Trends in survival from out-of-hospital cardiac arrest with a shockable rhythm and its association with bystander resuscitation: a retrospective study.

OBJECTIVE: Over 300 000 cases of out-of-hospital cardiac arrests (OHCAs) occur each year in the USA and Europe. Despite decades of investment and research, survival remains disappointingly low. We report the trends in survival after a ventricular fibrillation/pulseless ventricular tachycardia OHCA, over a 13-year period, in a French urban region, and describe the simultaneous evolution of the rescue system. METHODS: We investigated four 18-month periods between 2005 and 2018. The first period was considered baseline and included patients from the randomised controlled trial 'DEFI 2005'. The three following periods were based on the Paris Sudden Death Expertise Center Registry (France). Inclusion criteria were non-traumatic cardiac arrests treated with at least one external electric shock with an automated external defibrillator from the basic life support team and resuscitated by a physician-staffed ALS team. Primary outcome was survival at hospital discharge with a good neurological outcome. RESULTS: Of 21 781 patients under consideration, 3476 (16%) met the inclusion criteria. Over all study periods, survival at hospital discharge increased from 12% in 2005 to 25% in 2018 (p<0.001), and return of spontaneous circulation at hospital admission increased from 43% to 58% (p=0.004).Lay-rescuer cardiopulmonary resuscitation (CPR) and telephone CPR (T-CPR) rates increased significantly, but public defibrillator use remained limited. CONCLUSION: In a two-tiered rescue system, survival from OHCA at hospital discharge doubled over a 13-year study period. Concomitantly, the system implemented an OHCA patient registry and increased T-CPR frequency, despite a consistently low rate of public defibrillator use.

Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest.

BACKGROUND: Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. RESULTS: A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. CONCLUSIONS: A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).

Case series of massive direct oral anticoagulant ingestion-Treatment and pharmacokinetics data.

BACKGROUND: Direct oral anticoagulants (DOAC) are widely used due to favourable benefit/risk ratio. However, consequences of massive ingestion have been poorly investigated. OBJECTIVES: We aimed to report outcome and pharmacokinetic parameters in patients who massively ingested DOACs. METHODS: We conducted a 5-year cohort study including consecutive massive DOAC ingestion patients admitted to two critical care departments. Patients were managed in accordance with standards of care. We collected the main history, clinical, laboratory, management and outcome data. The time-course of plasma DOAC concentrations measured using specific assays was modelled. RESULTS: Twelve patients (3F/9M; age, 55 years [41-63], median [25th-75th percentiles]) were included. Ingestions involved rivaroxaban (n = 7), apixaban (n = 3) and dabigatran (n = 2), with presumed doses of 9.4-fold [5.0-22.0] the full daily dose. Six patients received activated charcoal but no antidote nor blood-derived product. No bleeding was observed. One patient died due to refractory cardiogenic shock related to bisoprolol co-intoxication. Highest observed peak plasma concentrations were 1720 ng/ml (rivaroxaban), 750 ng/ml (apixaban) and 644 ng/ml (dabigatran). Times to reach DOAC concentration below 50 ng/ml were ~20-45 h (rivaroxaban), ~125 h (apixaban) and ~30-50 h (dabigatran). Elimination half-lives were 2.5-25.5 h (rivaroxaban), 22.0 and 36.5 h (apixaban), and 5.8 and 15.5 h (dabigatran), with substantial interindividual variability and prolongation in case of cardiovascular failure related to co-intoxicants. Charcoal administration, even if delayed, may have contributed to limit toxicity, possibly by reducing absorption and/or enteroenteric recycling. CONCLUSION: No bleeding was observed in this series of massive DOAC ingestions despite elevated plasma concentrations. No patient required specific haemostatic agents. Charcoal administration should be considered to limit toxicity.

Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients. METHODS: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later. RESULTS: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality. CONCLUSIONS: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Incidence and Outcome of Subclinical Acute Kidney Injury Using penKid in Critically Ill Patients.

Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119-159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1-1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3-1.8]; P < 0.0001, respectively) after adjustment for age, sex, comorbidities, diagnosis, creatinine, diuresis, and study. Patients with sub-AKI had higher mortality compared with no AKI (HR, 2.4 [95% confidence interval, 1.5-3.7] in FROG-ICU and 2.5 [95% confidence interval, 1.1-5.9] in AdrenOSS-1).Conclusions: Sub-AKI defined using penKid occurred in 11.6-17.5% of patients without AKI and was associated with a risk of death close to patients with AKI.

Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.

AIMS: Out-of-hospital cardiac arrest (OHCA) without return of spontaneous circulation (ROSC) despite conventional resuscitation is common and has poor outcomes. Adding extracorporeal membrane oxygenation (ECMO) to cardiopulmonary resuscitation (extracorporeal-CPR) is increasingly used in an attempt to improve outcomes. METHODS AND RESULTS: We analysed a prospective registry of 13 191 OHCAs in the Paris region from May 2011 to January 2018. We compared survival at hospital discharge with and without extracorporeal-CPR and identified factors associated with survival in patients given extracorporeal-CPR. Survival was 8% in 525 patients given extracorporeal-CPR and 9% in 12 666 patients given conventional-CPR (P = 0.91). By adjusted multivariate analysis, extracorporeal-CPR was not associated with hospital survival [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.8-2.1; P = 0.24]. By conditional logistic regression with matching on a propensity score (including age, sex, occurrence at home, bystander CPR, initial rhythm, collapse-to-CPR time, duration of resuscitation, and ROSC), similar results were found (OR, 0.8; 95% CI, 0.5-1.3; P = 0.41). In the extracorporeal-CPR group, factors associated with hospital survival were initial shockable rhythm (OR, 3.9; 95% CI, 1.5-10.3; P = 0.005), transient ROSC before ECMO (OR, 2.3; 95% CI, 1.1-4.7; P = 0.03), and prehospital ECMO implantation (OR, 2.9; 95% CI, 1.5-5.9; P = 0.002). CONCLUSIONS: In a population-based registry, 4% of OHCAs were treated with extracorporeal-CPR, which was not associated with increased hospital survival. Early ECMO implantation may improve outcomes. The initial rhythm and ROSC may help select patients for extracorporeal-CPR.

One-Year Prognosis of Kidney Injury at Discharge From the ICU: A Multicenter Observational Study.

OBJECTIVES: The association between outcome and kidney injury detected at discharge from the ICU using different biomarkers remains unknown. The objective was to evaluate the association between 1-year survival and kidney injury at ICU discharge. DESIGN: Ancillary investigation of a prospective observational study. SETTING: Twenty-one ICUs with 1-year follow-up. PATIENTS: Critically ill patients receiving mechanical ventilation and/or hemodynamic support for at least 24 hours were included. INTERVENTIONS: Serum creatinine, plasma Cystatin C, plasma neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, plasma Proenkephalin A 119-159, and estimated glomerular filtration rate (on serum creatinine and plasma Cystatin C) were measured at ICU discharge among ICU survivors. MEASUREMENTS AND MAIN RESULTS: The association between kidney biomarkers at discharge and mortality was estimated using logistic model with and without adjustment for prognostic factors previously identified in this cohort. Subgroup analyses were performed in patients with discharge serum creatinine less than 1.5-fold baseline at ICU discharge. Among 1,207 ICU survivors included, 231 died during the year following ICU discharge (19.2%). Estimated glomerular filtration rate was significantly lower and kidney injury biomarkers higher at discharge in nonsurvivors. The association between biomarker levels or estimated glomerular filtration rate and mortality remained after adjustment to potential cofounding factors influencing outcome. In patients with low serum creatinine at ICU discharge, 25-47% of patients were classified as subclinical kidney injury depending on the biomarker. The association between kidney biomarkers and mortality remained and mortality was higher than patients without subclinical kidney injury. The majority of patients who developed acute kidney injury during ICU stay had elevated biomarkers of kidney injury at discharge even with apparent recovery based on serum creatinine (i.e., subclinical acute kidney disease). CONCLUSIONS: Elevated kidney biomarkers measured at ICU discharge are associated with poor 1-year outcome, including in patients with low serum creatinine at ICU discharge.

Temporal trends in the use of targeted temperature management after cardiac arrest and association with outcome: insights from the Paris Sudden Death Expertise Centre.

PURPOSE: Recent doubts regarding the efficacy may have resulted in a loss of interest for targeted temperature management (TTM) in comatose cardiac arrest (CA) patients, with uncertain consequences on outcome. We aimed to identify a change in TTM use and to assess the relationship between this change and neurological outcome. METHODS: We used Utstein data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing CA data from all secondary and tertiary hospitals located in the Great Paris area, France) between May 2011 and December 2017. All cases of non-traumatic OHCA patients with stable return of spontaneous circulation (ROSC) were included. After adjustment for potential confounders, we assessed the relationship between changes over time in the use of TTM and neurological recovery at discharge using the Cerebral Performance Categories (CPC) scale. RESULTS: Between May 2011 and December 2017, 3925 patients were retained in the analysis, of whom 1847 (47%) received TTM. The rate of good neurological outcome at discharge (CPC 1 or 2) was higher in TTM patients as compared with no TTM (33% vs 15%, P < 0.001). Gender, age, and location of CA did not change over the years. Bystander CPR increased from 55% in 2011 to 73% in 2017 (P < 0.001) and patients with a no-flow time longer than 3 min decreased from 53 to 38% (P < 0.001). The use of TTM decreased from 55% in 2011 to 37% in 2017 (P < 0.001). Meanwhile, the rate of patients with good neurological recovery remained stable (19 to 23%, P = 0.76). After adjustment, year of CA occurrence was not associated with outcome. CONCLUSIONS: We report a progressive decrease in the use of TTM in post-cardiac arrest patients over the recent years. During this period, neurological outcome remained stable, despite an increase in bystander-initiated resuscitation and a decrease in "no flow" duration.

Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest: a systematic review and meta-analysis.

BACKGROUND: Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. METHODS: We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. RESULTS: Our search identified 6886 studies; 22 studies (n = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75-0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62-1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. CONCLUSIONS: Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).

Outcomes after extracorporeal membrane oxygenation for the treatment of high-risk pulmonary embolism: a multicentre series of 52 cases.

Aims: The role of extracorporeal membrane oxygenation (ECMO) remains ill defined in pulmonary embolism (PE). We investigated outcomes in patients with high-risk PE undergoing ECMO according to initial therapeutic strategy. Methods and results: From 01 January 2014 to 31 December 2015, 180 patients from 13 Departments in nine centres with high-risk PE were retrospectively included. Among those undergoing ECMO, we compared characteristics and outcomes according to adjunctive treatment strategy (systemic thrombolysis, surgical embolectomy, or no reperfusion therapy). Primary outcome was all-cause 30-day mortality. Secondary outcome was 90-day major bleeding. One hundred and twenty-eight patients were treated without ECMO; 52 (mean age 47.6 years) underwent ECMO. Overall 30-day mortality was 48.3% [95% confidence interval (CI) 41-56] (87/180); 43% (95% CI 34-52) (55/128) in those treated without ECMO vs. 61.5% (95% CI 52-78) (32/52) in those with ECMO (P = 0.008). In patients undergoing ECMO, 30-day mortality was 76.5% (95% CI 57-97) (13/17) for ECMO + fibrinolysis, 29.4% (95% CI 51-89) (5/17) for ECMO + surgical embolectomy, and 77.7% (95% CI 59-97) (14/18) for ECMO alone (P = 0.004). Among patients with ECMO, 20 (38.5%, 95% CI 25-52) had a major bleeding event in-hospital; without significant difference across groups. Conclusion: In patients with high-risk PE, those with ECMO have a more severe presentation and worse prognosis. Extracorporeal membrane oxygenation in patients with failed fibrinolysis and in those with no reperfusion seems to be associated with particularly unfavourable prognosis compared with ECMO performed in addition to surgical embolectomy. Our findings suggest that ECMO does not appear justified as a stand-alone treatment strategy in PE patients, but shows promise as a complement to surgical embolectomy.

Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone on Reintubation Among Patients at High Risk of Extubation Failure: A Randomized Clinical Trial.

Importance: High-flow nasal oxygen may prevent postextubation respiratory failure in the intensive care unit (ICU). The combination of high-flow nasal oxygen with noninvasive ventilation (NIV) may be an optimal strategy of ventilation to avoid reintubation. Objective: To determine whether high-flow nasal oxygen with prophylactic NIV applied immediately after extubation could reduce the rate of reintubation, compared with high-flow nasal oxygen alone, in patients at high risk of extubation failure in the ICU. Design, Setting, and Participants: Multicenter randomized clinical trial conducted from April 2017 to January 2018 among 641 patients at high risk of extubation failure (ie, older than 65 years or with an underlying cardiac or respiratory disease) at 30 ICUs in France; follow-up was until April 2018. Interventions: Patients were randomly assigned to high-flow nasal oxygen alone (n = 306) or high-flow nasal oxygen alternating with NIV (n = 342) immediately after extubation. Main Outcomes and Measures: The primary outcome was the proportion of patients reintubated at day 7; secondary outcomes included postextubation respiratory failure at day 7, reintubation rates up until ICU discharge, and ICU mortality. Results: Among 648 patients who were randomized (mean [SD] age, 70 [10] years; 219 women [34%]), 641 patients completed the trial. The reintubation rate at day 7 was 11.8% (95% CI, 8.4%-15.2%) (40/339) with high-flow nasal oxygen and NIV and 18.2% (95% CI, 13.9%-22.6%) (55/302) with high-flow nasal oxygen alone (difference, -6.4% [95% CI, -12.0% to -0.9%]; P = .02). Among the 11 prespecified secondary outcomes, 6 showed no significant difference. The proportion of patients with postextubation respiratory failure at day 7 (21% vs 29%; difference, -8.7% [95% CI, -15.2% to -1.8%]; P = .01) and reintubation rates up until ICU discharge (12% vs 20%, difference -7.4% [95% CI, -13.2% to -1.8%]; P = .009) were significantly lower with high-flow nasal oxygen and NIV than with high-flow nasal oxygen alone. ICU mortality rates were not significantly different: 6% with high-flow nasal oxygen and NIV and 9% with high-flow nasal oxygen alone (difference, -2.4% [95% CI, -6.7% to 1.7%]; P = .25). Conclusions and Relevance: In mechanically ventilated patients at high risk of extubation failure, the use of high-flow nasal oxygen with NIV immediately after extubation significantly decreased the risk of reintubation compared with high-flow nasal oxygen alone. Trial Registration: ClinicalTrials.gov Identifier: NCT03121482.

Cardiac Arrest in Patients Managed for Convulsive Status Epilepticus: Characteristics, Predictors, and Outcome.

OBJECTIVES: Cardiac arrest is a catastrophic event that may arise during the management of convulsive status epilepticus. We aimed to report the clinical characteristics, outcomes, and early predictors of convulsive status epilepticus-related cardiac arrest. DESIGN: Retrospective multicenter study. SETTING: Seventeen university or university affiliated participating ICUs in France and Belgium. PATIENTS: Consecutive patients admitted to the participating ICUs for management of successfully resuscitated out-of-hospital cardiac arrest complicating the initial management of convulsive status epilepticus between 2000 and 2015. Patients were compared with controls without cardiac arrest identified in a single-center registry of convulsive status epilepticus patients, regarding characteristics, management, and outcome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 49 cases with convulsive status epilepticus-cardiac arrest and 235 controls. In the cases, median time from medical team arrival to cardiac arrest was 25 minutes (interquartile range, 5-85 min). First recorded rhythm was asystole in 25 patients (51%) and pulseless electrical activity in 13 patients (27%). A significantly larger proportion of patients had a favorable 1-year outcome (Glasgow Outcome Scale score of 5) among controls (90/235; 38%) than among cases (10/49; 21%; p = 0.02). By multivariate analysis, independent predictors of cardiac arrest were pulse oximetry less than 97% on scene (odds ratio, 2.66; 95% CI, 1.03-7.26; p = 0.04), drug poisoning as the cause of convulsive status epilepticus (odds ratio, 4.13; 95% CI, 1.27-13.53; p = 0.02), and complications during early management (odds ratio, 11.98; 95% CI, 4.67-34.69; p < 0.0001). Having at least one comorbidity among cardiac, respiratory, and neurologic (other than epilepsy) conditions predicted absence of cardiac arrest (odds ratio, 0.28; 95% CI, 0.10-0.80; p = 0.02). CONCLUSIONS: In patients managed for convulsive status epilepticus, relative hypoxemia, on-scene management complications, and drug poisoning as the cause of convulsive status epilepticus were strong early predictors of cardiac arrest, suggesting areas for improvement.

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study.

BACKGROUND: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. METHODS: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. RESULTS: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). CONCLUSIONS: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Determinants of long-term outcome in ICU survivors: results from the FROG-ICU study.

BACKGROUND: Intensive care unit (ICU) survivors have reduced long-term survival compared to the general population. Identifying parameters at ICU discharge that are associated with poor long-term outcomes may prove useful in targeting an at-risk population. The main objective of the study was to identify clinical and biological determinants of death in the year following ICU discharge. METHODS: FROG-ICU was a prospective, observational, multicenter cohort study of ICU survivors followed 1 year after discharge, including 21 medical, surgical or mixed ICUs in France and Belgium. All consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following ICU admission and discharged from ICU were included. The main outcome measure was all-cause mortality at 1 year after ICU discharge. Clinical and biological parameters on ICU discharge were measured, including the circulating cardiovascular biomarkers N-terminal pro-B type natriuretic peptide, high-sensitive troponin I, bioactive-adrenomedullin and soluble-ST2. Socioeconomic status was assessed using a validated deprivation index (FDep). RESULTS: Of 1570 patients discharged alive from the ICU, 333 (21%) died over the following year. Multivariable analysis identified age, comorbidity, red blood cell transfusion, ICU length of stay and abnormalities in common clinical factors at the time of ICU discharge (low systolic blood pressure, temperature, total protein, platelet and white cell count) as independent factors associated with 1-year mortality. Elevated biomarkers of cardiac and vascular failure independently associated with 1-year death when they are added to multivariable model, with an almost 3-fold increase in the risk of death when combined (adjusted odds ratio 2.84 (95% confidence interval 1.73-4.65), p < 0.001). CONCLUSIONS: The FROG-ICU study identified, at the time of ICU discharge, potentially actionable clinical and biological factors associated with poor long-term outcome after ICU discharge. Those factors may guide discharge planning and directed interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01367093 . Registered on 6 June 2011.

Synchronized Pulsatile Flow With Low Systolic Output From Veno-Arterial Extracorporeal Membrane Oxygenation Improves Myocardial Recovery After Experimental Cardiac Arrest in Pigs.

Circulatory failure following cardiac arrest (CA) requires catecholamine support and occasionally veno-arterial extracorporeal membrane oxygenation (vaECMO). VaECMO-generated blood flow is continuous and retrograde, increasing ventricular stroke work. Our aim was to assess the benefit of a device generating a pulsatile vaECMO flow synchronized with the heart rhythm lowering systolic vaECMO output on the left ventricular ejection fraction (LVEF) and pulmonary capillary pressure (Pcap) after CA. This experimental randomized study in pigs compared standard nonpulsatile vaECMO (control) with pulsatile synchronized vaECMO (study) group using a pulsatility-generating device. After sedation and intubation, ventricular fibrillation was induced by pacing. After 10-min ventricular fibrillation, cardiopulmonary resuscitation was performed for 20 min then vaECMO, defibrillation and 0.15 µg/kg/min intravenous epinephrine infusion were initiated. Hemodynamics, Pcap, LVEF by echocardiography and angiography were measured at baseline and every 30 min after the vaECMO start until vaECMO and epinephrine were stopped (at 120 min), and 30 min later. Baseline hemodynamics did not differ between groups; 120 min after vaECMO initiation, LVEF by echocardiography and angiography was significantly higher in the study than control group 55 ± 19% versus 34 ± 13% (P = 0.042), 50 ± 16% versus 33 ± 12% (P = 0.043), respectively. Pcap decreased from baseline by 4.2 ± 8.6 mm Hg in the study group but increased by 5.6 ± 5.9 mm Hg in the control group (P = 0.043). Thirty minutes later, LVEF remained higher in the study group 44 ± 7% versus 26 ± 11% (P = 0.008) while Pcap did not differ. A synchronized pulsatile device decreasing systolic output from vaECMO improved LVEF and Pcap in a pig model of CA and resuscitation.

The CAHP (Cardiac Arrest Hospital Prognosis) score: a tool for risk stratification after out-of-hospital cardiac arrest.

AIMS: Survival after out-of-hospital cardiac arrest (OHCA) remains disappointingly low. Among patients admitted alive, early prognostication remains challenging. This study aims to establish a stratification score for patients admitted in intensive care unit (ICU) after OHCA, according to their neurological outcome. METHODS AND RESULTS: The CAHP (Cardiac Arrest Hospital Prognosis) score was developed from the Sudden Death Expertise Center registry (Paris, France). The primary outcome was poor neurological outcome defined as Cerebral Performance Category 3, 4, or 5 at hospital discharge. Independent prognostic factors were identified using logistic regression analysis and thresholds defined to stratify low-, moderate-, and high-risk groups. The CAHP score was validated in both a prospective and an external data set (Parisian Cardiac Arrest Registry). The developmental data set included 819 patients admitted from May 2011 to December 2012. After multivariate analysis, seven variables were independently associated with poor neurological outcome and subsequently included in the CAHP score (age, non-shockable rhythm, time from collapse to basic life support, time from basic life support to return of spontaneous circulation, location of cardiac arrest, epinephrine dose, and arterial pH). Three risks groups were identified: low risk (score ≤150, 39% of unfavourable outcome), medium risk (score 150-200, 81% of unfavourable outcome) and high-risk group (score ≥200, 100% of unfavourable outcome). The AUC of the CAHP score were 0.93, and the discrimination value in the validation data sets was consistent (respectively, AUC 0.91 and 0.85). CONCLUSION: The CAHP score represents a simple tool for early stratification of patients admitted in ICU after OHCA. A high-risk category of patients with very poor prognosis can be easily identified.

Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study.

BACKGROUND: Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. METHODS AND RESULTS: Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1-2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93-2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96-2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). CONCLUSION: Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.

Out-of-hospital cardiac arrest from brain cause: epidemiology, clinical features, and outcome in a multicenter cohort*.

OBJECTIVES: Although sudden cardiac death has been broadly studied, little is known on cerebrovascular events revealed by out-of-hospital cardiac arrest. We aimed to describe clinical features and prognosis of these patients and identify characteristics that could suggest a cerebrovascular etiology of the out-of-hospital cardiac arrest. DESIGN: Retrospective review (1999-2012) of databases of three regional referral ICU centers for out-of-hospital cardiac arrest. SETTING: Patients admitted to ICU for management of successfully resuscitated out-of-hospital cardiac arrest. PATIENTS: Patients were included when subarachnoid hemorrhage, intracranial hemorrhage, ischemic stroke, sub/epidural hematoma, or cerebral thrombophlebitis was identified as the primary cause of out-of-hospital cardiac arrest. Traumatic or infectious causes were excluded. Patients were compared with a group of out-of-hospital cardiac arrest of nonneurological origin. INTERVENTIONS: All medical records of the three prospective ICU databases, registered according to the Utstein style, were reviewed. MEASUREMENTS AND MAIN RESULTS: Among 3,710 patients admitted for out-of-hospital cardiac arrest, 86 were included (mainly subarachnoid hemorrhage, n = 73). Prodromes were mostly neurological but falsely evoked a cardiac origin in six patients. Electrocardiogram displayed abnormalities in 64% of patients, with 23% of pseudoischemic pattern (ST-segment elevation or left bundle branch block). Mortality rate was 100%, with brain death as the leading cause. In comparison with the nonneurological out-of-hospital cardiac arrest group, female gender, onset of neurological prodromes, lack of other prodromes, initial nonshockable rhythm, and unspecific electrocardiogram repolarization abnormalities were independent predictive factors of a primary cerebrovascular etiology. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.86 (95% CI, 0.81-0.91). CONCLUSIONS: Presentation of cerebrovascular event complicated with out-of-hospital cardiac arrest may mimic coronary etiology, but several clinical elements may help to identify brain causes. Even if survival is null, the high proportion of brain deaths provides opportunity for organ donation.

[Shall we Follow the Guidelines for Isosorbide Dinitrate in Acute Pulmonary Edema?]. / Y a-t-il une place pour le dinitrate d'isosorbide dans l'œdème aigu pulmonaire ?

PURPOSE: Prospective evaluation of short (dyspnoea) and mid-term outcomes in 47 consecutive patients admitted in the intensive care unit for acute pulmonary edema treated on a liberal basis. RESULTS: Patients were elderly (83 year-old) and 60% had preserved left ventricular ejection fraction (>50%). Dyspnoea assessed by visual analogue score was weakly associated with treatment posology. Despite low use of inotropes (6%) and intubation (9%), hospital and D90 mortality was high (19% and 32% respectively). Higher mortality was noticed in patients receiving no isosorbide dinitrate (p = 0.04). In the multivariate analysis, only age and delta brain natriuretic peptide (difference between BNP on D1 and D0) remained significantly associated with mortality on D90 (OR 1.13; p = 0.03 and OR 1.004; p = 0.04 respectively). CONCLUSION: Acute pulmonary edema carried a dramatic in-hospital and mid-term mortality in our elderly patients. Isosorbide dinitrate was associated with decreased D90 mortality but not in the multivariate analysis.