Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study.

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0-24h) divided by the MIC (AUC0-24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).

Correction to: Changes in the clinical presentation and outcomes of patients treated for severe malaria in a referral French university intensive care unit from 2004 to 2017.

After publication of the original article [1], we were notified that family names have been exchanged with the first names for all authors. Below the name are tagged correctly.

Changes in the clinical presentation and outcomes of patients treated for severe malaria in a referral French university intensive care unit from 2004 to 2017.

BACKGROUND: In France, the incidence of severe imported malaria cases increased since early 2000. Artesunate was available (temporarily use authorization) since mid-2011 in France and commonly used for severe malaria since early 2013. Thus, the study objectives were to describe the patients with severe imported malaria admitted in intensive care unit (ICU) and assess the changes in clinical presentation and outcomes before and after this date. METHODS: Retrospective observational single-center study in the infectious diseases ICU of a referral university hospital, conducted on patients admitted for severe imported malaria from 2004 to 2017. Demographic variables, severity scores, WHO's severity criteria on admission, treatment, and ICU and hospital lengths of stay were collected. Patients' characteristics and outcomes were compared between both periods. A poor outcome was defined as the composite endpoint of death, or requirement for vasopressors, invasive mechanical ventilation and/or renal replacement therapy. RESULTS: 189 patients were included, 98 in 2004-2012 and 91 in 2013-2017, most often from West and Central African countries (96%). The number of WHO criteria for severe malaria was comparable in both groups, but SAPS II, SOFA and ICU length of stay were significantly higher in 2004-2012, while patients of African origin living in France were less frequent (p < 0.01). The outcome was poor for 41/98 cases in 2004-2012 and 12/91 cases in 2013-2017 (p < 0.01). The risk factors of poor outcome on the multivariate logistic regression were a neurological failure (adjusted odds ratio (adjOR = 3.23; 95% CI (1.03-10.08), p = 0.004), cardio-circulatory failure (adjOR = 9.92; 95% CI (2.34-42), p = <0.01) and creatinine blood levels > 265 µmol/L (adjOR = 10.76; 95% CI (3.17-36.53), p < 0.01). In the multivariate analysis, IV artesunate was not associated with a better outcome. Patients of African origin did not seem to have a better outcome than Caucasian patients or those from other origins (adjOR = 0.59; 95% CI (0.21-1.65), p = 0.31). CONCLUSION: Patients with imported malaria admitted in ICU in 2013-2017 were less severely ill than those in 2004-2012. These trends could be partially explained by the increasing proportion of African patients visiting friends or relatives or living in endemic areas.

Hemolysis and Plasma Free Hemoglobin During Extracorporeal Membrane Oxygenation Support: From Clinical Implications to Laboratory Details.

Venovenous and venoarterial extracorporeal membrane oxygenation (ECMO) are lifesaving supports that are more and more frequently used in critically ill patients. Despite of major technological improvements observed during the last 20 years, ECMO-associated hemolysis is still a complication that may arise during such therapy. Hemolysis severity, directly appreciated by plasma free hemoglobin concentration, may be present with various intensity, from a nonalarming and tolerable hemolysis to a highly toxic one. Here, we propose a review dedicated to extracorporeal membrane oxygenation (ECMO)-associated hemolysis, with a particular emphasis on pathophysiology, prevalence, and clinical consequences of such complication. We also focus on laboratory assessment of hemolysis and on the limits that have to be known by clinicians to prevent and manage hemolytic events.

Infectious complications following heart transplantation in the era of high-priority allocation and extracorporeal membrane oxygenation.

BACKGROUND: Infectious complications are a major cause of morbidity and mortality after heart transplantation (HT). However, the epidemiology and outcomes of these infections in the recent population of adult heart transplant recipients have not been investigated. METHODS: We conducted a single-center retrospective study on infectious complications occurring within 180 days following HT on consecutive heart transplant recipients, from January 2011 to June 2015 at Bichat University Hospital in Paris, France. Risk factors for non-viral infections occurring within 8, 30 and 180 days after HT were investigated using competing risk analysis. RESULTS: Overall, 113 patients were included. Fifty-eight (51%) HTs were high-priority allocations. Twenty-eight (25%) patients had an extracorporeal membrane oxygenation (ECMO) support at the time of transplantation. Ninety-two (81%) patients developed at least one infection within 180 days after HT. Bacterial and fungal infections (n = 181 episodes) occurred in 80 (71%) patients. The most common bacterial and fungal infections were pneumonia (n = 95/181 episodes, 52%), followed by skin and soft tissue infections (n = 26/181, 14%). Multi-drug-resistant bacteria were responsible for infections in 21 (19%) patients. Viral infections were diagnosed in 44 (34%) patients, mostly Cytomegalovirus infection (n = 39, 34%). In multivariate subdistribution hazard model, prior cardiac surgery (subdistribution hazard ratio sHR = 2.7 [95% CI 1.5-4.6] p < 0.01) and epinephrine or norepinephrine at the time of HT (sHR = 2.3 [95% CI 1.1-5.2] p  = 0.04) were significantly associated with non-viral infections within 8 days after HT. Prior cardiac surgery (sHR = 2.5 [95% CI 1.4-4.4] p < 0.01), recipient age over 60 years (sHR = 2.0 [95% CI 1.2-3.3] p < 0.01) and ECMO following HT (sHR = 1.7 [95% CI 1.0-2.8] p = 0.04) were significantly associated with non-viral infection within 30 days after HT, as well as within 180 days after HT. CONCLUSION: This study confirmed the high rate of infections following HT. Recipient age, prior cardiac surgery and ECMO following HT were independent risk factors for early and late bacterial and fungal infections.

Early Electroencephalography Findings in Cardiogenic Shock Patients Treated by Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: We aimed to assess early electroencephalography findings in patients treated by venoarterial extracorporeal membrane oxygenation and their association with neurologic outcome. DESIGN: Single-center observational study. SETTING: Medical ICU of a university hospital. PATIENTS: An early standardized electroencephalography assessment, that is, standard electroencephalography followed by continuous electroencephalography, was performed in consecutive cardiogenic shock patients requiring venoarterial extracorporeal membrane oxygenation. Associations between electroencephalography findings and outcome, defined as a composite of acute brain injury or death at 14 days, were investigated. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients with a median Full Outline of Unresponsiveness score of 4 (interquartile range, 3-6) were studied. Pupillary light reflex, corneal reflex, and cough reflex were preserved in 20 (90%), 17 (77%), and 17 (77%) patients, respectively. Overall, standard electroencephalography findings consisted of diffuse slowing in 21 patients (95%) and severe background abnormalities in 13 patients (59%) (i.e., a discontinuous [n = 5; 23%] and/or an unreactive background [n = 9; 41%]). Severe background abnormalities on standard electroencephalography (poor outcome rate: 69% vs 22%; p = 0.03) and absence of sleep transients on continuous electroencephalography (poor outcome rate: 67% vs 14%; p = 0.02) were associated with a poor outcome, whereas neurologic findings and doses of sedation were not. Patients without sleep transients on continuous electroencephalography tended to have lower Full Outline of Unresponsiveness scores than patients with preserved sleep transients-appearing patterns. CONCLUSIONS: In patients treated by venoarterial extracorporeal membrane oxygenation, early severe background abnormalities on standard electroencephalography provide important information on neurologic outcome. The lack of sleep transients on continuous electroencephalography reflects the severity of brain dysfunction and might represent an additional prognostic marker.

Respective impact of implementation of prevention strategies, colonization with multiresistant bacteria and antimicrobial use on the risk of early- and late-onset VAP: An analysis of the OUTCOMEREA network.

RATIONALE: The impact of prevention strategies and risk factors for early-onset (EOP) versus late-onset (LOP) ventilator-associated pneumonia (VAP) are still debated. OBJECTIVES: To evaluate, in a multicenter cohort, the risk factors for EOP and LOP, as the evolution of prevention strategies. METHODS: 7,784 patients with mechanical ventilation (MV) for at least 48 hours were selected into the multicenter prospective OUTCOMEREA database (1997-2016). VAP occurring between the 3rd and 6th day of MV defined EOP, while those occurring after defined LOPs. We used a Fine and Gray subdistribution model to take the successful extubation into account as a competing event. MEASUREMENTS AND MAIN RESULTS: Overall, 1,234 included patients developed VAP (EOP: 445 (36%); LOP: 789 (64%)). Male gender was a risk factor for both EOP and LOP. Factors specifically associated with EOP were admission for respiratory distress, previous colonization with multidrug-resistant Pseudomonas aeruginosa, chest tube and enteral feeding within the first 2 days of MV. Antimicrobials administrated within the first 2 days of MV were all protective of EOP. ICU admission for COPD exacerbation or pneumonia were early risk factors for LOP, while imidazole and vancomycin use within the first 2 days of MV were protective factors. Late risk factors (between the 3rd and the 6th day of MV) were the intra-hospital transport, PAO2-FIO2<200 mmHg, vasopressor use, and known colonization with methicillin-resistant Staphylococcus aureus. Among the antimicrobials administered between the 3rd and the 6th day, fluoroquinolones were the solely protective one.Contrarily to LOP, the risk of EOP decreased across the study time periods, concomitantly with an increase in the compliance with bundle of prevention measures. CONCLUSION: VAP risk factors are mostly different according to the pneumonia time of onset, which should lead to differentiated prevention strategies.

Systematic overdosing of oxa- and cloxacillin in severe infections treated in ICU: risk factors and side effects.

BACKGROUND: Oxacillin and cloxacillin are the most frequently used penicillins for the treatment of severe methicillin-susceptible Staphylococcus aureus infections in intensive care units (ICUs), especially endocarditis. International recommendations do not suggest any adaptation of the dosage in case of renal impairment. We wanted to assess the risk factors for overdosing in ICU and the related observed side effects. METHODS: All patients with a therapeutic drug monitoring of oxa- or cloxacillin between 2008 and 2014 were included. The target range of trough concentration for total antibiotic activity was considered to be 20-50 mg/L. Data concerning the infection, the given treatment, the renal function, and the attributed side effects of overdosing were collected. A logistic regression model was used to compute the measured trough concentrations. RESULTS: Sixty-two patients were included in this study. We found a median trough plasma concentration of 134.3 mg/L (IQR 65.3-201 mg/L). Ten patients (16.1%) reached the target concentration; all other patients (83.9%) were overdosed. Eleven patients (17.7%) experienced neurological side effects attributed to a high antibiotic concentration, i.e. persistent coma and delirium. When adjusted on the dosage used, the risk of overdosing was significantly associated with a creatinine clearance <10 mL/min (with or without hemodialysis). CONCLUSION: With the suggested dose of 12 g/day for cloxacillin treatment in case of endocarditis and severe infections occurring in ICU, 83.9% of patients are largely overdosed. Considering the observed side effects, doses should be accurately monitored and reduced, particularly when renal replacement therapy is needed.

Viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia.

BACKGROUND: Multiplex polymerase chain reaction (mPCR) enables recovery of viruses from airways of patients with community-acquired pneumonia (CAP), although their clinical impact remains uncertain. METHODS: Among consecutive adult patients who had undergone a mPCR within 72 hours following their admission to one intensive care unit (ICU), we retrospectively included those with a final diagnosis of CAP. Four etiology groups were clustered: bacterial, viral, mixed (viral-bacterial) and no etiology. A composite criterion of complicated course (hospital death or mechanical ventilation > 7 days) was used. A subgroup analysis compared patients with bacterial and viral-bacterial CAP matched on the bacterial pathogens. RESULTS: Among 174 patients (132 men [76 %], age 63 [53-75] years, SAPSII 38 [27;55], median PSI score 106 [78;130]), bacterial, viral, mixed and no etiology groups gathered 46 (26 %), 53 (31 %), 45 (26 %) and 30 (17 %) patients, respectively. Virus-infected patients displayed a high creatine kinase serum level, a low platelet count, and a trend toward more frequent alveolar-interstitial infiltrates. A complicated course was more frequent in the mixed group (31/45, 69 %), as compared to bacterial (18/46, 39 %), viral (15/53, 28 %) and no etiology (12/30, 40 %) groups (p < 0.01). In multivariate analysis, the mixed (viral-bacterial) infection was independently associated with complicated course (reference: bacterial pneumonia; OR, 3.58; CI 95 %, 1.16-11; p = 0.03). The subgroup analysis of bacteria-matched patients confirmed these findings. CONCLUSIONS: Viral-bacterial coinfection during severe CAP in adults is associated with an impaired presentation and a complicated course.

Early-onset status epilepticus in patients with acute encephalitis.

Status epilepticus (SE) is a common complication of acute encephalitis, but its determinants and prognostic value in this setting are not known.Risk factors for early-onset SE (within 48 hours of intensive care unit [ICU] admission) in consecutive adult patients with all-cause encephalitis admitted to the medical ICU of a university hospital (1991-2013) were evaluated by multivariate logistic regression analysis. To examine the prognostic value of SE, patients were classified into 3 groups: no SE, nonrefractory SE (NRSE), and refractory SE (RSE). Poor neurologic outcome was defined by a modified Rankin score of 4 to 6.Among the 290 patients, 58 (20%, 95% CI: 15%-25%) developed early-onset SE, comprising 44 patients with NRSE and 14 patients with RSE. Coma (adjusted odds ratio [OR]: 3.1, 95% CI: 1.5-6.3), cortical lesions on neuroimaging (adjusted OR: 3.7, 95% CI: 1.8-7.8), and nonneurologic organ failure(s) (adjusted OR: 13.6, 95% CI: 4.9-37.7) were found to be independent risk factors for SE. By contrast, a bacterial etiology had a protective effect (adjusted OR: 0.3, 95% CI: 0.1-0.7). Age, body temperature, and blood sodium levels were not independently associated with SE. Poor neurologic outcomes were observed at day 90 in respectively 23% (95% CI: 17%-28%), 23% (95% CI: 10%-35%), and 71% (95% CI: 48%-95%) of no SE, NRSE, and RSE patients (P < 0.01). After adjusting for confounders, RSE, but not NRSE, remained independently associated with 90-day mortality (adjusted OR: 6.0, 95% CI: 1.5-23.3).Coma, cortical involvement on neuroimaging, and nonneurologic organ failure(s) are independent risk factors for SE in patients with acute encephalitis. Conversely, a bacterial etiology is associated with a lower risk of SE.These findings may help identify patients who may benefit from prophylactic antiepileptic drugs.