Healthcare-associated infections in patients with severe COVID-19 supported with extracorporeal membrane oxygenation: a nationwide cohort study.

BACKGROUND: Both critically ill patients with coronavirus disease 2019 (COVID-19) and patients receiving extracorporeal membrane oxygenation (ECMO) support exhibit a high incidence of healthcare-associated infections (HAI). However, data on incidence, microbiology, resistance patterns, and the impact of HAI on outcomes in patients receiving ECMO for severe COVID-19 remain limited. We aimed to report HAI incidence and microbiology in patients receiving ECMO for severe COVID-19 and to evaluate the impact of ECMO-associated infections (ECMO-AI) on in-hospital mortality. METHODS: For this study, we analyzed data from 701 patients included in the ECMOSARS registry which included COVID-19 patients supported by ECMO in France. RESULTS: Among 602 analyzed patients for whom HAI and hospital mortality data were available, 214 (36%) had ECMO-AI, resulting in an incidence rate of 27 ECMO-AI per 1000 ECMO days at risk. Of these, 154 patients had bloodstream infection (BSI) and 117 patients had ventilator-associated pneumonia (VAP). The responsible microorganisms were Enterobacteriaceae (34% for BSI and 48% for VAP), Enterococcus species (25% and 6%, respectively) and non-fermenting Gram-negative bacilli (13% and 20%, respectively). Fungal infections were also observed (10% for BSI and 3% for VAP), as were multidrug-resistant organisms (21% and 15%, respectively). Using a Cox multistate model, ECMO-AI were not found associated with hospital death (HR = 1.00 95% CI [0.79-1.26], p = 0.986). CONCLUSIONS: In a nationwide cohort of COVID-19 patients receiving ECMO support, we observed a high incidence of ECMO-AI. ECMO-AI were not found associated with hospital death. Trial registration number NCT04397588 (May 21, 2020).

Electrocardiographic Changes at the Early Stage of Status Epilepticus: First Insights From the ICTAL Registry.

OBJECTIVES: To describe early electrocardiogram (ECG) abnormalities after status epilepticus (SE) and evaluate their association with 90-day neurological outcomes. DESIGN: Retrospective analysis of a multicenter, national prospective registry between February 2018 and June 2020. SETTING: Sixteen ICUs in France, IctalGroup Research Network. PATIENTS: Adults with available ECG performed less than or equal to 24 hours after the onset of SE and less than or equal to 12 hours after its resolution. INTERVENTION: Double-blinded review of all ECGs was performed by two independent cardiologists. ECGs were categorized as normal/abnormal and then with minor/major early ECG abnormalities according to the Novacode ECG Classification system. MEASUREMENTS AND MAIN RESULTS: Among 155 critically ill patients with SE, early ECG abnormalities were encountered in 145 (93.5%), categorized as major in 91 of 145 (62.8%). In addition to sinus tachycardia, the main abnormalities were in the ST segment (elevation [16.6%] or depression [17.9%]) or negative T waves (42.1%). Major early ECG abnormalities were significantly associated with respiratory distress and sinus tachycardia at the scene and hyperlactatemia at ICU admission. By multivariable analysis, three variables were significantly associated with 90-day poor outcome: age, preexisting ultimately fatal comorbidity, and cerebral insult as the cause of SE. Early major ECG abnormalities were not independently associated with 90-day functional outcome. CONCLUSIONS: In our study, early ECG abnormalities in the acute phase of SE were frequent, often unrecognized and were associated with clinical and biological stigma of hypoxemia. Although they were not independently associated with 90-day functional outcome, ECG changes at the early stage of SE should be systematically evaluated. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03457831 .

Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19.

COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper "Th1-Th17" profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19.

Post-cardiac surgery fungal mediastinitis: clinical features, pathogens and outcome.

OBJECTIVES: The occurrence of mediastinitis after cardiac surgery remains a rare and severe complication associated with poor outcomes. Whereas bacterial mediastinitis have been largely described, little is known about their fungal etiologies. We report incidence, characteristics and outcome of post-cardiac surgery fungal mediastinitis. METHODS: Multicenter retrospective study among 10 intensive care units (ICU) in France and Belgium of proven cases of fungal mediastinitis after cardiac surgery (2009-2019). RESULTS: Among 73,688 cardiac surgery procedures, 40 patients developed fungal mediastinitis. Five were supported with left ventricular assist device and five with veno-arterial extracorporeal membrane oxygenation before initial surgery. Twelve patients received prior heart transplantation. Interval between initial surgery and mediastinitis was 38 [17-61] days. Only half of the patients showed local signs of infection. Septic shock was uncommon at diagnosis (12.5%). Forty-three fungal strains were identified: Candida spp. (34 patients), Trichosporon spp. (5 patients) and Aspergillus spp. (4 patients). Hospital mortality was 58%. Survivors were younger (59 [43-65] vs. 65 [61-73] yo; p = 0.013), had lower body mass index (24 [20-26] vs. 30 [24-32] kg/m2; p = 0.028) and lower Simplified Acute Physiology Score II score at ICU admission (37 [28-40] vs. 54 [34-61]; p = 0.012). CONCLUSION: Fungal mediastinitis is a very rare complication after cardiac surgery, associated with a high mortality rate. This entity should be suspected in patients with a smoldering infectious postoperative course, especially those supported with short- or long-term invasive cardiac support devices, or following heart transplantation.

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome Associated with COVID-19: An Emulated Target Trial Analysis.

Rationale: Whether patients with coronavirus disease (COVID-19) may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. Objectives: To estimate the effect of ECMO on 90-day mortality versus IMV only. Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO versus no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 80 or PaCO2 ⩾ 60 mm Hg). We controlled for confounding using a multivariable Cox model on the basis of predefined variables. Measurements and Main Results: A total of 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability on Day 7 from the onset of eligibility criteria (87% vs. 83%; risk difference, 4%; 95% confidence interval, 0-9%), which decreased during follow-up (survival on Day 90: 63% vs. 65%; risk difference, -2%; 95% confidence interval, -10 to 5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand and when initiated within the first 4 days of IMV and in patients who are profoundly hypoxemic. Conclusions: In an emulated trial on the basis of a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and regions with ECMO capacities specifically organized to handle high demand.

Extracorporeal Membrane Oxygenation for Respiratory Failure Related to COVID-19: A Nationwide Cohort Study.

BACKGROUND: Despite expanding use, knowledge on extracorporeal membrane oxygenation support during the COVID-19 pandemic remains limited. The objective was to report characteristics, management, and outcomes of patients receiving extracorporeal membrane oxygenation with a diagnosis of COVID-19 in France and to identify pre-extracorporeal membrane oxygenation factors associated with in-hospital mortality. A hypothesis of similar mortality rates and risk factors for COVID-19 and non-COVID-19 patients on venovenous extracorporeal membrane oxygenation was made. METHODS: The Extracorporeal Membrane Oxygenation for Respiratory Failure and/or Heart failure related to Severe Acute Respiratory Syndrome-Coronavirus 2 (ECMOSARS) registry included COVID-19 patients supported by extracorporeal membrane oxygenation in France. This study analyzed patients included in this registry up to October 25, 2020, and supported by venovenous extracorporeal membrane oxygenation for respiratory failure with a minimum follow-up of 28 days after cannulation. The primary outcome was in-hospital mortality. Risk factors for in-hospital mortality were analyzed. RESULTS: Among 494 extracorporeal membrane oxygenation patients included in the registry, 429 were initially supported by venovenous extracorporeal membrane oxygenation and followed for at least 28 days. The median (interquartile range) age was 54 yr (46 to 60 yr), and 338 of 429 (79%) were men. Management before extracorporeal membrane oxygenation cannulation included prone positioning for 411 of 429 (96%), neuromuscular blockage for 419 of 427 (98%), and NO for 161 of 401 (40%). A total of 192 of 429 (45%) patients were cannulated by a mobile extracorporeal membrane oxygenation unit. In-hospital mortality was 219 of 429 (51%), with a median follow-up of 49 days (33 to 70 days). Among pre-extracorporeal membrane oxygenation modifiable exposure variables, neuromuscular blockage use (hazard ratio, 0.286; 95% CI, 0.101 to 0.81) and duration of ventilation (more than 7 days compared to less than 2 days; hazard ratio, 1.74; 95% CI, 1.07 to 2.83) were independently associated with in-hospital mortality. Both age (per 10-yr increase; hazard ratio, 1.27; 95% CI, 1.07 to 1.50) and total bilirubin at cannulation (6.0 mg/dl or more compared to less than 1.2 mg/dl; hazard ratio, 2.65; 95% CI, 1.09 to 6.5) were confounders significantly associated with in-hospital mortality. CONCLUSIONS: In-hospital mortality was higher than recently reported, but nearly half of the patients survived. A high proportion of patients were cannulated by a mobile extracorporeal membrane oxygenation unit. Several factors associated with mortality were identified. Venovenous extracorporeal membrane oxygenation support should be considered early within the first week of mechanical ventilation initiation.

Ultrasound Guidance and Risk for Central Venous Catheter-Related Infections in the Intensive Care Unit: A Post Hoc Analysis of Individual Data of 3 Multicenter Randomized Trials.

BACKGROUND: Ultrasound (US) guidance is frequently used in critically ill patients for central venous catheter (CVC) insertion. The effect of US on infectious risk remains controversial, and randomized controlled trials (RCTs) have assessed mainly noninfectious complications. This study assessed infectious risk associated with catheters inserted with US guidance vs use of anatomical landmarks. METHODS: We used individual data from 3 large RCTs for which a prospective, high-quality data collection was performed. Adult patients were recruited in various intensive care units (ICUs) in France as soon as they required short-term CVC insertion. We applied marginal Cox models with inverse probability weighting to estimate the effect of US-guided insertion on catheter-related bloodstream infections (CRBSIs, primary outcome) and major catheter-related infections (MCRIs, secondary outcome).We also evaluated insertion site colonization at catheter removal. RESULTS: Our post hoc analysis included 4636 patients and 5502 catheters inserted in 2088 jugular, 1733 femoral, and 1681 subclavian veins, in 19 ICUs. US guidance was used for 2147 catheter insertions. Among jugular and femoral CVCs and after weighting, we found an association between US and CRBSI (hazard ratio [HR], 2.21 [95% confidence interval {CI}, 1.17-4.16]; P = .014) and between US and MCRI (HR, 1.55 [95% CI, 1.01-2.38]; P = .045). Catheter insertion site colonization at removal was more common in the US-guided group (P = .0045) among jugular and femoral CVCs in situ for ≤7 days (n = 606). CONCLUSIONS: In prospectively collected data in which catheters were not randomized to insertion by US or anatomical landmarks, US guidance was associated with increased risk of infection.

Diagnostic yield of routine daily blood culture in patients on veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Bloodstream infections (BSIs) are frequent on veno-arterial extracorporeal membrane oxygenation (V-A ECMO). Performing routine blood cultures (BCs) may identify early paucisymptomatic BSIs. We investigated the contribution of systematic daily BCs to detect BSIs on V-A ECMO. METHODS: This was a retrospective study including all adult patients requiring V-A ECMO and surviving more than 24 h. Our protocol included routine daily BCs, from V-A ECMO insertion up to 5 days after withdrawal; other BCs were performed on-demand. RESULTS: On the 150 V-A ECMO included, 2146 BCs were performed (1162 routine and 984 on-demand BCs); 190 (9%) were positive, including 68 contaminants. Fifty-one (4%) routine BCs revealed BSIs; meanwhile, 71 (7%) on-demand BCs revealed BSIs (p = 0.005). Performing routine BCs was negatively associated with BSIs diagnosis (OR 0.55, 95% CI [0.38; 0.81], p = 0.002). However, 16 (31%) BSIs diagnosed by routine BCs would have been missed by on-demand BCs. Independent variables for BSIs diagnosis after routine BCs were: V-A ECMO for cardiac graft failure (OR 2.43, 95% CI [1.20; 4.92], p = 0.013) and sampling with on-going antimicrobial therapy (OR 2.15, 95% CI [1.08; 4.27], p = 0.029) or renal replacement therapy (OR 2.05, 95% CI [1.10; 3.81], p = 0.008). Without these three conditions, only two BSIs diagnosed with routine BCs would have been missed by on-demand BCs sampling. CONCLUSIONS: Although routine daily BCs are less effective than on-demand BCs and expose to contamination and inappropriate antimicrobial therapy, a policy restricted to on-demand BCs would omit a significant proportion of BSIs. This argues for a tailored approach to routine daily BCs on V-A ECMO, based on risk factors for positivity.

Complete percutaneous angio-guided approach using preclosing for venoarterial extracorporeal membrane oxygenation implantation and explantation in patients with refractory cardiogenic shock or cardiac arrest.

BACKGROUND: The approach for veno-arterial extracorporeal membrane oxygenation implantation (VA-ECMO) in patients with cardiogenic shock can be either surgical or percutaneous. Complete angio-guided percutaneous implantation and explantation could decrease vascular complications. We sought to describe the initial results of complete percutaneous angio-guided ECMO implantation and explantation using preclosing. METHODS: All consecutive patients who underwent peripheral femoro-femoral VA-ECMO percutaneous implantation for refractory cardiogenic shock or cardiac arrest were enrolled in a prospective registry (03/2018-12/2020). Percutaneous preclosing using two closing devices (Perclose ProGlide, Abbott) inserted before cannulation was used in both femoral artery and vein. Explantation was performed using a crossover technique under angiographic guidance. The occurrence of vascular complication was recorded. RESULTS: Among the 56 patients who underwent percutaneous VA-ECMO implantation for cardiogenic shock or refractory cardiac arrest, 41 underwent preclosing. Femoral vessel cannulation was successful in all patients and total cannulation time was 20 (10-40) min. Weaning from ECMO was possible in 22/41 patients (54%) and 12 (29%) patients were alive at day 30. Significant vascular complications occurred in 2/41 patients. Percutaneous decannulation was performed in 20 patients with 19/20 technical success rate. All femoral arteries and veins were properly closed using the pre-closing devices without bleeding on the angiographic control except for one patient in whom surgical closure of the artery was required. No patient required transfusion for access related significant bleeding and no other vascular complication occurred. Furthermore, no groin infection was observed after full percutaneous implantation and removal of ECMO. CONCLUSION: Emergent complete percutaneous angio-guided VA-ECMO implantation and explantation using pre-closing technique can be an attractive strategy in patients referred for refractory cardiogenic shock.

Clinical practice recommendations on the management of perioperative cardiac arrest: A report from the PERIOPCA Consortium.

BACKGROUND: Perioperative cardiac arrest is a rare complication with an incidence of around 1 in 1400 cases, but it carries a high burden of mortality reaching up to 70% at 30 days. Despite its specificities, guidelines for treatment of perioperative cardiac arrest are lacking. Gathering the available literature may improve quality of care and outcome of patients. METHODS: The PERIOPCA Task Force identified major clinical questions about the management of perioperative cardiac arrest and framed them into the therapy population [P], intervention [I], comparator [C], and outcome [O] (PICO) format. Systematic searches of PubMed, Embase, and the Cochrane Library for articles published until September 2020 were performed. Consensus-based treatment recommendations were created using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The strength of consensus among the Task Force members about the recommendations was assessed through a modified Delphi consensus process. RESULTS: Twenty-two PICO questions were addressed, and the recommendations were validated in two Delphi rounds. A summary of evidence for each outcome is reported and accompanied by an overall assessment of the evidence to guide healthcare providers. CONCLUSIONS: The main limitations of our work lie in the scarcity of good quality evidence on this topic. Still, these recommendations provide a basis for decision making, as well as a guide for future research on perioperative cardiac arrest.

Six-Month Survival After Extracorporeal Membrane Oxygenation for Severe COVID-19.

OBJECTIVES: The authors evaluated the outcome of adult patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) requiring the use of extracorporeal membrane oxygenation (ECMO). DESIGN: Multicenter retrospective, observational study. SETTING: Ten tertiary referral university and community hospitals. PARTICIPANTS: Patients with confirmed severe COVID-19-related ARDS. INTERVENTIONS: Venovenous or venoarterial ECMO. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-two patients (mean age 51.1 ± 9.7 years, female 17.4%) were treated with ECMO for confirmed severe COVID-19-related ARDS. Before ECMO, the mean Sequential Organ Failure Assessment score was 10.1 ± 4.4, mean pH was 7.23 ± 0.09, and mean PaO2/fraction of inspired oxygen ratio was 77 ± 50 mmHg. Venovenous ECMO was adopted in 122 patients (92.4%) and venoarterial ECMO in ten patients (7.6%) (mean duration, 14.6 ± 11.0 days). Sixty-three (47.7%) patients died on ECMO and 70 (53.0%) during the index hospitalization. Six-month all-cause mortality was 53.0%. Advanced age (per year, hazard ratio [HR] 1.026, 95% CI 1.000-1-052) and low arterial pH (per unit, HR 0.006, 95% CI 0.000-0.083) before ECMO were the only baseline variables associated with increased risk of six-month mortality. CONCLUSIONS: The present findings suggested that about half of adult patients with severe COVID-19-related ARDS can be managed successfully with ECMO with sustained results at six months. Decreased arterial pH before ECMO was associated significantly with early mortality. Therefore, the authors hypothesized that initiation of ECMO therapy before severe metabolic derangements subset may improve survival rates significantly in these patients. These results should be viewed in the light of a strict patient selection policy and may not be replicated in patients with advanced age or multiple comorbidities. CLINICAL TRIAL REGISTRATION: identifier, NCT04383678.

Argon Attenuates Multiorgan Failure in Relation with HMGB1 Inhibition.

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups (n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.

Amoxicillin-induced crystal nephropathy: A nationwide French pharmacovigilance databases study.

AIMS: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is a rarely reported adverse drug reaction (ADR) but its increase has been recently reported in the Paris area. Our aim was to investigate the incidence, characteristics and outcome of AICN in France. METHODS: Retrospective analysis of all AICN cases reported to the French National Pharmacovigilance Database and the Marketing Authorization Holders Pharmacovigilance Database. AICN notification rate was compared to intravenous AMX and AMX-clavulanate sales. RESULTS: In total, 101 AICN cases were included. Intravenous AMX/AMX-clavulanate was prescribed as surgical prophylaxis (32 surgical patients) or to treat infection (69 medical patients). AKI KDIGO stage 3 was observed in 70 patients and 24/70 patients required renal replacement therapy and/or intensive care unit admission. The annual notification rate of AICN was increased by a factor of 13 since 2010 (6 [0;7] and 77 [24;111] cases per 100 000 patient-years of exposure, before and after 2010 respectively; P < .001). In surgical patients, the increase in AICN has been reported since 2010 and was mainly related to inadequate AMX administration. In medical patients, the increase in AICN was observed since 2014. After 2014, medical patients were older (67 [42;77] vs 74 years [64;84] respectively; P < .05) and were treated more frequently for endocarditis (0/20 vs 15/49 respectively; P < .01). A contributing factor was observed or suspected in 62 patients. CONCLUSION: AICN is a severe ADR that dramatically increased in France since 2010. Assessment of AICN contributing factors and AMX drug monitoring in patients receiving high dose of AMX could reduce the risk of AICN.

Clinical relevance and impact of Corynebacterium isolation in lower respiratory tract of critically ill patients requiring mechanical ventilation.

PURPOSE: Corynebacterium spp. (C. spp.) is commonly considered as a contaminant in respiratory specimens. No study has ever focused on its clinical relevance in the lower respiratory tract of patients admitted to the intensive care unit (ICU) and requiring mechanical ventilation. The aims were to describe the characteristics of ICU patients with a C. spp. positive deep respiratory specimen, to investigate the impact of C. spp. on the occurrence of pneumonia, and to evaluate the outcomes of these pneumonia. METHODS: We retrospectively included all adult patients admitted to ICU in a 1000-bed University Hospital (2007-2017) who had a C. spp. positive lower respiratory tract specimen at a significant quantitative level. We used clinical, radiological, and microbiological criteria to classify the likelihood of such pneumonia. RESULTS: Among the 31 patients included, acute respiratory failure and postoperative care after major surgery were the main reasons of admission. SAPS II was 47 [34-60]. C. spp. pneumonia was considered as probable, possible and unlikely in 10, 14, and 7 patients, respectively. Fifty-two and 94% of C. spp. strains were sensitive to amoxicillin, and vancomycin/linezolid, respectively. Seventeen patients had a complete course of antibiotic against C. spp. The overall ICU mortality was 58%. CONCLUSION: Corynebacterium spp seems to be responsible for authentic pneumonia in mechanically ventilated patients. It should be considered as clinically relevant when predominantly present in respiratory specimen from patients suspected with pneumonia in ICU, and empirically treated.

Hypothermia for Neuroprotection in Convulsive Status Epilepticus.

BACKGROUND: Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. METHODS: In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, "super-refractory" status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. RESULTS: A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. CONCLUSIONS: In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

Outcomes of Stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study.

BACKGROUND: There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy. METHODS: This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy. RESULTS: Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5-18] days. The Simplified Acute Physiology Score II was 47 [36-63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively). CONCLUSIONS: S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival. TRIAL REGISTRATION: clinicaltrials.gov, NCT03506191.