modified Rankin Scale score ≤2. Patient groups were compared using those treated with bridging therapy as reference. Differences in baseline characteristics were reduced after propensity score-matching, with a maximum absolute standardized difference of 14% for occlusion site. RESULTS: Among 1872 patients included, 970 (51.8%) received bridging therapy, 128 (6.8%) received intravenous thrombolysis alone, and the remaining 774 (41.4%) received MT alone. The rate of favorable outcome was comparable between groups. Excellent outcome (90-day modified Rankin Scale score 0-1) was achieved more frequently in the bridging therapy group compared with the MT alone (odds ratio after propensity score-matching, 0.70 [95% CI, 0.50-0.96]). Regarding safety outcomes, hemorrhagic complications were similar between the groups, but 90-day mortality was significantly higher in the MT alone group compared with the bridging therapy group (odds ratio, 1.60 [95% CI, 1.09-2.37]). CONCLUSIONS: This real-world observational study of patients with anterior circulation large vessel occlusion demonstrated a similar rate of favorable outcome following successful reperfusion with different therapeutic strategies. However, our results suggest that bridging therapy compared with MT alone is significantly associated with excellent clinical outcome and lower mortality. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03776877.

Time from I.V. Thrombolysis to Thrombectomy and Outcome in Acute Ischemic Stroke.

OBJECTIVE: Whether the time from intravenous thrombolysis (IVT) to endovascular treatment (EVT) in patients with acute ischemic stroke has an effect on the functional outcome is unknown. METHODS: The Endovascular Treatment in Ischemic Stroke (ETIS) registry is an ongoing, prospective, multicenter, observational study that perform EVT in France. Data were analyzed from patients treated by IVT and EVT between October 2013 and December 2018 in 6 comprehensive stroke centers. In the primary analysis, we assessed the association of time from IVT administration to start of EVT with functional outcome (measured with the modified Rankin Scale [mRS]), by means of ordinal logistic regression. Secondary end points included angiographic and safety outcomes. RESULTS: We analyzed 1,986 patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent IVT and EVT. An increased IVT to start of EVT time was associated with a worse functional outcome at 90 days (mRS = 0-2, adjusted odds ratio [OR] per 30 minutes increase in time = 0.91, 95% confidence interval [CI] = 0.86-0.96; mRS = 0-1, adjusted OR per 30 minutes increase in time = 0.89, 95% CI = 0.84-0.94), a lower chance of modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b to 3 reperfusion (adjusted OR per 30 minutes increase in time = 0.93, 95% CI = 0.87-0.98), and an increased probability of symptomatic intracerebral hemorrhage (adjusted OR per 30 minutes increase in time = 1.09, 95% CI = 0.99-1.18). INTERPRETATION: These findings provide a basis for further studies to determine if the functional outcome of patients with stroke can be greatly improved by optimizing IVT to EVT times. ANN NEUROL 2021;89:511-519.

Withholding and withdrawal of life-sustaining therapy in 8569 trauma patients: A multicentre, analytical registry study.

BACKGROUND: This study aimed to determine the prevalence of withholding or withdrawal of life-sustaining therapy (WLST) decisions in trauma ICU patients, using a large registry. We hypothesised that this prevalence is similar to that of the general population admitted to an ICU. As secondary aims, it sought to describe the trauma patients for whom the decision was made for WLST and the factors associated with this decision. DESIGN: This observational study assessed data from 14 French centres listed in the TraumaBaseTM registry. All trauma patients hospitalised for more than 48 h were pro-spectively included. RESULTS: Data from 8569 trauma patients, obtained from January 2016 to December 2018, were included in this study. A WLST decision was made in 6% of all cases. In the WLST group, 67% of the patients were older men (age: 62 versus 36, P  < 0.001); more often they had a prior medical history and higher median severity scores than the patients in the no WLST decision group; SAPS II 58 (46 to 69) versus 21 (13 to 35) and ISS 26 (22 to 24) versus 12 (5 to 22), P  < 0.001. Neurological status was strongly associated with WLST decisions. The geographic area of the ICUs affected the rate of the WLST decisions. The ICU mortality was 11% (n = 907) of which 47% (n = 422) were preceded by WLST decisions. Fourteen percent of WLST orders were not associated to the death. CONCLUSION: Among 8569 patients, medical history, trauma severity criteria, notably neurological status and geographical areas were associated with WLST. These regional differences deserve to be investigated in future studies.

Endovascular Therapy of Anterior Circulation Tandem Occlusions: Pooled Analysis From the TITAN and ETIS Registries.

Background and Purpose: Endovascular therapy for tandem occlusion strokes of the anterior circulation is an effective and safe treatment. The best treatment approach for the cervical internal carotid artery (ICA) lesion is still unknown. In this study, we aimed to compare the functional and safety outcomes between different treatment approaches for the cervical ICA lesion during endovascular therapy for acute ischemic strokes due to tandem occlusion in current clinical practice. Methods: Individual patients' data were pooled from the French prospective multicenter observational ETIS (Endovascular Treatment in Ischemic Stroke) and the international TITAN (Thrombectomy in Tandem Lesions) registries. TITAN enrolled patients from January 2012 to September 2016, and ETIS from January 2013 to July 2019. Patients with acute ischemic stroke due to anterior circulation tandem occlusion who were treated with endovascular therapy were included. Patients were divided based on the cervical ICA lesion treatment into stent and no-stent groups. Outcomes were compared between the two treatment groups using propensity score methods. Results: A total of 603 patients were included, of whom 341 were treated with acute cervical ICA stenting. In unadjusted analysis, the stent group had higher rate of favorable outcome (90-day modified Rankin Scale score, 0­2; 57% versus 45%) and excellent outcome (90-day modified Rankin Scale score, 0­1; 40% versus 27%) compared with the no-stent group. In inverse probability of treatment weighting propensity score­adjusted analyses, stent group had higher odds of favorable outcome (adjusted odds ratio, 1.09 [95% CI, 1.01­1.19]; P=0.036) and successful reperfusion (modified Thrombolysis in Cerebral Ischemia score, 2b-3; adjusted odds ratio, 1.19 [95% CI, 1.11­1.27]; P<0.001). However, stent group had higher odds of any intracerebral hemorrhage (adjusted odds ratio, 1.10 [95%, 1.02­1.19]; P=0.017) but not higher rate of symptomatic intracerebral hemorrhage or parenchymal hemorrhage type 2. Subgroup analysis demonstrated heterogeneity according to the lesion type (atherosclerosis versus dissection; P for heterogeneity, 0.01), and the benefit from acute carotid stenting was only observed for patients with atherosclerosis. Conclusions: Patients treated with acute cervical ICA stenting for tandem occlusion strokes had higher odds of 90-day favorable outcome, despite higher odds of intracerebral hemorrhage; however, most of the intracerebral hemorrhages were asymptomatic.

Obesity and mortality in critically ill COVID-19 patients with respiratory failure.

BACKGROUND: Patients with obesity are at increased risk of severe COVID-19, requiring mechanical ventilation due to acute respiratory failure. However, conflicting data are obtained for intensive care unit (ICU) mortality. OBJECTIVE: To analyze the relationship between obesity and in-hospital mortality of ICU patients with COVID-19. SUBJECTS/METHODS: Patients admitted to the ICU for COVID-19 acute respiratory distress syndrome (ARDS) were included retrospectively. The following data were collected: comorbidities, body mass index (BMI), the severity of ARDS assessed with PaO2/FiO2 (P/F) ratios, disease severity measured by the Simplified Acute Physiology Score II (SAPS II), management and outcomes. RESULTS: For a total of 222 patients, there were 34 patients (15.3%) with normal BMI, 92 patients (41.4%) who were overweight, 80 patients (36%) with moderate obesity (BMI:30-39.9 kg/m2), and 16 patients (7.2%) with severe obesity (BMI ≥ 40 kg/m2). Overall in-hospital mortality was 20.3%. Patients with moderate obesity had a lower mortality rate (13.8%) than patients with normal weight, overweight or severe obesity (17.6%, 21.7%, and 50%, respectively; P = 0.011. Logistic regression showed that patients with a BMI ≤ 29 kg/m2 (odds ratio [OR] 3.64, 95% CI 1.38-9.60) and those with a BMI > 39 kg/m2 (OR 10.04, 95% CI 2.45-41.09) had a higher risk of mortality than those with a BMI from 29 to 39 kg/m2. The number of comorbidities (≥2), SAPS II score, and P/F < 100 mmHg were also independent predictors for in-hospital mortality. CONCLUSIONS: COVID-19 patients admitted to the ICU with moderate obesity had a lower risk of death than the other patients, suggesting a possible obesity paradox.

Age and Outcome after Endovascular Treatment in Anterior Circulation Large-Vessel Occlusion Stroke: ETIS Registry Results.

BACKGROUND: Increasing patient age has been identified in clinical trials as a poor prognostic factor for functional independence after endovascular treatment (EVT) for acute ischemic stroke. These findings may not be fully generalizable to clinical practice due to strict inclusion and exclusion criteria in these trials. We aim to assess and quantify the association of patient age, especially in patients >80 and >90 years old, with functional outcome after EVT in current, everyday clinical practice. METHODS: The ETIS (Endovascular Treatment in Ischemic Stroke) Registry is an ongoing, prospective, observational study of 6 comprehensive stroke centers in France. We analyzed 1,708 patients treated between January 2017 and December 2018 and assessed the association of patient age with functional outcome adjusting for demographic and procedural predictors of functional outcome. RESULTS: The positive effect of mechanical thrombectomy diminished significantly with increasing age: compared to the 18-80 years age group, the odds for achieving a good functional outcome at 90 days after the procedure decreased in the 80-90 and >90 years groups (multilevel OR: 0.38, 95% CI: 0.28-0.51 and OR: 0.2, 95% CI: 0.09-0.45, respectively, p < 0.001). Increasing age was associated with increased mortality (multilevel OR: 2.46, 95% CI: 1.72-3.54 for the 80-90 years group and multilevel OR: 5.49, 95% CI: 2.97-10.16 for the >90 years group). CONCLUSION: Patient age is strongly associated with functional outcome after EVT for acute ischemic stroke. The positive effect of thrombectomy persists in older age groups, even after adjustment for prognostic factors related to poor functional outcome. Stroke physicians should provide EVT irrespective of the patient's age.

Local Anesthesia Without Sedation During Thrombectomy for Anterior Circulation Stroke Is Associated With Worse Outcome.

BACKGROUND AND PURPOSE: The best anesthetic management for mechanical thrombectomy of large vessel occlusion strokes is still uncertain and could impact the quality of reperfusion and clinical outcome. We aimed to compare the efficacy and safety outcomes between local anesthesia (LA) and conscious sedation in a large cohort of acute ischemic stroke patients with anterior circulation large vessel occlusion strokes treated with mechanical thrombectomy in current, everyday clinical practice. METHODS: Patients undergoing mechanical thrombectomy for anterior large vessel occlusion strokes at 4 comprehensive stroke centers in France between January 1, 2018, and December 31, 2018, were pooled from the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France. Intention-to-treat and per-protocol analyses were used. RESULTS: Among the included 1034 patients, 762 were included in the conscious sedation group and 272 were included in the LA group. In the propensity score matched cohort, the rate of favorable outcome (90-day modified Rankin Scale score 0-2) was significantly lower in the LA group than in the conscious sedation group (40.0% versus 52.0%, matched relative risk=0.76 [95% CI, 0.60-0.97]), as well as the rate of successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3; 76.6% versus 87.1%; matched relative risk=0.88 [95% CI, 0.79-0.98]). There was no difference in procedure time between the 2 groups. In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar significant differences were found for favorable outcomes and successful reperfusion. In inverse probability of treatment weighting-propensity score-adjusted cohort, a higher rate of 90-day mortality and a lower parenchymal hematoma were observed after LA. The sensitivity analysis restricted to our per-protocol sample provided similar results in the matched- and inverse probability of treatment weighting-propensity cohorts. CONCLUSIONS: In the Endovascular Treatment in Ischemic Stroke registry mainly included patients in early time window (<6 hours), LA was associated with lower odds of favorable outcome, successful reperfusion, and higher odds of mortality compared with conscious sedation for mechanical thrombectomy of large vessel occlusion.

Endovascular treatment of distal anterior cerebral artery aneurysms: Long-term results.

BACKGROUND AND PURPOSE: Endovascular therapy is the first-line therapeutic option for intracranial aneurysms, however the results of the endovascular approach for distal anterior cerebral artery (DACA) aneurysms are not well-known. We assessed the immediate and long-term clinical and angiographic outcomes after endovascular coiling of DACA aneurysms. MATERIALS AND METHODS: We performed a retrospective analysis of all consecutive DACA aneurysms treated by endovascular coiling. Procedural complications, clinical, and angiographic results were prospectively recorded in an institutional aneurysm database between 1992 and 2013. RESULTS: Satisfactory initial occlusion was achieved for 85.9% of cases (79/92). There were three cases of intraprocedural rupture of the aneurysmal sac and three treatment failures, all involving small aneurysms (< 4 mm). Rates of procedure-related mortality and morbidity were respectively 1.1% and 0%. Scores of 5 (good recovery) or 4 (moderate disability) on the Glasgow Outcome Scale, indicating favorable outcome, were observed for 79.3% of patients (73/92) at hospital discharge. In follow-up, 13 cases of recanalization were observed, 12 of which were classified as major. Ten of the recanalizations underwent a complementary intervention. CONCLUSIONS: The endovascular management of DACA aneurysms appears to be efficacious and safe, although certain technical difficulties may emerge when aneurysms are small. A higher proportion of major recanalization events may imply a more frequent deployment of complementary interventions in comparison to aneurysms situated elsewhere.

An assessment of advance relatives approach for brain death organ donation.

BACKGROUND:: Advance announcement of forthcoming brain death has developed to enable intensivists and organ procurement organisation coordinators to more appropriately, and separately from each other, explain to relatives brain death and the subsequent post-mortem organ donation opportunity. RESEARCH AIM:: The aim was to assess how potentially involved healthcare professionals perceived ethical issues surrounding the strategy of advance approach. RESEARCH DESIGN:: A multi-centre opinion survey using an anonymous self-administered questionnaire was conducted in the six-member hospitals of the publicly funded East of France regional organ and tissue procurement network called 'Prélor'. PARTICIPANTS:: The study population comprised 460 physicians and nurses in the Neurosurgical, Surgical and Medical Intensive Care Units, the Stroke Units and the Emergency Departments. ETHICAL CONSIDERATIONS:: The project was approved by the board of the Lorraine University Diploma in Medical Ethics and the Prélor Network administrators. MAIN FINDINGS:: A slight majority of 53.5% of respondents had previously participated in an advance relatives approach: 83% of the physicians and 42% of the nurses. A majority of healthcare professionals (68%) think that the main justification for advance relatives approach is the comprehensive care of the dying patient and the research of his or her most likely opinion (74%). The misunderstanding of the related issues by relatives is an obstacle for 47% of healthcare professionals and 51% think that the answer given by the relatives regarding the most likely opinion of the person regarding post-mortem organ donation really corresponds to the person opinion in only 50% of the cases or less. CONCLUSION:: Time given by advance approach should be employed to help and enable relatives to authentically bear the values and interests of the potential donor in the post-mortem organ donation discussion. Nurses' attendance of advance relatives approach seems necessary to enable them to optimally support the families facing death and post-mortem organ donation issues.

Non-therapeutic intensive care for organ donation: A healthcare professionals' opinion survey.

BACKGROUND AND PURPOSE: Providing non-therapeutic intensive care for some patients in hopeless condition after cerebrovascular stroke in order to protect their organs for possible post-mortem organ donation after brain death is an effective but ethically tricky strategy to increase organ grafting. Finding out the feelings and opinion of the involved healthcare professionals and assessing the training needs before implementing such a strategy is critical to avoid backlash even in a presumed consent system. PARTICIPANTS AND METHODS: A single-centre opinion survey of healthcare professionals was conducted in 2013 in the potentially involved wards of a French University Hospital: the Neurosurgical, Surgical and Medical Intensive Care Units, the Stroke Unit and the Emergency Department. A questionnaire with multiple-choice questions and one open-ended question was made available in the different wards between February and May 2013. ETHICAL CONSIDERATIONS: The project was approved by the board of the Lorraine University Diploma in Medical Ethics. RESULTS: Of a total of 340 healthcare professionals, 51% filled the form. Only 21.8% received a specific education on brain death, and only 18% on potential donor's family approach and support. Most healthcare professionals (93%) think that non-therapeutic intensive care is the continuity of patient's care. But more than 75% of respondents think that the advance patient's consent and the consent of the family must be obtained despite the presumed consent rule regarding post-mortem organ donation in France. CONCLUSION: The acceptance by healthcare professionals of non-therapeutic intensive care for brain death organ donation seems fairly good, despite a suboptimal education regarding brain death, non-therapeutic intensive care and families' support. But they ask to require previously expressed patient's consent and family's approval. So, it seems that non-therapeutic intensive care should only remain an ethically sound mean of empowerment of organ donors and their families to make post-mortem donation happen as a full respect of individual autonomy.

Epinephrine, compared with arginine vasopressin, is associated with similar haemodynamic effects but significantly improved brain oxygenation in the early phase of anaphylactic shock in rats: An experimental study.

BACKGROUND: In contrast to other types of shock, anaphylactic shock decreases cerebral blood flow more than would be expected from severe arterial hypotension, thus potentially affecting survival through brain ischaemia/hypoxia. We hypothesised that epinephrine (EPI) used as a first-line treatment of anaphylactic shock and arginine vasopressin (AVP) proposed in case of EPI refractoriness may have different effects on brain oxygenation. OBJECTIVES: To compare the effect of EPI and AVP on brain oxygenation under similar macro-haemodynamic target values in an anaphylactic shock model. DESIGN: Prospective laboratory study. SETTING: University laboratory. ANIMALS: Male brown Norway rats (n = 27). INTERVENTIONS: Twenty-seven rats were sensitised with ovalbumin (OVA). Twenty rats had anaphylactic shock induced with OVA and were resuscitated with either 0.9% saline (OVA group), EPI (EPI group) or AVP (AVP group). Sensitised control rats received only 0.9% saline and no OVA (CON group). MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), carotid artery blood flow (CaBF), cerebral cortical blood flow (CBF) and hippocampal oxygen partial pressure (PtiO2) were recorded. RESULTS: All rats in the OVA group died within 15 min. EPI and AVP restored comparable levels of MAP, carotid artery blood flow and CBF, and extended survival time. EPI was associated with biologically relevant and significantly (P < 0.05) higher PtiO2 values (nadir values at 20 min: 25.0 ± 2.2 mmHg) compared with the AVP group (14.9 ± 2.0 mmHg). The slopes of the correlations of MAP vs. PtiO2 and CBF were significantly steeper with AVP (more pressure dependence) compared with EPI. By the end of the experiment, hippocampal PtiO2 values between the EPI (24.1 ± 2.1 mmHg) and the AVP (20.8 ± 2.0 mmHg) groups were similar. CONCLUSION: At early, but not at late time points, resuscitation of anaphylactic shock with EPI or AVP to similar MAP and CBF endpoints resulted in hippocampal PtiO2 being significantly higher after EPI. In addition, the PtiO2 after EPI always remained above the threshold for brain hypoxia, whereas PtiO2 after AVP was below the hypoxic threshold most of the time. Because of this early brain hypoxia, AVP may not be the drug of first choice for resuscitation of anaphylactic shock.

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.

Methylene blue and epinephrine: a synergetic association for anaphylactic shock treatment.

BACKGROUND: Severe hypotension resulting from anaphylactic shock may be refractory to epinephrine and impair cerebral oxygenation and metabolism contributing to anaphylactic shock morbidity and mortality. Refractoriness to epinephrine could be corrected by nitric oxide pathway inhibitors such as methylene blue. OBJECTIVES: To compare the systemic and regional (brain and skeletal muscle) effects of epinephrine and methylene blue given alone or in combination in a rat model of anaphylactic shock. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Male Brown-Norway rats (n = 60). INTERVENTIONS: After sensitization and induction of anaphylactic shock by ovalbumin, animals received either vehicle (ovalbumin group) or a 3-mg/kg methylene blue bolus (methylene blue group) or epinephrine (epinephrine group) or both (methylene blue-epinephrine group). Sensitized control rats received only vehicle and no ovalbumin (control group). MEASUREMENT AND MAIN RESULTS: Mean arterial pressure, cardiac output, cerebral blood flow, skeletal muscular oxygen partial pressure, cerebral oxygen partial pressure, skeletal muscular, and cerebral interstitial lactate/pyruvate ratio were measured. Cleaved caspase 3 and hypoxia-inducible factor-1α expression were analyzed in the cerebral cortex by Western blot. Without treatment, rats died rapidly within 15 mins from a decrease in cardiac output and mean arterial pressure, whereas treated rats survived until the end of the experiment. Methylene blue alone extended survival time but without significant improvement of hemodynamic variables and tissue perfusion and did not prevent neuronal injury. Epinephrine restored partially systemic hemodynamic variables and cerebral perfusion preventing glutamate-induced excitotoxicity. Compared with epinephrine alone, the methylene blue-epinephrine association avoided neuronal excitotoxicity and had an additive effect both on hemodynamic variables and for prevention of brain ischemia. Neither treatment could significantly restore cardiac output or prevent muscular compartment ischemia and microvascular leakage. CONCLUSIONS: Anaphylactic shock is associated with severe impairment of cerebral blood flow despite correction of arterial hypotension. Epinephrine must still be considered as the first-line vasoconstrictive agent to treat anaphylactic shock. The epinephrine-methylene blue association was the most effective treatment to prevent cerebral ischemia and could be used in anaphylactic shock refractory to epinephrine.

Gene expression profile of blood cells for the prediction of delayed cerebral ischemia after intracranial aneurysm rupture: a pilot study in humans.

BACKGROUND: Delayed cerebral ischemia (DCI) is a potentially devastating complication after intracranial aneurysm rupture and its mechanisms remain poorly elucidated. Early identification of the patients prone to developing DCI after rupture may represent a major breakthrough in its prevention and treatment. The single gene approach of DCI has demonstrated interest in humans. We hypothesized that whole genome expression profile of blood cells may be useful for better comprehension and prediction of aneurysmal DCI. METHODS: Over a 35-month period, 218 patients with aneurysm rupture were included in this study. DCI was defined as the occurrence of a new delayed neurological deficit occurring within 2 weeks after aneurysm rupture with evidence of ischemia either on perfusion-diffusion MRI, CT angiography or CT perfusion imaging, or with cerebral angiography. DCI patients were matched against controls based on 4 out of 5 criteria (age, sex, Fisher grade, aneurysm location and smoking status). Genome-wide expression analysis of blood cells obtained at admission was performed by microarrays. Transcriptomic analysis was performed using long oligonucleotide microarrays representing 25,000 genes. Quantitative PCR: 1 µg of total RNA extracted was reverse-transcribed, and the resulting cDNA was diluted 10-fold before performing quantitative PCR. Microarray data were first analyzed by 'Significance Analysis of Microarrays' software which includes the Benjamini correction for multiple testing. In a second step, microarray data fold change was compared using a two-tailed, paired t test. Analysis of receiver-operating characteristic (ROC) curves and the area under the ROC curves were used for prediction analysis. Logistic regression models were used to investigate the additive value of multiple biomarkers. RESULTS: A total of 16 patients demonstrated DCI. Significance Analysis of Microarrays software failed to retrieve significant genes, most probably because of the heterogeneity of the patients included in the microarray experiments and the small size of the DCI population sample. Standard two-tailed paired t test and C-statistic revealed significant associations between gene expression and the occurrence of DCI: in particular, the expression of neuroregulin 1 was 1.6-fold upregulated in patients with DCI (p = 0.01) and predicted DCI with an area under the ROC curve of 0.96. Logistic regression analyses revealed a significant association between neuroregulin 1 and DCI (odds ratio 1.46, 95% confidence interval 1.02-2.09, p = 0.02). CONCLUSIONS: This pilot study suggests that blood cells may be a reservoir of prognostic biomarkers of DCI in patients with intracranial aneurysm rupture. Despite an evident lack of power, this study elicited neuroregulin 1, a vasoreactivity-, inflammation- and angiogenesis-related gene, as a possible candidate predictor of DCI. Larger cohort studies are needed but genome-wide microarray-based studies are promising research tools for the understanding of DCI after intracranial aneurysm rupture.

Elective non-therapeutic intensive care and the four principles of medical ethics.

The chronic worldwide lack of organs for transplantation and the continuing improvement of strategies for in situ organ preservation have led to renewed interest in elective non-therapeutic ventilation of potential organ donors. Two types of situation may be eligible for elective intensive care: patients definitely evolving towards brain death and patients suitable as controlled non-heart beating organ donors after life-supporting therapies have been assessed as futile and withdrawn. Assessment of the ethical acceptability and the risks of these strategies is essential. We here offer such an ethical assessment using the four principles of medical ethics of Beauchamp and Childress applying them in their broadest sense so as to include patients and their families, their caregivers, other potential recipients of intensive care, and indeed society as a whole. The main ethical problems emerging are the definition of beneficence for the potential organ donor, the dilemma between the duty to respect a dying patient's autonomy and the duty not to harm him/her, and the possible psychological and social harm for families, caregivers other potential recipients of therapeutic intensive care, and society more generally. Caution is expressed about the ethical acceptability of elective non-therapeutic ventilation, along with some proposals for precautionary measures to be taken if it is to be implemented.

Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial.

BACKGROUND: Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. METHODS: We did an open-label, randomised controlled superiority trial at 25 French tertiary referral centres. Within 16 h of brain injury, patients with severe traumatic brain injury (aged 18-75 years) were randomly assigned via a website to be managed during the first 5 days of admission to the intensive care unit either by intracranial pressure monitoring only or by both intracranial pressure and PbtO2 monitoring. Randomisation was stratified by age and centre. The study was open label due to the visibility of the intervention, but the statisticians and outcome assessors were masked to group allocation. The therapeutic objectives were to maintain intracranial pressure of 20 mm Hg or lower, and to keep PbtO2 (for those in the dual-monitoring group) above 20 mm Hg, at all times. The primary outcome was the proportion of patients with an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability) at 6 months after injury. The primary analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew consent or had protocol violations. This trial is registered with ClinicalTrials.gov, NCT02754063, and is completed. FINDINGS: Between June 15, 2016, and April 17, 2021, 318 patients were randomly assigned to receive either intracranial pressure monitoring only (n=160) or both intracranial pressure and PbtO2 monitoring (n=158). 27 individuals with protocol violations were not included in the modified intention-to-treat analysis. Thus, the primary outcome was analysed for 144 patients in the intracranial pressure only group and 147 patients in the intracranial pressure and PbtO2 group. Compared with intracranial pressure monitoring only, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with GOSE score 1-4 (51% [95% CI 43-60] in the intracranial pressure monitoring only group vs 52% [43-60] in the intracranial pressure and PbtO2 monitoring group; odds ratio 1·0 [95% CI 0·6-1·7]; p=0·95). Two (1%) of 144 participants in the intracranial pressure only group and 12 (8%) of 147 participants in the intracranial pressure and PbtO2 group had catheter dysfunction (p=0.011). Six patients (4%) in the intracranial pressure and PbtO2 group had an intracrebral haematoma related to the catheter, compared with none in the intracranial pressure only group (p=0.030). No significant difference in deaths was found between the two groups at 12 months after injury. At 12 months, 33 deaths had occurred in the intracranial pressure group: 25 (76%) were attributable to the brain trauma, six (18%) were end-of-life decisions, and two (6%) due to sepsis. 34 deaths had occured in the intracranial pressure and PbtO2 group at 12 months: 25 (74%) were attributable to the brain trauma, six (18%) were end-of-life decisions, one (3%) due to pulmonary embolism, one (3%) due to haemorrhagic shock, and one (3%) due to cardiac arrest. INTERPRETATION: After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission. FUNDING: The French National Program for Clinical Research, La Fondation des Gueules Cassées, and Integra Lifesciences.

Diffusion tensor imaging to predict long-term outcome after cardiac arrest: a bicentric pilot study.

BACKGROUND: Prognostication in comatose survivors of cardiac arrest is a major clinical challenge. The authors' objective was to determine whether an assessment with diffusion tensor imaging, a brain magnetic resonance imaging sequence, increases the accuracy of 1 yr functional outcome prediction in cardiac arrest survivors. METHODS: Prospective, observational study in two intensive care units. Fifty-seven comatose survivors of cardiac arrest underwent brain magnetic resonance imaging. Fractional anisotropy (FA), a diffusion tensor imaging value, was measured in predefined white matter regions, and apparent diffusion coefficient was assessed in predefined grey matter regions. Prediction of unfavorable outcome at 1 yr was compared using four prognostic models: FA global, FA selected, apparent diffusion coefficient, and clinical classifiers. RESULTS: Of the 57 patients included in the study, 49 had an unfavorable outcome at 12 months. Areas under the receiver operating characteristic curve (95% CI) to predict unfavorable outcome for the FA global, FA selected, clinical, and apparent diffusion coefficient models were 0.92 (0.82-0.98), 0.96 (0.87-0.99), 0.78 (0.65-0.88), and 0.86 (0.74-0.94), respectively. The FA selected model had the best overall accuracy for predicting outcome, with a score above 0.44 having 94% (95% CI, 83-99%) sensitivity and 100% (95% CI, 63-100%) specificity for the prediction of unfavorable outcome. CONCLUSION: Quantitative diffusion tensor imaging indicates that white matter damage is widespread after cardiac arrest. A prognostic model based on FA values in selected white matter tracts seems to predict accurately 1 yr functional outcome. These preliminary results need to be confirmed in a larger population.