Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration.

OBJECTIVES: Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 is likely due to a cytokine storm characterised by a major release of pro-inflammatory cytokines, including interleukin-6 (IL-6). Blocking excessive IL-6 production might be the key to the COVID-19-ARDS treatment. Beneficial effects of IL-6 blockade using a humanised anti-IL-6 receptor antibody, tocilizumab (TCZ) were previously reported in patients with COVID-19 related ARDS. The aim of the study was to study the variation over time of several biomarkers, demonstrated to be predictors of poor prognostic, in subjects successfully treated with TCZ for severe COVID-19. METHODS: Retrospective analysis of a case series of patients with COVID-19-ARDS, evidenced by RT-PCR and lung CT-scan. Patients with increasing O2 requirements, within the window of opportunity for TCZ treatment (Day 7 to Day 17 after onset of symptoms) were treated with TCZ (2 infusions of 8 mg/kg). Demographic, biological and clinical data were collected from the patients' files. Serum levels of CRP, ferritin, fibrinogen, lymphocytes, platelets, creatinine, D-dimer and liver enzymes were assayed at the time of the first TCZ administration, then every two days for 8 days. RESULTS: 40 patients were treated with TCZ. Most of them had several comorbidities, and all had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer, liver enzymes). 30 patients (75%) benefited from TCZ and 10 patients died. In the survivors, following TCZ administration CRP decreased dramatically as early as day 4 (-86.7%, p<0.0001) and returned to normal at day 6. Fibrinogen and lymphocyte count returned to normal values at day 6. Ferritin also decreased significantly. No significant change was observed for D-dimer (p=0.68) and other studied biomarkers (haemoglobin, leucocyte count, AST). CONCLUSIONS: In patients with COVID-19 acute respiratory distress syndrome, treatment with TCZ resulted in favourable evolution in 75% of the cases. Biomarkers of inflammation (CRP, ferritin, fibrinogen) decreased dramatically as early as the 4th day after TCZ injection. Lymphopenia, a predictor of poor prognostic, was reversed 6 days after TCZ injection.

Being Convinced and Taking Responsibility: A Qualitative Study of Family Members' Experience of Organ Donation Decision and Bereavement After Brain Death.

OBJECTIVES: Family members of brain dead patients experience an unprecedented situation in which not only they are told that their loved one is dead but are also asked to consider organ donation. The objective of this qualitative study was to determine 1) what it means for family members to make the decision and to take responsibility, 2) how they interact with the deceased patient in the ICU, 3) how family members describe the impact of the process and of the decision on their bereavement process. DESIGN: Qualitative study using interviews with bereaved family members who were approached for organ donation after the death of their relative in the ICU (brain death). SETTING: Family members from 13 ICUs in France. SUBJECTS: Bereaved family members who were approached for organ donation after the death of their relative in the ICU (brain death). INTERVENTION: None. MEASUREMENTS AND RESULTS: Twenty-four interviews were conducted with 16 relatives of organ donor patients and with eight relatives of nonorgan donor patients. Three themes emerged: 1) taking responsibility-relatives explain how they endorse decisional responsibility but do not experience it as a burden, on the contrary; 2) ambiguous perceptions of death-two groups of relatives emerge: those for whom ambiguity hinders their acceptance of the patient's death; those for whom ambiguity is an opportunity to accept the death and say goodbye; and 3) donation as a comfort during bereavement. CONCLUSIONS: In spite of caregivers' efforts to focus organ donation discussions and decision on the patient, family members feel a strong decisional responsibility that is not experienced as a burden but a proof of their strong connection to the patient. Brain death however creates ambivalent experiences that some family members endure whereas others use as an opportunity to perform separation rituals. Last, organ donation can be experienced as a form of comfort during bereavement provided family members remain convinced their decision was right.

Grief Symptoms in Relatives Who Experienced Organ Donation Requests in the ICU.

RATIONALE: Studies show that the quality of end-of-life communication and care have a significant impact on the living long after the death of a relative and have been implicated in the burden of psychological symptoms after the ICU experience. In the case of organ donation, the patient's relatives are centrally involved in the decision-making process; yet, few studies have examined the impact of the quality of communication on the burden of psychological symptoms after death. OBJECTIVES: To assess the experience of the organ donation process and grief symptoms in relatives of brain-dead patients who discussed organ donation in the ICU. METHODS: We conducted a multicenter longitudinal study in 28 ICUs in France. Participants were the relatives of brain-dead patients who were approached to discuss organ donation. Relatives were followed-up by phone at three time points: at 1 month, to complete a questionnaire describing their experience of the organ donation process; at 3 months, to complete the Hospital Anxiety and Depression Scale and the Impact of Event Scale-Revised; and at 9 months, to complete the Impact of Event Scale-Revised and the Inventory of Complicated Grief. MEASUREMENTS AND MAIN RESULTS: In total, 202 relatives of 202 patients were included, of whom 158 consented to and 44 refused organ donation. Interviews were conducted at 1, 3, and 9 months with 78%, 68%, and 58% of relatives, respectively. The overall experience of the organ donation process was significantly more burdensome for relatives of nondonors. They were more dissatisfied with communication (27% vs. 10%; P = 0.021), more often shocked by the request (65% vs. 19%; P < 0.0001), and more often found the decision difficult (53% vs. 27%; P = 0.017). However, there were no significant differences in grief symptoms measured at 3 and 9 months between the two groups. Understanding of brain death was associated with grief symptoms; our results show a higher prevalence of complicated grief symptoms among relatives who did not understand the brain death process than among those who did (75% vs. 46.1%; P = 0.026). CONCLUSIONS: Experience of the organ donation process varied between relatives of donor versus nondonor patients, with relatives of nondonors experiencing lower-quality communication, but the decision was not associated with subsequent grief symptoms. Importantly, understanding of brain death is a key element of the organ donation process for relatives.

Profile of the risk of death after septic shock in the present era: an epidemiologic study.

OBJECTIVES: To investigate mortality of ICU patients over a 3-month period after an initial episode of septic shock and to identify factors associated with mortality. DESIGN: Prospective multicenter observational cohort study. SETTING: Fourteen ICUs from 10 French nonacademic and university teaching hospitals. PATIENTS: All consecutive adult patients with septic shock admitted between October 2009 and September 2011 were eligible. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Multivariable analyses were performed using a Cox proportional hazard model and a flexible extension of the Cox model. In total, 1,495 of 10,941 patients (13.7%) had septic shock and 1,488 patients (99.5%) were included. Median age was 68 years (range, 58-78 yr). The majority of admissions (84%) were medical. Median (interquartile range) Simplified Acute Physiological Score II and Sequential Organ Failure Assessment were, respectively, 56 (45-70) and 11 (9-14). ICU and hospital mortality were, respectively, 39.4% and 48.6%. At 3 months, 776 patients (52.2%) had died. Factors significantly associated with increased risk of death in the multivariable Cox model were older age, male sex, comorbidities (immune deficiency, cirrhosis), Knaus C/D score, and high Sequential Organ Failure Assessment score. Flexible analyses indicated that the impact of Sequential Organ Failure Assessment score was greatest early after septic shock, while the onset of the effect of age, nosocomial infection, and cirrhosis was later. CONCLUSIONS: This is the most recent large-scale epidemiological study to investigate medium-term mortality in nonselected patients hospitalized in the ICU for septic shock. Advances in early management have improved survival at the initial phase, but risk of death persists in the medium term. Flexible modeling techniques yield insights into the profile of the risk of death in the first 3 months.

The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study.

INTRODUCTION: To provide up-to-date information on the prognostic factors associated with 28-day mortality in a cohort of septic shock patients in intensive care units (ICUs). METHODS: Prospective, multicenter, observational cohort study in ICUs from 14 French general (non-academic) and university teaching hospitals. All consecutive patients with septic shock admitted between November 2009 and March 2011 were eligible for inclusion. We prospectively recorded data regarding patient characteristics, infection, severity of illness, life support therapy, and discharge. RESULTS: Among 10,941 patients admitted to participating ICUs between October 2009 and September 2011, 1,495 (13.7%) patients presented inclusion criteria for septic shock and were included. Invasive mechanical ventilation was needed in 83.9% (n=1248), inotropes in 27.7% (n=412), continuous renal replacement therapy in 32.5% (n=484), and hemodialysis in 19.6% (n=291). Mortality at 28 days was 42% (n=625). Variables associated with time to mortality, right-censored at day 28: age (for each additional 10 years) (hazard ratio (HR)=1.29; 95% confidence interval (CI): 1.20-1.38), immunosuppression (HR=1.63; 95%CI: 1.37-1.96), Knaus class C/D score versus class A/B score (HR=1.36; 95%CI:1.14-1.62) and Sepsis-related Organ Failure Assessment (SOFA) score (HR=1.24 for each additional point; 95%CI: 1.21-1.27). Patients with septic shock and renal/urinary tract infection had a significantly longer time to mortality (HR=0.56; 95%CI: 0.42-0.75). CONCLUSION: Our observational data of consecutive patients from real-life practice confirm that septic shock is common and carries high mortality in general ICU populations. Our results are in contrast with the clinical trial setting, and could be useful for healthcare planning and clinical study design.

Systematic Review and Subgroup Meta-analysis of Randomized Trials to Determine Tocilizumab's Place in COVID-19 Pneumonia.

INTRODUCTION: Tocilizumab randomized clinical trial results are heterogeneous because of the heterogenous population included in them. METHODS: We conducted a meta-analysis with subgroup meta-analysis (PRISMA guidelines) between severe and non-severe COVID-19. RESULTS: We included nine trials. Overall, the mortality rate was 24.5% (821/3357) in the tocilizumab group and 29.1% (908/3125) in the control group at day 28-30 (pooled OR, 0.85; 95% CI 0.76-0.96; p = 0.006). Considering the subgroup analysis, this benefit on mortality was confirmed and amplified in the severe COVID-19 group (pooled OR, 0.82; 95% CI 0.73-0.93; p = 0.001) but not in the non-severe COVID-19 group (pooled OR, 1.46; 95% CI 0.91-2.34; p = 0.12). For patients who were not mechanically ventilated at baseline (5523/6482), the pooled OR (0.74; 95% CI 0.64-0.85; p < 0.0001) for mechanical ventilation incidence at day 28-30 was in favor of tocilizumab (cumulative incidence of 14.8% versus 19.4% in tocilizumab and control arm, respectively). This benefit was confirmed in both subgroups, i.e., severe and non-severe COVID-19. CONCLUSION: Tocilizumab is an effective treatment in hospitalized patients with COVID-19 and hypoxemia by improving survival and decreasing mechanical ventilation requirement. The greatest benefit is observed in severe COVID-19.

Admission criteria and management of critical care patients in a pandemic context: position of the Ethics Commission of the French Intensive Care Society, update of April 2021.

Intensive care unit professionals have experience in critical care and its proportionality, collegial decision-making, withholding or withdrawal of treatment deemed futile, and communication with patients' relatives. These elements rely on ethical values from which we must not deviate in a pandemic situation. The recommendations made by the Ethics Commission of the French Intensive Care Society reflect an approach of responsibility and solidarity towards our citizens regarding the potential impact of a pandemic on critical care resources in France, with the fundamental requirement of respect for human dignity and equal access to health care for all.

Trisodium citrate 4% versus heparin as a catheter lock for non-tunneled hemodialysis catheters in critically ill patients: a multicenter, randomized clinical trial.

BACKGROUND: Non-tunneled hemodialysis catheters are currently used for critically ill patients with acute kidney injury requiring extracorporeal renal replacement therapy. Strategies to prevent catheter dysfunction and infection with catheter locks remain controversial. METHODS: In a multicenter, randomized, controlled, double-blind trial, we compared two strategies for catheter locking of non-tunneled hemodialysis catheters, namely trisodium citrate at 4% (intervention group) versus unfractionated heparin (control group), in patients aged 18 years or older admitted to the intensive care unit and in whom a first non-tunneled hemodialysis catheter was to be inserted by the jugular or femoral vein. The primary endpoint was length of event-free survival of the first non-tunneled hemodialysis catheter. Secondary endpoints were: rate of fibrinolysis, incidence of catheter dysfunction and incidence of catheter-related bloodstream infection (CRBSI), all per 1000 catheter-days; number of hemorrhagic events requiring transfusion, length of stay in intensive care and in hospital; 28-day mortality. RESULTS: Overall, 396 randomized patients completed the trial: 199 in the citrate group and 197 in the heparin group. There was no significant difference in baseline characteristics between groups. The duration of event-free survival of the first non-tunneled hemodialysis catheter was not significantly different between groups: 7 days (IQR 3-10) in the citrate group and 5 days (IQR 3-11) in the heparin group (p = 0.51). Rates of catheter thrombosis, CRBSI, and adverse events were not statistically different between groups. CONCLUSIONS: In critically ill patients, there was no significant difference in the duration of event-free survival of the first non-tunneled hemodialysis catheter between trisodium citrate 4% and heparin as a locking solution. Catheter thrombosis, catheter-related infection, and adverse events were not statistically different between the two groups. Trial registration Registered with Clinicaltrials.gov under the number NCT01962116. Registered 14 October 2013.

Procalcitonin levels to guide antibiotic therapy in adults with non-microbiologically proven apparent severe sepsis: a randomised controlled trial.

OBJECTIVE: Some patients with the phenotype of severe sepsis may have no overt source of infection or identified pathogen. We investigated whether a procalcitonin-based algorithm influenced antibiotic use in patients with non-microbiologically proven apparent severe sepsis. DESIGN: This multicentre, randomised, controlled, single-blind trial was performed in two parallel groups. SETTING: Eight intensive care units in France. PARTICIPANTS: Adults with the phenotype of severe sepsis and no overt source of infection, negative microbial cultures from multiple matrices and no antibiotic exposure shortly before intensive care unit admission. INTERVENTION: The initiation and duration of antibiotic therapy was based on procalcitonin levels in the experimental arm and on the intensive care unit physicians' clinical judgement without reference to procalcitonin values in the control arm. MAIN OUTCOME MEASURE: The primary outcome was the proportion of patients on antibiotics on day 5 postrandomisation. RESULTS: Over a 3-year period, 62/1250 screened patients were eligible for the study, of whom 31 were randomised to each arm; 4 later withdrew their consent. At day 5, 18/27 (67%) survivors were on antibiotics in the experimental arm, versus 21/26 (81%) controls (p=0.24; relative risk=0.83, 95% CI: 0.60 to 1.14). Only 8/58 patients (13%) had baseline procalcitonin <0.25 µg/l; in these patients, physician complied poorly with the algorithm. CONCLUSIONS: In intensive care unit patients with the phenotype of severe sepsis or septic shock and without an overt source of infection or a known pathogen, the current study was unable to confirm that a procalcitonin-based algorithm may influence antibiotic exposure. However, the premature termination of the trial may not allow definitive conclusions.