Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Antibiotic definitive treatment in ventilator associated pneumonia caused by AmpC-producing Enterobacterales in critically ill patients: a prospective multicenter observational study.

BACKGROUND: Ventilator associated pneumonia (VAP) due to wild-type AmpC-producing Enterobacterales (wtAE) is frequent in intensive care unit (ICU) patients. Despite a low level of evidence, definitive antimicrobial therapy (AMT) with third generation cephalosporins (3GCs) or piperacillin is discouraged. METHODS: Observational prospective study including consecutive wtAE VAP patients in 20 French ICUs. The primary objective was to assess the association of the choice of definitive AMT, i.e. piperacillin ± tazobactam (PTZ), 3GCs or other molecule (4GCs, carbapenems, quinolones, cotrimoxazole; control group), with treatment success at day-7. Recurrence of infection was collected as a secondary outcome, and analyzed accounting for the competing risk of death. RESULTS: From February 2021 to June 2022, 274 patients were included. Enterobacter cloacae was the most prevalent specie (31%). Seventy-eight patients (28%) had PTZ as definitive AMT while 44 (16%) had 3GCs and 152 (56%) were classified in the control group. Day-7 success rate was similar between the 3 groups (74% vs. 73% vs. 68% respectively, p = 0.814). Recurrence probability at day-28 was 31% (95% CI 21-42), 40% (95% CI 26-55) and 21% (95% CI 15-28) for PTZ, 3GCs and control groups (p = 0.020). In multivariable analysis, choice of definitive AMT was not associated with clinical success, but definitive AMT with 3GCs was associated with recurrence at day-28 [csHR(95%CI) 10.9 (1.92-61.91)]. CONCLUSION: Choice of definitive antimicrobial therapy was not associated with treatment success at day 7. However, recurrence of pneumonia at day-28 was higher in patients treated with third generation cephalosporins with no differences in mortality or mechanical ventilation duration.

Perioperative Outcomes During Double-Lung Transplantation and Retransplantation in Cystic Fibrosis Patients: A Monocentric Cohort Study.

OBJECTIVE: Life expectancy for lung-transplant patients, especially those with cystic fibrosis (CF), is leading increasingly to more retransplantations. DESIGN: Retrospective monocentric cohort study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: CF patients having had a primary double-lung transplantation (pLgTx) or a retransplantation (reLgTx) from 2012 to 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors compared the main intraoperative and early postoperative features between pLgTx (n = 258) and reLgTx (n = 24). Demographic characteristics were similar. No patients with retransplantations had a preoperative bridge with extracorporeal membrane oxygenation (ECMO); however, 23 patients had it in the pLgTx group (p = 0.24). Patients with retransplants had longer second graft ischemic time (p = 0.02), larger intraoperative bleeding volume (p = 0.001) and blood transfusion (p = 0.009 for packed red blood cells), increased blood lactate concentrations (p = 0.002), and higher norepinephrine dose at end-surgery (p = 0.001). Extracorporeal membrane oxygenation was used during surgery in 94 patients in the pLgTx group and 12 patients in the reLgTx group (p = 0.39). Extracorporeal membrane oxygenation could not be weaned after surgery in 55 patients in the pLgTx group and 4 in the reLgTx group (p = 0.54). Despite worse preoperative renal function in the reLgTx group (p < 0.001), there was no difference concerning renal replacement therapy in the intensive care unit between groups (p = 0.08). There were no differences between groups concerning the main complications, including primary graft dysfunction. Although the difference was not statistically different (p = 0.17), mortality was 3 times higher in the reLgTx group. CONCLUSIONS: Intraoperative period of retransplantation was more convoluted but had a similar ECMO profile to primary transplantation. In addition, the early postoperative period was similar.

Efficacy of plasma exchange in patients with anti-MDA5 rapidly progressive interstitial lung disease.

BACKGROUND: Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and severe manifestation of anti-MDA5 dermatomyositis (MDA5-DM) associated with poor outcome. The optimal treatment regimen for MDA5-DM RP-ILD is yet to be determined. Specifically, the value of adding plasma exchange (PLEX) to corticosteroids and immunosuppressants remains unclear. We aimed to evaluate the effect of PLEX on the outcome of patients with MDA5-DM RP-ILD. METHODS: This French nationwide multicentre retrospective study included all MDA5-DM RP-ILD patients from 2012 to 2021 admitted to 18 centres. The primary endpoint was one-year transplant-free survival. RESULTS: 51 patients with MDA5-DM RP-ILD (female 67%; mean age at disease onset: 51 ± 11.6 years) were included. Thirty-two (63%) patients required mechanical ventilation and twenty-five (49%) received PLEX. One-year mortality or lung transplant occurred in 63% cases after a median follow-up of 77 [38-264] days. The Cox proportional hazards multivariable model only retained mechanical ventilation but not PLEX (p = 0.7) as independent predictor of the primary endpoint. One-year transplant-free survival rates in PLEX + vs. PLEX-were 20% vs. 54% (p = 0.01), respectively. The Kaplan-Meier estimated probabilities of one-year transplant-free survival was statistically higher in PLEX-compared to PLEX + patients (p = 0.05). PLEX + compared to PLEX-patients more frequently received mechanical ventilation and immunosuppressants suggesting PLEX + patients had a more severe disease. CONCLUSION: MDA5-DM RP-ILD is associated with poor rate of one-year transplant-free survival. The use of PLEX was not associated with a better outcome albeit they were mainly given to more severe patients. While our study reports the largest series of MDA5-DM RP-ILD given PLEX, these results needs to be interpreted with caution owing the numerous selection, indication and interpretation bias. Further studies are needed to evaluate their efficacy in this setting.

Blood Lactate During Double-Lung Transplantation: A Predictor of Grade-3 Primary Graft Dysfunction.

OBJECTIVE: Many prognostic factors of grade-3 primary graft dysfunction at postoperative day 3 (PGD3-T72) have been reported, but intraoperative blood lactate level has not been studied. The present retrospective study was done to test the hypothesis that intraoperative blood lactate level (BLL) could be a predictor of PGD3-T72 after double-lung transplantation. DESIGN: Retrospective monocentric cohort study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: Patients having received a double-lung transplantation between 2012 and 2019. Patients transplanted twice during the study period, having undergone a multiorgan transplantation, or cardiopulmonary bypass, and those under preoperative extracorporeal membrane oxygenation, were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis was performed on a cohort of 449 patients. Seventy-two (16%) patients had a PGD3-T72. Blood lactate level increased throughout surgery to reach a median value of 2.2 (1.6-3.2) mmol/L in the No-PGD3-T72 group and 3.4 (2.3-5.0) mmol/L in the PGD3-T72 group after second lung implantation. The best predictive model for PGD3-T72 was obtained adding a lactate threshold of 2.6 mmol/L at the end of surgery to the clinical model, and the area under the curve was 0.867, with a sensitivity = 76.9% and specificity = 85.4%. Repeated-measures mixed model of BLL during surgery remained significant after adjustment for covariates (F ratio= 4.22, p < 0.001 for interaction). CONCLUSIONS: Blood lactate level increases during surgery and reaches a maximum after the second lung implantation. A value below the threshold of 2.6 mmol/L at the end of surgery has a high negative predictive value for the occurrence of a grade-3 primary graft dysfunction at postoperative day 3.

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis.

BACKGROUND: High levels of serum interleukin-6 (IL-6) correlate with disease severity in COVID-19. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. METHODS: The TOCICOVID study included a prospective cohort of patients aged 16-80 years with severe (requiring > 6 L/min of oxygen therapy to obtain Sp02 > 94%) rapidly deteriorating (increase by ≥ 3 L/min of oxygen flow within the previous 12 h) COVID-19 pneumonia with ≥ 5 days of symptoms and C-reactive protein levels > 40 mg/L. They entered a compassionate use program of treatment with intravenous tocilizumab (8 mg/kg with a maximum of 800 mg per infusion; and if needed a second infusion 24 to 72 h later). A control group was retrospectively selected with the same inclusion criteria. Outcomes were assessed at D28 using inverse probability of treatment weighted (IPTW) methodology. RESULTS: Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, baseline disease severity, and concomitant medications were broadly similar between the tocilizumab (n = 49) and the control (n = 47) groups. In the IPTW analysis, treatment with tocilizumab was associated with a reduced need for overall ventilatory support (49 vs. 89%, wHR: 0.39 [0.25-0.56]; p < 0.001). Albeit lacking statistical significance, there was a substantial trend towards a reduction of mechanical ventilation (31% vs. 45%; wHR: 0.58 [0.36-0.94]; p = 0.026). However, tocilizumab did not improve overall survival (wHR = 0.68 [0.31-1.748], p = 0.338). Among the 85 (89%) patients still alive at D28, patients treated with tocilizumab had a higher rate of oxygen withdrawal (82% vs. 73.5%, wHR = 1.66 [1.17-2.37], p = 0.005), with a shorter delay before being weaned of oxygen therapy (mean 11 vs. 16 days; p < 0.001). At D28, the rate of patients discharged from hospital was higher in the tocilizumab group (70% vs. 40%, wHR = 1.82 [1.22-2.75]; p = 0.003). The levels of CRP and fibrinogen post therapy (p < 0.001 for both variables) were significantly lower in the tocilizumab group (interaction test, mixed model). Rates of neutropenia (35% vs. 0%; p < 0.001) were higher in the tocilizumab group, yet rates of infections (22% vs. 38%, p = 0.089) including ventilator-acquired pneumonia (8% vs. 26%, p = 0.022) were higher in the control group. CONCLUSION: These data could be helpful for the design of future trials aiming to counter COVID-19-induced inflammation, especially before patients require admission to the intensive care unit.

A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with pre-formed donor-specific antibodies: 3-year outcome.

BACKGROUND: Pre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised. METHODS: For all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan-Meier analysis and Cox multivariate analysis. RESULTS: We compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (p<0.001, p<0.01 and p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high-level DSAs than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-level, low-level and no pre-formed DSAs (p=0.019, p=0.025 and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (hazard ratio 0.12, 95% CI 0.02-0.85 versus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02-9.17 versus no pre-formed DSAs; p=0.048). CONCLUSION: The desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

A low level of CD16pos monocytes in SARS-CoV-2 infected patients is a marker of severity.

OBJECTIVES: Severe forms of coronavirus disease 2019 (COVID-19) are characterized by an excessive production of inflammatory cytokines. Activated monocytes secrete high levels of cytokines. Human monocytes are divided into three major populations: conventional (CD14posCD16neg), non-classical (CD14dimCD16pos), and intermediate (CD14posCD16pos) monocytes. The aim of this study was to analyze whether the distribution of conventional (CD16neg) and CD16pos monocytes is different in patients with COVID-19 and whether the variations could be predictive of the outcome of the disease. METHODS: We performed a prospective study on 390 consecutive patients referred to the Emergency Unit, with a proven diagnosis of SARS-CoV 2 infection by RT-PCR. Using the CytoDiff™ reagent, an automated routine leukocyte differential, we quantified CD16neg and CD16pos monocytes. RESULTS: In the entire population, median CD16neg and CD16pos monocyte levels (0.398 and 0.054×109/L, respectively) were in the normal range [(0.3-0.7×109/L) and (0.015-0.065×109/L), respectively], but the 35 patients in the intensive care unit (ICU) had a significantly (p<0.001) lower CD16pos monocyte count (0.018 × 109/L) in comparison to the 70 patients who were discharged (0.064 × 109/L) or were hospitalized in conventional units (0.058 × 109/L). By ROC curve analysis, the ratio [absolute neutrophil count/CD16pos monocyte count] was highly discriminant to identify patients requiring ICU hospitalization: with a cut-off 193.1, the sensitivity and the specificity were 74.3 and 81.8%, respectively (area under the curve=0.817). CONCLUSIONS: Quantification of CD16pos monocytes and the ratio [absolute neutrophil count/CD16pos monocyte count] could constitute a marker of the severity of disease in COVID-19 patients.

Teaching Important Basic EEG Patterns of Bedside Electroencephalography to Critical Care Staffs: A Prospective Multicenter Study.

BACKGROUND: Continuous electroencephalography (cEEG) is commonly recommended for neurocritical care patients. Routine implementation of such monitoring requires the specific training of professionals. The aim of this research was to evaluate the effectiveness of a training program on initiation of the basic interpretation of cEEG for critical care staff in a prospective multicenter study. METHODS: After completion of a pretest, participants (senior physicians, fellows, residents, medical students, and nurses) recruited in six French ICUs participated in a face-to-face electroencephalogram (EEG) training program followed by additional e-learning sessions at day 1 (post-course), day 15, day 30, and day 90, based on training tests followed by illustrated and commented answers. Each test was designed to evaluate knowledge and skills through correct recognition of ten predefined EEG sequences covering the most common normal and abnormal patterns. The primary objective was to achieve a success rate > 80% correct answers at day 90 by at least 75% of the participants. RESULTS: Among 250 participants, 77/108 (71.3%) who completed the full training program achieved at least 80% correct answers at day 90. Paired comparisons between the scores obtained at each evaluation showed an increase over time. The rate of correct answers at day 90 was > 80% for all common predefined EEG sequences, except for the recognition of periodic and burst-suppression patterns and reactivity, which were identified in only 42.6% (95% CI 36.4-48.8), 60.2% (54.1-66.3), and 70.4% (64.7-76.1) of the tests, respectively. CONCLUSIONS: A training strategy for the basic interpretation of EEG in ICUs, consisting of a face-to-face EEG course supplemented with reinforcement of knowledge by e-learning, was associated with significant resignation and an effectiveness of training allowing 71% of learners to accurately recognize important basic EEG patterns encountered in critically ill patients. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT03545776.

Long-term Quality of Life in Adult Patients Surviving Purpura Fulminans: An Exposed-Unexposed Multicenter Cohort Study.

BACKGROUND: Long-term health-related quality of life (HR-QOL) of patients surviving the acute phase of purpura fulminans (PF) has not been evaluated. METHODS: This was a French multicenter exposed-unexposed cohort study enrolling patients admitted in 55 intensive care units (ICUs) for PF from 2010 to 2016. Adult patients surviving the acute phase of PF (exposed group) were matched 1:1 for age, sex, and Simplified Acute Physiology Score II with septic shock survivors (unexposed group). HR-QOL was assessed during a phone interview using the 36-Item Short-Form Health Survey (SF-36) questionnaire, the Hospital Anxiety and Depression (HAD) scale, the Impact of Event Scale-Revised (IES-R), and the activity of daily living (ADL) and instrumental ADL (IADL) scales. The primary outcome measure was the physical component summary (PCS) of the SF-36 questionnaire. RESULTS: Thirty-seven survivors of PF and 37 of septic shock were phone-interviewed at 55 (interquartile range [IQR], 35-83) months and 44 (IQR, 35-72) months, respectively, of ICU discharge (P = .23). The PCS of the SF-36 was not significantly different between exposed and unexposed patients (median, 47 [IQR, 36-53] vs 54 [IQR, 36-57]; P = .18). There was also no significant difference between groups regarding the mental component summary of the SF-36, and the HAD, IES-R, ADL and IADL scales. Among the 37 exposed patients, those who required limb amputation (n = 12/37 [32%]) exhibited lower PCS (34 [IQR, 24-38] vs 52 [IQR, 42-56]; P = .001) and IADL scores (7 [IQR, 4-8] vs 8 [IQR, 7-8]; P = .021) compared with nonamputated patients. CONCLUSIONS: Long-term HR-QOL does not differ between patients surviving PF and those surviving septic shock unrelated to PF. Amputated patients have an impaired physical HR-QOL but a preserved mental health. CLINICAL TRIALS REGISTRATION: NCT03216577.

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.

Endocarditis caused by Streptococcus canis: an emerging zoonosis?

We report a human case of infective endocarditis caused by Streptococcus canis. Identification was carried out from positive blood culture using mass spectrometry and SodA gene sequencing. S. canis related zoonotic invasive infections may have been previously underdiagnosed due to inadequate identification of group G Streptococcus species.

High Level of Endotoxemia Following Out-of-Hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock.

OBJECTIVE: To investigate the contribution of endotoxemia to the severity of postcardiac arrest shock. DESIGN: A prospective monocentric study. SETTING: A tertiary hospital in Paris, France. PATIENTS: Patients admitted in our ICU after a successfully resuscitated out-of-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endotoxin measurement was performed in the 12 hours following return of spontaneous circulation using the endotoxin activity assay. Endotoxin level was classified as low (< 0.4 endotoxin activity), intermediate (0.4 to < 0.6 endotoxin activity), or high (≥ 0.6 endotoxin activity) according to manufacture guidelines. Severity of shock was assessed by the vasopressor-free days and by the mean daily dose of vasopressor to insure a mean arterial pressure of 65-75 mm Hg. Among 92 patients included in the study, 60 presented a postcardiac arrest shock. Endotoxemia level was higher in patients with postcardiac arrest shock. Among these patients, by multivariate linear regression, high endotoxin class (adjusted estimate -2.0; 95% CI, -3.90 to -0.11), public place of cardiac arrest (adjusted estimate, 1.47; 95% CI, 0.007 to 2.93), and time to return of spontaneous circulation (adjusted estimate -0.08; 95% CI, -0.13 to -0.03) were independently associated with the number of vasopressor-free days. Furthermore, high endotoxin class (adjusted estimate, 97.95; 95% CI, 20.5 to 175.4) and a nonshockable rhythm (adjusted estimate, 59.9; 95% CI, 6.2 to 113.7) were the sole factors independently associated with the mean daily dose of vasopressors. CONCLUSIONS: In patients successfully resuscitated from cardiac arrest with a postcardiac arrest shock, high level of endotoxemia is independently associated with duration of postcardiac arrest shock and the amount of vasopressive drugs. Whether treatment targeting endotoxemia could be beneficial in the management of postcardiac arrest shock needs to be studied in further randomized controlled studies.

Short- and long-term outcome in elderly patients after out-of-hospital cardiac arrest: a cohort study.

OBJECTIVE: Determinants of outcome and long-term survival are unknown in elderly patients successfully resuscitated after out-of-hospital cardiac arrest. Our aim was to identify factors associated with short- and long-term neurologic outcome in such patients. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in Paris, France. PATIENTS: Patients aged over 75 admitted in our ICU after an out-of-hospital cardiac arrest between 2000 and 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty-five patients were included in the study. Fifty-seven patients (25.3%) had a good neurologic outcome at ICU discharge (Cerebral Performance Category 1-2). By multivariate logistic regression analysis, factors associated with good short-term outcome were time from collapse to cardiopulmonary resuscitation less than or equal to 3 minutes (odds ratio = 4.06; 95% CI, 1.49-11.09, p = 0.006) and blood lactate level less than or equal to 5.1 mmol/L (odds ratio = 3.30; 95% CI, 1.05-10.39, p = 0.04), but age less than or equal to 79.5 years and use of induced hypothermia were not. Long-term survivors were assessed for cognitive and functional status (using Cerebral Performance Category and Overall Performance Category scales), and their survival was compared with a large community-based cohort of participants over 75 years. The 1-year survival of ICU survivors (mean follow-up, 28.4 mo) was 69.3% (95% CI, 55.8-79.5) as compared with 95.3% (95% CI, 93.3-97.3) in the control community-based cohort (p< 0.001), resulting in a standardized mortality ratio of 3.49 (95% CI, 2.42-4.85). By multivariate Cox proportional hazard model, factors associated with long-term survival were initial shockable rhythm (hazard ratio = 1.41; 95% CI, 1.01-1.96; p = 0.04), epinephrine cumulate dose less than or equal to 3 mg (hazard ratio = 1.48; 95% CI, 1.06-2.08; p = 0.02), and blood lactate level less than or equal to 5.1 mmol/L (hazard ratio = 2.11; 95% CI, 1.5-2.96; p < 0.001). When available at end of follow-up, 91% and 74% of the patients were classified Cerebral Performance Category 1 and Overall Performance Category 1, respectively. CONCLUSIONS: Neurologic outcome in successfully resuscitated elderly patients depends on cardiac arrest characteristics rather than age. Short-term survival is 25% with acceptable long-term outcome among survivors.

Toll-like receptor 2 deficiency increases resistance to Pseudomonas aeruginosa pneumonia in the setting of sepsis-induced immune dysfunction.

BACKGROUND: Sepsis is characterized by a dysregulated inflammatory response followed by immunosuppression that favors the development of secondary infections. Toll-like receptors (TLRs) are major regulators of the host's response to infections. How variability in TLR signaling may impact the development of sepsis-induced immune dysfunction has not been established. We sought to establish the role of TLR2, TLR4, and TLR5 in postseptic mice with Pseudomonas aeruginosa pneumonia. METHODS: We used an experimental model of sublethal polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wild-type, tlr2(-/-), tlr4(-/-), tlr5(-/-), tlr2 4(-/-) mice that underwent CLP were secondarily subjected to P. aeruginosa pulmonary infection. RESULTS: Postseptic wild-type and tlr4(-/-) and tlr5(-/-) mice displayed high susceptibility to P. aeruginosa pneumonia. In contrast, TLR2-deficient mice, either tlr2(-/-)or tlr2 4(-/-), that underwent CLP were resistant to the secondary pulmonary infection. As compared to wild-type mice, tlr2(-/-) mice displayed improvement in bacterial clearance, decreased bacteremic dissemination, and attenuated lung damage. Furthermore, tlr2(-/-) mice exhibited a pulmonary proinflammatory cytokine balance, with increased production of tumor necrosis factor α and decreased release of interleukin 10. CONCLUSIONS: In a model of secondary P. aeruginosa pneumonia in postseptic mice, TLR2 deficiency improves survival by promoting efficient bacterial clearance and restoring a proinflammatory cytokine balance in the lung.

Stratification of COVID-19 Severity Using SeptiCyte RAPID, a Novel Host Immune Response Test.

SeptiCyte® RAPID is a gene expression assay measuring the relative expression levels of host response genes PLA2G7 and PLAC8, indicative of a dysregulated immune response during sepsis. As severe forms of COVID-19 may be considered viral sepsis, we evaluated SeptiCyte RAPID in a series of 94 patients admitted to Foch Hospital (Suresnes, France) with proven SARS-CoV-2 infection. EDTA blood was collected in the emergency department (ED) in 67 cases, in the intensive care unit (ICU) in 23 cases and in conventional units in 4 cases. SeptiScore (0-15 scale) increased with COVID-19 severity. Patients in ICU had the highest SeptiScores, producing values comparable to 8 patients with culture-confirmed bacterial sepsis. Receiver operating characteristic (ROC) curve analysis had an area under the curve (AUC) of 0.81 for discriminating patients requiring ICU admission from patients who were immediately discharged or from patients requiring hospitalization in conventional units. SeptiScores increased with the extent of the lung injury. For 68 patients, a chest computed tomography (CT) scan was performed within 24 h of COVID-19 diagnosis. SeptiScore >7 suggested lung injury ≥50% (AUC = 0.86). SeptiCyte RAPID was compared to other biomarkers for discriminating Critical + Severe COVID-19 in ICU, versus Moderate + Mild COVID-19 not in ICU. The mean AUC for SeptiCyte RAPID was superior to that of any individual biomarker or combination thereof. In contrast to C-reactive protein (CRP), correlation of SeptiScore with lung injury was not impacted by treatment with anti-inflammatory agents. SeptiCyte RAPID can be a useful tool to identify patients with severe forms of COVID-19 in ED, as well as during follow-up.