Jean-François Timsit

Ectopic Activation of Germline and Placental Genes Identifies Aggressive Metastasis-Prone Lung Cancers

Large-scale detection of ectopic gene activations reveals a source of potential cancer biomarkers and correlates with aggressive metastasis-prone lung tumors. In the Wrong Place and at the Wrong Time As an old saying goes, there is a time and a place for everything, including gene expression. Unfortunately, cancer cells are not bound by such conventional wisdom. Now, Rousseaux and co-authors show just how problematic lung cancers can be when they turn on the expression of genes that are normally reserved for the placenta and testes. The authors systematically characterized gene expression in 1776 human tumors from 14 different types of cancer, comparing them to normal samples from a variety of organs. They demonstrated that a subset of genes, called testis-specific/placenta-specific (TS/PS) genes, which are normally active only in the testes or placenta, respectively, was not expressed in any other normal organs. In most of the tumors, however, the TS/PS genes were actively expressed. The authors linked this observation to demethylation of the promoters for TS/PS genes in cancer cells. In a separate series of 293 lung cancer patients at all stages of disease, the authors identified 26 TS/PS genes and showed that expression of these genes strongly correlated with worse prognosis independent of cancer stage. Future work may replicate these prognostic findings in additional cancer types because experiments from the current study showed evidence of TS/PS gene expression in a variety of different tumors. Additional studies will be needed to validate the TS/PS gene signature in lung cancer and clarify its implications for patient treatment. Someday, with more sophisticated targeted therapies, we may yet be able to teach cancer cells that the adult lung is not the proper time and place for expression of TS/PS genes. Activation of normally silent tissue-specific genes and the resulting cell “identity crisis” are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale “off-context” gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature–guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.

Association between hypernatraemia acquired in the ICU and mortality: a cohort study

BACKGROUNDnThe aim of this study is to describe the prevalence and outcomes of intensive care unit (ICU)-acquired hypernatraemia (IAH).nnnMETHODSnA retrospective analysis was performed on a prospectively collected database fed by 12 ICUs. Subjects are unselected patients with ICU stay >48 h. Mild and moderate to severe hypernatraemia were defined as serum sodium >145 and >150 mmol/L, respectively. IAH was hypernatraemia occurring >or=24 h after ICU admission in patients with normal serum sodium at ICU admission.nnnRESULTSnOf the 8441 patients, 301 were excluded because they had hypernatraemia at ICU admission. Of the remaining 8140 patients, 901 (11.1%) experienced mild hypernatraemia, and 344 (4.2%) experienced moderate to severe hypernatraemia. Factors independently associated with IAH were male gender, severity at admission as assessed by the Simplified Acute Physiology Score version II (SAPS II), and organ failure or life-supporting treatment at ICU admission. Unadjusted hospital mortality was 15.2% in patients without hypernatraemia compared to 29.5% in patients with mild IAH and 46.2% in those with moderate to severe IAH (P < 0.0001). When any degree of IAH was handled as a time-dependent variable in a subdistribution hazard model, the subdistribution hazard ratio (SHR) for ICU mortality was 4.26 [95% confidence interval (CI), 3.74-4.84]. After stratification by centre and adjustment for confounders, both mild IAH and moderate to severe IAH were independently associated with mortality [SHR 2.03 (95% CI 1.73-2.39) and 2.67 (95% CI 2.19-3.26), respectively].nnnCONCLUSIONnIAH is frequent and associated with mortality after adjustment on severity at ICU admission.

Skin antisepsis with chlorhexidine–alcohol versus povidone iodine–alcohol, with and without skin scrubbing, for prevention of intravascular-catheter-related infection (CLEAN): an open-label, multicentre, randomised, controlled, two-by-two factorial trial

BACKGROUNDnIntravascular-catheter-related infections are frequent life-threatening events in health care, but incidence can be decreased by improvements in the quality of care. Optimisation of skin antisepsis is essential to prevent short-term catheter-related infections. We hypothesised that chlorhexidine-alcohol would be more effective than povidone iodine-alcohol as a skin antiseptic to prevent intravascular-catheter-related infections.nnnMETHODSnIn this open-label, randomised controlled trial with a two-by-two factorial design, we enrolled consecutive adults (age ≥18 years) admitted to one of 11 French intensive-care units and requiring at least one of central-venous, haemodialysis, or arterial catheters. Before catheter insertion, we randomly assigned (1:1:1:1) patients via a secure web-based random-number generator (permuted blocks of eight, stratified by centre) to have all intravascular catheters prepared with 2% chlorhexidine-70% isopropyl alcohol (chlorhexidine-alcohol) or 5% povidone iodine-69% ethanol (povidone iodine-alcohol), with or without scrubbing of the skin with detergent before antiseptic application. Physicians and nurses were not masked to group assignment but microbiologists and outcome assessors were. The primary outcome was the incidence of catheter-related infections with chlorhexidine-alcohol versus povidone iodine-alcohol in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01629550 and is closed to new participants.nnnFINDINGSnBetween Oct 26, 2012, and Feb 12, 2014, 2546 patients were eligible to participate in the study. We randomly assigned 1181 patients (2547 catheters) to chlorhexidine-alcohol (594 patients with scrubbing, 587 without) and 1168 (2612 catheters) to povidone iodine-alcohol (580 patients with scrubbing, 588 without). Chlorhexidine-alcohol was associated with lower incidence of catheter-related infections (0·28 vs 1·77 per 1000 catheter-days with povidone iodine-alcohol; hazard ratio 0·15, 95% CI 0·05-0·41; p=0·0002). Scrubbing was not associated with a significant difference in catheter colonisation (p=0·3877). No systemic adverse events were reported, but severe skin reactions occurred more frequently in those assigned to chlorhexidine-alcohol (27 [3%] patients vs seven [1%] with povidone iodine-alcohol; p=0·0017) and led to chlorhexidine discontinuation in two patients.nnnINTERPRETATIONnFor skin antisepsis, chlorhexidine-alcohol provides greater protection against short-term catheter-related infections than does povidone iodine-alcohol and should be included in all bundles for prevention of intravascular catheter-related infections.nnnFUNDINGnUniversity Hospital of Poitiers, CareFusion.

Noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes

PurposeNoninvasive ventilation (NIV) had proven benefits in clinical trials that included selected patients admitted to highly skilled centers. Whether these benefits apply to every patient and in everyday practice deserves appraisal. The aim of the study was to assess the use and outcomes of NIV over the last 15xa0years.MethodsMulticenter database study of critically ill patients who required ventilatory support for acute respiratory failure between 1997 and 2011. The impact of first-line NIV on 60-day mortality was evaluated using a marginal structural model. Follow-up was censored on day 60.ResultsOf 3,163 patients, 1,232 (39xa0%) received NIV. Over the study period, first-line NIV increased from 29 to 42xa0%, and NIV success rates increased from 69 to 84xa0%. NIV decreased 60-day mortality [adjusted hazard ratio (aHR), 0.75; 95xa0% confidence interval (95xa0% CI), 0.68–0.83; Pxa0<xa00.0001]. This protective effect was observed in patients with acute-on-chronic respiratory failure (aHR, 0.71; 95xa0% CI, 0.57–0.90; Pxa0=xa00.004), but not in patients with cardiogenic pulmonary edema (aHR, 0.85; 95xa0% CI, 0.70–1.03; Pxa0=xa00.10) or in patients with hypoxemic ARF, either immunocompetent (aHR, 1.18; 95xa0% CI, 0.87–1.59; Pxa0=xa00.30) or immunocompromised (aHR, 0.89; 95xa0% CI, 0.70–1.13; Pxa0=xa00.35). NIV failure was an independent time-dependent risk factor for mortality (aHR, 4.2; 95xa0% CI, 2.8–6.2; Pxa0<xa00.0001).ConclusionsThe use of NIV increased steadily over the study period. First-line NIV was associated with better 60-day survival and fewer ICU-acquired infections compared to first-line intubation. Survival benefits from NIV occurred only in patients with acute-on-chronic respiratory failure and immunocompromised patients.

Prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change

IntroductionTo assess the prevalence of dysnatremia, including borderline changes in serum sodium concentration, and to estimate the impact of these dysnatremia on mortality after adjustment for confounders.MethodsObservational study on a prospective database fed by 13 intensive care units (ICUs). Unselected patients with ICU stay longer than 48 h were enrolled over a 14-year period were included in this study. Mild to severe hyponatremia were defined as serum sodium concentration < 135, < 130, and < 125 mmol/L respectively. Mild to severe hypernatremia were defined as serum sodium concentration > 145, > 150, and > 155 mmol/L respectively. Borderline hyponatremia and hypernatremia were defined as serum sodium concentration between 135 and 137 mmol/L or 143 and 145 respectively.ResultsA total of 11,125 patients were included in this study. Among these patients, 3,047 (27.4%) had mild to severe hyponatremia at ICU admission, 2,258 (20.3%) had borderline hyponatremia at ICU admission, 1,078 (9.7%) had borderline hypernatremia and 877 (7.9%) had mild to severe hypernatremia. After adjustment for confounder, both moderate and severe hyponatremia (subdistribution hazard ratio (sHR) 1.82, 95% CI 1.002 to 1.395 and 1.27, 95% CI 1.01 to 1.60 respectively) were associated with day-30 mortality. Similarly, mild, moderate and severe hypernatremia (sHR 1.34, 95% CI 1.14 to 1.57; 1.51, 95% CI 1.15 to 1.99; and 2.64, 95% CI 2.00 to 3.81 respectively) were independently associated with day-30 mortality.ConclusionsOne-third of critically ill patients had a mild to moderate dysnatremia at ICU admission. Dysnatremia, including mild changes in serum sodium concentration, is an independent risk factor for hospital mortality and should not be neglected.

A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit

Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.

Impact of antifungal prescription on relative distribution and susceptibility of Candida spp. – Trends over 10 years

INTRODUCTIONnThe incidence of Candida spp. infections is worrisome, particularly in critically ill patients. Previous reports suggested that increasing use of antifungal therapy might affect resistance profiles of invasive strains. The study objective was to describe the distribution resistance profile of Candida spp. strains, and to correlate it with antifungal consumptions within one ICU.nnnMETHODnAntifungal drug consumption was measured as the number of defined daily doses per 1000 hospital days. The distribution of Candida spp. over a 10 year period 2004-2013 and the MICs of antifungal drugs over 2007-2013 were determined. Time series analyses were performed.nnnRESULTSnOf 2403 identified Candida spp. from 5360 patients, Candida albicans predominated (53.1%), followed by Candida glabrata (16.2%), Candida parapsilosis (7.9%) and Candida tropicalis (7.5%). C. parapsilosis increased from 5.7% in 2004 to 8.4% in 2013 (Pxa0=xa00.02). The increase in caspofungin use is correlated with the increase in caspofungin MICs of C. parapsilosis (Pxa0=xa00.01), C. glabrata (Pxa0=xa00.001) and C. albicans (Pxa0=xa00.02). Polyenes consumption correlated with an increase in amphotericin B MICs of C. glabrata (Pxa0=xa00.04).nnnCONCLUSIONnPrevious history of antifungal prescription within an ICU influences Candida species distribution and susceptibility profile to antifungal agents. The significant selective pressure exerted by caspofungin and amphotericin B on C. glabrata is a concern.

The ADMIN-ICU survey: a survey on antimicrobial dosing and monitoring in ICUs

OBJECTIVESnThere is little evidence and few guidelines to inform the most appropriate dosing and monitoring for antimicrobials in the ICU. We aimed to survey current practices around the world.nnnMETHODSnAn online structured questionnaire was developed and sent by e-mail to obtain information on local antimicrobial prescribing practices for glycopeptides, piperacillin/tazobactam, carbapenems, aminoglycosides and colistin.nnnRESULTSnA total of 402 professionals from 328 hospitals in 53 countries responded, of whom 78% were specialists in intensive care medicine (41% intensive care, 30% anaesthesiology, 14% internal medicine) and 12% were pharmacists. Vancomycin was used as a continuous infusion in 31% of units at a median (IQR) daily dose of 25 (25-30) mg/kg. Piperacillin/tazobactam was used as an extended infusion by 22% and as a continuous infusion by 7%. An extended infusion of carbapenem (meropenem or imipenem) was used by 27% and a continuous infusion by 5%. Colistin was used at a daily dose of 7.5 (3.9-9) million IU (MIU)/day, predominantly as a short infusion. The most commonly used aminoglycosides were gentamicin (55%) followed by amikacin (40%), with administration as a single daily dose reported in 94% of the cases. Gentamicin was used at a daily dose of 5 (5-6) mg/day and amikacin at a daily dose of 15 (15-20) mg/day. Therapeutic drug monitoring of vancomycin, piperacillin/tazobactam and meropenem was used by 74%, 1% and 2% of the respondents, respectively. Peak aminoglycoside concentrations were sampled daily by 28% and trough concentrations in all patients by 61% of the respondents.nnnCONCLUSIONSnWe found wide variability in reported practices for antibiotic dosing and monitoring. Research is required to develop evidence-based guidelines to standardize practices.

Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data

PurposeSystemic antifungal therapy (SAT) of invasive candidiasis needs to be initiated immediately upon clinical suspicion. Controversies exist about adequate time and potential harm of antifungal de-escalation (DE) in documented and suspected candidiasis in ICU patients. Our objective was to investigate whether de-escalation within 5xa0days of antifungal initiation is associated with an increase of the 28-day mortality in SAT-treated non-neutropenic adult ICU patients.MethodsFrom the 835 non-neutropenic adults recruited in the multicenter prospective observational AmarCAND2 study, we selected the patients receiving systemic antifungal therapy for a documented or suspected invasive candidiasis in the ICU and who were still alive 5xa0days after SAT initiation. They were included into two groups according to the occurrence of observed SAT de-escalation before dayxa06. The average causal SAT de-escalation effect on 28-day mortality was evaluated by using a double robust estimation.ResultsAmong the 647 included patients, early de-escalation at dayxa05 after antifungal initiation occurred in 142 patients (22xa0%), including 48 (34xa0%) patients whose SAT was stopped before dayxa06. After adjustment for the baseline confounders, early SAT de-escalation was the solely factor not associated with increased 28-day mortality (RR 1.12, 95xa0% CI 0.76–1.66).ConclusionIn non-neutropenic critically ill adult patients with documented or suspected invasive candidiasis, SAT de-escalation within 5xa0days was not related to increased day-28 mortality but it was associated with decreased SAT consumption. These results suggest for the first time that SAT de-escalation may be safe in these patients.

Severe Hypothermia Increases the Risk for Intensive Care Unit–Acquired Infection

BACKGROUNDnAlthough hypothermia is widely accepted as a risk factor for subsequent infection in surgical patients, it has not been well defined in medical patients. We sought to assess the risk of acquiring intensive care unit (ICU)--acquired infection after hypothermia among medical ICU patients.nnnMETHODSnAdults (≥18 years) admitted to French ICUs for at least 2 days between April 2000 and November 2010 were included. Surgical patients were excluded. Patient were classified as having had mild hypothermia (35.0°C-35.9°C), moderate hypothermia (32°C-34.9°C), or severe hypothermia (<32°C), and were followed for the development of pneumonia or bloodstream infection until ICU discharge.nnnRESULTSnA total of 6237 patients were included. Within the first day of admission, 648 (10%) patients had mild hypothermia, 288 (5%) patients had moderate hypothermia, and 45 (1%) patients had severe hypothermia. Among the 5256 patients who did not have any hypothermia at day 1, subsequent hypothermia developed in 868 (17%), of which 673 (13%), 176 (3%), and 19 (<1%) patients had lowest temperatures of 35.0°C-35.9°C, 32.0°C-34.9°C, and <32°C, respectively. During the course of ICU admission, 320 (5%) patients developed ICU-acquired bloodstream infection and 724 (12%) patients developed ICU-acquired pneumonia. After controlling for confounding variables in multivariable analyses, severe hypothermia was found to increase the risk for subsequent ICU-acquired infection, particularly in patients who did not present with severe sepsis or septic shock.nnnCONCLUSIONSnThe presence of severe hypothermia is a risk factor for development of ICU-acquired infection in medical patients.