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1.  Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial 
Meta-analyses of nonrandomized studies have provided conflicting data on therapeutic hypothermia, or targeted temperature management (TTM), at 33°C in patients successfully resuscitated after nonshockable cardiac arrest. Nevertheless, the latest recommendations issued by the International Liaison Committee on Resuscitation and by the European Resuscitation Council recommend therapeutic hypothermia. New data are available on the adverse effects of therapeutic hypothermia, notably infectious complications. The risk/benefit ratio of therapeutic hypothermia after nonshockable cardiac arrest is unclear.
HYPERION is a multicenter (22 French ICUs) trial with blinded outcome assessment in which 584 patients with successfully resuscitated nonshockable cardiac arrest are allocated at random to either TTM between 32.5 and 33.5°C (therapeutic hypothermia) or TTM between 36.5 and 37.5°C (therapeutic normothermia) for 24 hours. Both groups are managed with therapeutic normothermia for the next 24 hours. TTM is achieved using locally available equipment. The primary outcome is day-90 neurological status assessed by the Cerebral Performance Categories (CPC) Scale with dichotomization of the results (1 + 2 versus 3 + 4 + 5). The primary outcome is assessed by a blinded psychologist during a semi-structured telephone interview of the patient or next of kin. Secondary outcomes are day-90 mortality, hospital mortality, severe adverse events, infections, and neurocognitive performance. The planned sample size of 584 patients will enable us to detect a 9% absolute difference in day-90 neurological status with 80% power, assuming a 14% event rate in the control group and a two-sided Type 1 error rate of 4.9%. Two interim analyses will be performed, after inclusion of 200 and 400 patients, respectively.
The HYPERION trial is a multicenter, randomized, controlled, assessor-blinded, superiority trial that may provide an answer to an issue of everyday relevance, namely, whether TTM is beneficial in comatose patients resuscitated after nonshockable cardiac arrest. Furthermore, it will provide new data on the tolerance and adverse events (especially infectious complications) of TTM at 32.5-33.5°C.
Trial registration NCT01994772.
PMCID: PMC4353458  PMID: 25882712
Cardiac arrest; Therapeutic hypothermia; Nonshockable rhythm
2.  Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: a prospective multicentre study 
Critical Care  2014;18(6):609.
In septic shock patients, the prevalence of low (<70%) central venous oxygen saturation (ScvO2) on admission to the intensive care unit (ICU) and its relationship to outcome are unknown. The objectives of the present study were to estimate the prevalence of low ScvO2 in the first hours of ICU admission and to assess its potential association with mortality in patients with severe sepsis or septic shock.
This was a prospective, multicentre, observational study conducted over a one-year period in ten French ICUs. Clinicians were asked to include patients with severe sepsis or septic shock preferably within 6 hours of ICU admission and as soon as possible without changing routine practice. ScvO2 was measured at inclusion and 6 hours later (H6), by blood sampling.
We included 363 patients. Initial ScvO2 below 70% was present in 111 patients and the pooled estimate for its prevalence was 27% (95% Confidence interval (95%CI): 18% to 37%). At time of inclusion, among 166 patients with normal lactate concentration (≤2 mmol/L), 55 (33%) had a low initial ScvO2 (<70%), and among 136 patients who had already reached the classic clinical endpoints for mean arterial pressure (≥65 mmHg), central venous pressure (≥8 mmHg), and urine output (≥0.5 mL/Kg of body weight), 43 (32%) had a low initial ScvO2 (<70%). Among them, 49% had lactate below 2 mmol/L. The day-28 mortality was higher in case of low initial ScvO2 (37.8% versus 27.4%; P = 0.049). When adjusted for confounders including the Simplified Acute Physiology Score and initial lactate concentration, a low initial ScvO2 (Odds ratio (OR) = 3.60, 95%CI: 1.76 to 7.36; P = 0.0004) and a low ScvO2 at H6 (OR = 2.18, 95%CI: 1.12 to 4.26; P = 0.022) were associated with day-28 mortality by logistic regression.
Low ScvO2 was common in the first hours of admission to the ICU for severe sepsis or septic shock even when clinical resuscitation endpoints were achieved and even when arterial lactate was normal. A ScvO2 below 70% in the first hours of ICU admission and six hours later was associated with day-28 mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0609-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4265332  PMID: 25529124
3.  Role of biomarkers in the management of antibiotic therapy: an expert panel review: I – currently available biomarkers for clinical use in acute infections 
In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, suPAR, ProADM, and Presepsin. New approaches to biomarkers of infections include point-of-care testing and genomics.
PMCID: PMC3708786  PMID: 23837559
Infection; Sepsis; Emergency medicine; Biomarkers; Procalcitonin; C-reactive protein; sTREM-1; suPAR; proADM; Presepsin
4.  Role of biomarkers in the management of antibiotic therapy: an expert panel review II: clinical use of biomarkers for initiation or discontinuation of antibiotic therapy 
Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest®; a single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has been obtained. For ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is < 0.5 ng/mL or has decreased by >80% relative to the highest level recorded, irrespective of the severity of the infectious episode; in bacteremic patients, a minimal duration of therapy of 5 days is recommended.
PMCID: PMC3716933  PMID: 23830525
Infection; Sepsis; Emergency medicine; Biomarkers; Procalcitonin; C-reactive protein; Pancreatitis; Meningitis; Pneumonia
5.  Suffering among carers working in critical care can be reduced by an intensive communication strategy on end-of-life practices 
Intensive Care Medicine  2011;38(1):55-61.
Burn-out syndrome (BOS) has frequently been reported in healthcare workers, and precipitating factors include communication problems in the workplace, and stress related to end-of-life situations. We evaluated the effect of an intensive communication strategy on BOS among caregivers working in intensive care (ICU).
Longitudinal, monocentric, before-and-after, interventional study. BOS was evaluated using the Maslach Burnout Inventory (MBI) and depression using the Centre for Epidemiologic Studies Depression Scale (CES-D) in 2007 (period 1) and 2009 (period 2). Between periods, an intensive communication strategy on end-of-life practices was implemented, based on improved organisation, better communication, and regular staff meetings.
Among 62 caregivers in the ICU, 53 (85%) responded to both questionnaires in period 1 and 49 (79%) in period 2. We observed a significant difference between periods in all three components of the MBI (emotional exhaustion, p=0.04; depersonalization p=0.04; personal accomplishment, p=0.01). MBI classified burnout as severe in 15 (28%) caregivers in period 1 vs 7 (14%) in period 2, p<0.01, corresponding to a 50% risk reduction. Symptoms of depression as evaluated by the CES-D were present in 9 (17%) caregivers in period 1 vs 3 (6%) in period 2, p<0.05, corresponding to a risk reduction of almost 60%.
The implementation of an active, intensive communication strategy regarding end-of-life care in the ICU was associated with a significant reduction in the rate of burn-out syndrome and depression in a stable population of caregiving staff.
PMCID: PMC3678991  PMID: 22127481
Adult; Female; France; Hospitals, University; Humans; Intensive Care Units; Interdisciplinary Communication; Male; Medical Staff, Hospital; psychology; Middle Aged; Questionnaires; Stress, Psychological; prevention & control; Terminal Care; Young Adult; ethics; critical care organisation; communication
6.  Impact of an intensive communication strategy on end-of-life practices in the intensive care unit 
Intensive Care Medicine  2011;38(1):145-152.
Since the 2005 French law on end of life and patients’ rights, it is unclear whether practices have evolved. We investigated whether an intensive communication strategy based on this law would influence practices in terms of withholding and withdrawing treatment (WWT), and outcome of patients hospitalised in intensive care (ICU).
Single-centre two-period study, before and after the law. Between periods, an intensive strategy for communication was developed and implemented, comprising regular meetings and modalities for WWT. We examined medical records of all patients who died in the ICU or in-hospital during both periods.
In total, out of 2478 patients admitted in period 1, 678(31%) died in ICU and 823/2940 (28%) in period 2. In period 1, among patients who died in ICU, 45% died further to a decision to WWT vs 85% in period 2 (p<0.01). Among these, median time delay between ICU admission and initiation of decision-making process was significantly different (6–7 days in period 1 vs 3–5 days in period 2, p<0.05). Similarly, median time from admission to actual WWT decision was significantly shorter in period 2 (11–13 days in period 1 vs 4–6 days in period 2, p<0.05). Finally, median time from admission to death in ICU further to a decision to WWT was 13–15 days in period 1 vs 7–8 days in period 2, p<0.05. Reasons for WWT were not significantly different between periods.
Intensive communication brings about quicker end-of-life decision-making in the ICU. The new law has the advantage of providing a legal framework.
PMCID: PMC3385851  PMID: 22127479
7.  Pulse Wave Transit Time Measurements of Cardiac Output in Septic Shock Patients: A Comparison of the Estimated Continuous Cardiac Output System with Transthoracic Echocardiography 
PLoS ONE  2015;10(6):e0130489.
We determined reliability of cardiac output (CO) measured by pulse wave transit time cardiac output system (esCCO system; COesCCO) vs transthoracic echocardiography (COTTE) in mechanically ventilated patients in the early phase of septic shock. A secondary objective was to assess ability of esCCO to detect change in CO after fluid infusion.
Mechanically ventilated patients admitted to the ICU, aged >18 years, in sinus rhythm, in the early phase of septic shock were prospectively included. We performed fluid infusion of 500ml of crystalloid solution over 20 minutes and recorded CO by EsCCO and TTE immediately before (T0) and 5 minutes after (T1) fluid administration. Patients were divided into 2 groups (responders and non-responders) according to a threshold of 15% increase in COTTE in response to volume expansion.
In total, 25 patients were included, average 64±15 years, 15 (60%) were men. Average SAPSII and SOFA scores were 55±21.3 and 13±2, respectively. ICU mortality was 36%. Mean cardiac output at T0 was 5.8±1.35 L/min by esCCO and 5.27±1.17 L/min by COTTE. At T1, respective values were 6.63 ± 1.57 L/min for esCCO and 6.10±1.29 L/min for COTTE. Overall, 12 patients were classified as responders, 13 as non-responders by the reference method. A threshold of 11% increase in COesCCO was found to discriminate responders from non-responders with a sensitivity of 83% (95% CI, 0.52-0.98) and a specificity of 77% (95% CI, 0.46-0.95).
We show strong correlation esCCO and echocardiography for measuring CO, and change in CO after fluid infusion in ICU patients.
PMCID: PMC4488420  PMID: 26126112
8.  Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2) 
Trials  2014;15:507.
Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock.
The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs.
The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015.
Trial registration Identifier: NCT01802099 (registered 27 February 2013)
PMCID: PMC4307984  PMID: 25539571
Critical illness; Enteral nutrition; Mechanical ventilation; Mortality; Nosocomial infection; Parenteral nutrition; Shock; Vasoactive drugs
9.  Comparison of heparin to citrate as a catheter locking solution for non-tunneled central venous hemodialysis catheters in patients requiring renal replacement therapy for acute renal failure (VERROU-REA study): study protocol for a randomized controlled trial 
Trials  2014;15:449.
The incidence of acute kidney injury (AKI) is estimated at 10 to 20% in patients admitted to intensive care units (ICU) and often requires renal replacement therapy (RRT). ICU mortality in AKI patients can exceed 50%. Venous catheters are the preferred vascular access method for AKI patients requiring RRT, but carry a risk of catheter thrombosis or infection. Catheter lock solutions are commonly used to prevent such complications. Heparin and citrate locks are both widely used for tunneled, long-term catheters, but few studies have compared citrate versus heparin for patients with short-term, non-tunneled catheters. We aim to compare citrate 4% catheter lock solution versus heparin in terms of event-free survival of the first non-tunneled hemodialysis catheter inserted in ICU patients with AKI requiring RRT. Secondary objectives are the rate of fibrinolysis, incidence of catheter thrombosis and catheter-related infection per 1,000 catheter days, length of stay in ICU and in-hospital and 28-day mortality.
The VERROU-REA study is a randomized, prospective, multicenter, double-blind, parallel-group, controlled superiority study carried out in the medical, surgical and nephrological ICUs of two large university hospitals in eastern France. A catheter lock solution composed of trisodium citrate at 4% will be compared to unfractionated heparin at a concentration of 5,000 IU/mL. All consecutive adult patients with AKI requiring extracorporeal RRT, and in whom a first non-tunneled catheter is to be inserted by the jugular or femoral approach, will be eligible. Catheters inserted by the subclavian approach, patients with acute liver failure, thrombopenia or contraindication to systemic anticoagulation will be excluded. Patients will be followed up daily in accordance with standard practices for RRT until death or discharge.
Data is scarce regarding the use of non-tunneled catheters in the ICU setting in patients with AKI. This study will provide an evidence base for recommendations regarding the use of anticoagulant catheter locks for the prevention of dysfunction in non-tunneled hemodialysis catheters in patients with AKI in critical or intensive care.
Trial registration
Registered with (registration number: NCT01962116) on 27 August 2013.
PMCID: PMC4289224  PMID: 25409678
Citrate lock; Heparin lock; Catheter lock; Acute renal failure; Hemodialysis; Critically ill patient
10.  Mechanisms and etiologies of thrombocytopenia in the intensive care unit: impact of extensive investigations 
Thrombocytopenia is common in the intensive care unit. Potential mechanisms and etiologies behind this phenomenon are multiple and often entangled. We assessed the effect of a systematic approach, using routinely available tests, on the proportion of patients in whom the mechanism (primary objective) and etiology (secondary objective) of thrombocytopenia in a mixed intensive care unit (ICU) could be identified.
Before-and-after study of all patients with thrombocytopenia was used. ‘Before’ group had no intervention. New standard operating procedures for thrombocytopenia management were introduced. In the ‘After’ group, bone marrow aspiration; determination of fibrinogen dosage, prothrombin time, factor V, D-dimers; assay of fibrin monomers, ferritin, triglycerides, lactic acid dehydrogenase, aspartate transaminase, alanine aminotransferase, vitamin B12, folates, reticulocytes, haptoglobin, and bilirubin were performed.
In the Before group (n = 20), the mechanism (central, peripheral, or mixed) was identified in 10 % versus 83% in After group (n = 23) (p < 0.001) (48% peripheral, 35% mixed). Before intervention, ≥1 etiology was identified in 15% versus 95.7% in the After group (p < 0.001).
Systematic and extensive investigation using routine tests highlights the mechanisms and etiology of thrombocytopenia in most cases.
PMCID: PMC4273722  PMID: 25593741
Thrombocytopenia; Intensive care unit; Bone marrow aspiration
11.  Empirical antifungal therapy with an echinocandin in critically-ill patients: prospective evaluation of a pragmatic Candida score-based strategy in one medical ICU 
BMC Infectious Diseases  2014;14:385.
Invasive candidiasis (IC) is a life-threatening ICU-acquired infection. A strong correlation between time to antifungal therapy (AFT) administration and outcome has been established. Empirical therapy benefit should be balanced with the risk of echinocandin overuse. We assessed therefore a decision rule that aimed at guiding empirical therapy.
A 45-month prospective cohort study in a teaching medical ICU. All of the patients with suspected IC (uncontrolled sepsis despite broad spectrum antibiotics without any bacterial proven infection in patients with Candida score ≥ 3 points including multifocal Candida sp. colonization) were eligible. The primary endpoint was proven IC diagnosis (i.e., candidemia) following treatment onset. Timing of AFT administration was also investigated in those latter patients. Antifungal therapy step-down and discontinuation was done according to international guidelines in patients with candidemia. Otherwise, echinocandin discontinuation was encouraged in patients without proven IC, excepting when a clinical improvement was achieved without any other explanation that antifungals initiation (i.e., probable IC). In addition, a survival multivariate analysis using a Cox model was conducted.
Fifty-one patients were given an echinocandin with respect to our decision rule. Among them, candidemia was diagnosed thereafter in 9 patients. Over the same period, antifungal therapy was triggered by candidemia announcement (i.e., definite therapy) in 12 patients who did not fulfill criteria for empirical therapy before. Time elapsed from candidemia onset to echinocandin therapy initiation was shortened (0.4 [0.5] vs. 2.4 [2.8] hours; p = 0.04) when it was given empirically. In addition, 18 patients clinically improved under empirical antifungal therapy without any obvious other explanation, despite IC remained unproven. Moreover, echinocandin exposure duration was independently related to survival in those patients. Over the same period, our predefined criteria for empirical therapy were overruled in 55 cases. None of them develop IC thereafter. Finally, Our decision rule allowed IC early recognition of proven/probable IC with sensitivity, specificity, positive and negative predictive value of 69.2%, 82.1%, 69.2% and 82.1%, respectively.
Implementation of pragmatic guidelines for empirical AFT based on CS and fungal colonization assessment could be useful in selecting patients who really benefit from an echinocandin.
PMCID: PMC4227296  PMID: 25015848
Invasive candidiasis; Candidemia; Candida sp; Sepsis; Echinocandin; Nosocomial infection
12.  Impact on mortality of the timing of renal replacement therapy in patients with severe acute kidney injury in septic shock: the IDEAL-ICU study (initiation of dialysis early versus delayed in the intensive care unit): study protocol for a randomized controlled trial 
Trials  2014;15:270.
One of the most dreaded complications of septic shock is acute kidney injury. It occurs in around 50% of patients, with a mortality rate of about 60% at 3 months. There is no consensus on the optimal time to initiate renal replacement therapy. Retrospective and observational studies suggest that early implementation of renal replacement therapy could improve the prognosis for these patients.
This protocol summarizes the rationale and design of a randomized, controlled, multicenter trial investigating the effect of early versus delayed renal replacement therapy in patients with severe acute kidney injury in early septic shock. In total, 864 critically ill adults with septic shock and evidence of acute kidney injury, defined as the failure stage of the RIFLE classification, will be enrolled. The primary outcome is mortality at 90 days. Secondary outcomes include safety, number of days free of mechanical ventilation, number of days free of renal replacement therapy, intensive care length of stay, in-hospital length of stay, quality of life as evaluated by the EQ-5D and renal replacement therapy dependence at hospital discharge. The primary analysis will be intention to treat. Recruitment started in March 2012 and will be completed by March 2015.
This protocol for a randomized controlled study investigating the impact of the timing of renal replacement therapy initiation should provide an answer to a key question for the management of patients with acute kidney injury in the context of septic shock, for whom the mortality rate remains close to 60% despite improved understanding of physiopathology and recent therapeutic advances.
Trial registration identifier NCT01682590, registered on 10 September 2012.
PMCID: PMC4226975  PMID: 24998258
severe acute kidney injury; septic shock; renal replacement therapy; intensive care
13.  Impact of prior statin therapy on the outcome of patients with suspected ventilator-associated pneumonia: an observational study 
Critical Care  2014;18(2):R83.
Ventilator-associated pneumonia (VAP) is the most commonly acquired infection in intensive care units (ICU). Its outcome is related, at least in part, to the host’s response. Statins have anti-inflammatory effects and may thus improve the outcome. We aimed to assess the impact of prior statin use in the setting of VAP.
A six-year cohort study was conducted in a French ICU at a teaching hospital. All of the patients with suspected VAP were included. Baseline characteristics, outcomes, statin exposure, and the description of suspected episodes were collected prospectively. The primary endpoint was 30-day mortality. Patients who were taking statins before admission to the ICU whether or not treatment was continued thereafter (‘previous users’ group) were compared to those without prior statin therapy (‘statin-naive’ group). A survival analysis using a Cox model was conducted in the whole cohort and in the subgroup of prior statin users.
Among the 349 patients included, 93 (26.6%) had taken statins. At baseline, these patients were at higher risk of complications than statin-naive ones (for example, older, more likely to be men and to have underlying diseases, greater simplified acute physiology score II (SAPS II)). There was, however, no difference regarding severity at the time VAP was suspected (sequential organ failure assessment (SOFA): 9.0 (4.0 to 16.0) versus 8.0 (4.0 to 17.0); P = 0.11). Nonetheless, 30-day mortality in statin users was not different from that in statin-naive patients (35.5% versus 26.2%, respectively; adjusted hazard ratio (HR) = 1.23 (0.79 to 1.90) 95% confidence interval (CI); P = 0.36). In contrast, after limiting analysis to prior statin users and adjusting for potential confounders, those who continued the treatment had better survival than those who did not (HR = 0.47; (0.22 to 0.97) 95% CI; P = 0.04).
Statin continuation in prior users could provide protective effects in patients with suspected VAP.
PMCID: PMC4075255  PMID: 24774941
14.  The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study 
Critical Care  2013;17(2):R65.
To provide up-to-date information on the prognostic factors associated with 28-day mortality in a cohort of septic shock patients in intensive care units (ICUs).
Prospective, multicenter, observational cohort study in ICUs from 14 French general (non-academic) and university teaching hospitals. All consecutive patients with septic shock admitted between November 2009 and March 2011 were eligible for inclusion. We prospectively recorded data regarding patient characteristics, infection, severity of illness, life support therapy, and discharge.
Among 10,941 patients admitted to participating ICUs between October 2009 and September 2011, 1,495 (13.7%) patients presented inclusion criteria for septic shock and were included. Invasive mechanical ventilation was needed in 83.9% (n = 1248), inotropes in 27.7% (n = 412), continuous renal replacement therapy in 32.5% (n = 484), and hemodialysis in 19.6% (n = 291). Mortality at 28 days was 42% (n = 625). Variables associated with time to mortality, right-censored at day 28: age (for each additional 10 years) (hazard ratio (HR) = 1.29; 95% confidence interval (CI): 1.20-1.38), immunosuppression (HR = 1.63; 95%CI: 1.37-1.96), Knaus class C/D score versus class A/B score (HR = 1.36; 95%CI:1.14-1.62) and Sepsis-related Organ Failure Assessment (SOFA) score (HR = 1.24 for each additional point; 95%CI: 1.21-1.27). Patients with septic shock and renal/urinary tract infection had a significantly longer time to mortality (HR = 0.56; 95%CI: 0.42-0.75).
Our observational data of consecutive patients from real-life practice confirm that septic shock is common and carries high mortality in general ICU populations. Our results are in contrast with the clinical trial setting, and could be useful for healthcare planning and clinical study design.
PMCID: PMC4056892  PMID: 23561510
15.  Intrahospital transport of critically ill patients (excluding newborns) recommendations of the Société de Réanimation de Langue Française (SRLF), the Société Française d'Anesthésie et de Réanimation (SFAR), and the Société Française de Médecine d'Urgence (SFMU) 
Critically ill adult patients often require multiple examinations in the hospital and need transport from one department to another, or even between hospitals. However, to date, no guidelines exist regarding optimum practices for transport of these fragile patients. We present recommendations for intrahospital transport of critically ill patients, excluding newborns, developed by an expert group of the French-Language Society of Intensive Care (Société de Réanimation de Langue Française (SRLF), the Société Française d’Anesthésie et de Réanimation (SFAR), and the Société Française de Médecine d’Urgence (SFMU). The recommendations cover five fields of application: epidemiology of adverse events; equipment, monitoring, and maintenance; preparation of patient before transport; human resources and training for caregivers involved in transport processes; and guidelines for planning, structure, and traceability of transport processes.
PMCID: PMC3395853  PMID: 22304940
intrahospital transport; critical care; adults
16.  Bedside adherence to clinical practice guidelines for enteral nutrition in critically ill patients receiving mechanical ventilation: a prospective, multi-centre, observational study 
Critical Care  2010;14(2):R37.
The primary aim was to measure the amount of nutrients required, prescribed and actually administered in critically ill patients. Secondary aims were to assess adherence to clinical practice guidelines, and investigate factors leading to non-adherence.
Observational, multicenter, prospective study, including 203 patients in a total of 19 intensive care units in France. The prescribed calorie supply was compared with the theoretical minimal required calorie intake (25 Kcal/Kg/day) and with the supply actually delivered to the patient to calculate the ratio of calories prescribed/required and the ratio of calories delivered/prescribed. Clinical factors suspected to influence enteral nutrition were analyzed by univariate and multivariate analysis.
The median ratio of prescribed/required calories per day was 43 [37-54] at day 1 and increased until day 7. From day 4 until the end of the study, the median ratio was > 80%. The median ratio of delivered/prescribed per day was > 80% for all 7 days from the start of enteral nutrition. Among the variables tested (hospital type, use of a local nutrition protocol, sedation, vasoactive drugs, number of interruptions of enteral nutrition and measurement of gastric residual volume), only measurement of residual volume was significant by univariate analysis. This was confirmed by multivariate analysis, where gastric residual volume measurement was the only variable independently associated with the ratio of delivered/prescribed calories (OR = 1.38; 95%CI, 1.12-2.10, p = .024).
The translation of clinical research and recommendations for enteral nutrition into routine bedside practice in critically ill patients receiving mechanical ventilation was satisfactory, but could probably be improved with a multidisciplinary approach.
PMCID: PMC2887144  PMID: 20233424
17.  Serum procalcitonin for the early recognition of nosocomial infection in the critically ill patients: a preliminary report 
The usefulness of procalcitonin (PCT) measurement in critically ill medical patients with suspected nosocomial infection is unclear. The aim of the study was to assess PCT value for the early diagnosis of bacterial nosocomial infection in selected critically ill patients.
An observational cohort study in a 15-bed intensive care unit was performed. Seventy patients with either proven (n = 47) or clinically suspected but not confirmed (n = 23) nosocomial infection were included. Procalcitonin measurements were obtained the day when the infection was suspected (D0) and at least one time within the 3 previous days (D-3 to D0). Patients with proven infection were compared to those without. The diagnostic value of PCT on D0 was determined through the construction of the corresponding receiver operating characteristic (ROC) curve. In addition, the predictive value of PCT variations preceding the clinical suspicion of infection was assessed.
PCT on D0 was the best predictor of proven infection in this population of ICU patients with a clinical suspicion of infection (AUROCC = 0.80; 95% CI, 0.68–0.91). Thus, a cut-off value of 0.44 ng/mL provides sensitivity and specificity of 65.2% and 83.0%, respectively. Procalcitonin variation between D-1 and D0 was calculated in 45 patients and was also found to be predictive of nosocomial infection (AUROCC = 0.89; 95% CI, 0.79–0.98) with a 100% positive predictive value if the +0.26 ng/mL threshold value was applied. Comparable results were obtained when PCT variation between D-2 and D0, or D-3 and D0 were considered. In contrast, CRP elevation, leukocyte count and fever had a poor predictive value in our population.
PCT monitoring could be helpful in the early diagnosis of nosocomial infection in the ICU. Both absolute values and variations should be considered and evaluated in further studies.
PMCID: PMC2679028  PMID: 19386110
18.  Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome 
Critical Care  2009;13(2):R38.
Management of the early stage of sepsis is a critical issue. As part of it, infection control including appropriate antibiotic therapy administration should be prompt. However, microbiological findings, if any, are generally obtained late during the course of the disease. The potential interest of procalcitonin (PCT) as a way to assess the clinical efficacy of the empirical antibiotic therapy was addressed in the present study.
An observational cohort study including 180 patients with documented sepsis was conducted in our 15-bed medical intensive care unit (ICU). Procalcitonin measurement was obtained daily over a 4-day period following the onset of sepsis (day 1 (D1) to D4). The PCT time course was analyzed according to the appropriateness of the first-line empirical antibiotic therapy as well as according to the patient outcome.
Appropriate first-line empirical antibiotic therapy (n = 135) was associated with a significantly greater decrease in PCT between D2 and D3 (ΔPCT D2–D3) (-3.9 (35.9) vs. +5.0 (29.7), respectively; P < 0.01). In addition, ΔPCT D2–D3 was found to be an independent predictor of first-line empirical antibiotic therapy appropriateness. In addition, a trend toward a greater rise in PCT between D1 and D2 was observed in patients with inappropriate antibiotics as compared with those with appropriate therapy (+5.2 (47.4) and +1.7 (35.0), respectively; P = 0.20). The D1 PCT level failed to predict outcome, but higher levels were measured in the nonsurvivors (n = 51) when compared with the survivors (n = 121) as early as D3 (40.8 (85.7) and 21.3 (41.0), respectively; P = 0.04). Moreover, PCT kinetics between D2 and D3 were also found to be significantly different, since a decrease ≥ 30% was expected in the survivors (log-rank test, P = 0.04), and was found to be an independent predictor of survival (odds ratio = 2.94; 95% confidence interval 1.22 to 7.09; P = 0.02).
In our study in an ICU, appropriateness of the empirical antibiotic therapy and the overall survival were associated with a greater decline in PCT between D2 and D3. Further studies are needed to assess the utility of the daily monitoring of PCT in addition to clinical evaluation during the early management of sepsis.
PMCID: PMC2689475  PMID: 19291325
19.  Impact of previous sepsis on the accuracy of procalcitonin for the early diagnosis of blood stream infection in critically ill patients 
Blood stream infections (BSI) are life-threatening infections in intensive care units (ICU), and prognosis is highly dependent on early detection. Procalcitonin levels have been shown to accurately and quickly distinguish between BSI and noninfectious inflammatory states in critically ill patients. It is, however, unknown to what extent a recent history of sepsis (namely, secondary sepsis) can affect diagnosis of BSI using PCT.
review of the medical records of every patient with BSI in whom PCT dosage at the onset of sepsis was available between 1st September, 2006 and 31st July, 2007.
179 episodes of either primary (n = 117) or secondary (n = 62) sepsis were included. Procalcitonin levels were found to be markedly lower in patients with secondary sepsis than in those without (6.4 [9.5] vs. 55.6 [99.0] ng/mL, respectively; p < 0.001), whereas the SOFA score was similar in the two groups. Although patients in the former group were more likely to have received steroids and effective antibiotic therapy prior to the BSI episode, and despite a higher proportion of candidemia in this group, a low PCT value was found to be independently associated with secondary sepsis (Odd Ratio = 0.33, 95% Confidence Interval: 0.16–0.70; p = 0.004). Additional patients with suspected but unconfirmed sepsis were used as controls (n = 23). Thus, diagnostic accuracy of PCT as assessed by the area under the receiver-operating characteristic curves (AUROCC) measurement was decreased in the patients with secondary sepsis compared to those without (AUROCC = 0.805, 95% CI: 0.699–0.879, vs. 0.934, 95% CI: 0.881–0.970, respectively; p < 0.050).
In a critically ill patient with BSI, PCT elevation and diagnosis accuracy could be lower if sepsis is secondary than in those with a first episode of infection.
PMCID: PMC2614426  PMID: 19055740
20.  Performance of N-terminal-pro-B-type natriuretic peptide in critically ill patients: a prospective observational cohort study 
Critical Care  2008;12(6):R137.
The purpose of this study was to assess the accuracy of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) as a diagnostic tool to recognize acute respiratory failure of cardiac origin in an unselected cohort of critically ill patients.
We conducted a prospective observational study of medical ICU patients. NT-proBNP was measured at ICU admission, and diagnosis of cardiac dysfunction relied on the patient's clinical presentation and echocardiography.
Of the 198 patients included in this study, 102 (51.5%) had evidence of cardiac dysfunction. Median NT-proBNP concentrations were 5,720 ng/L (1,430 to 15,698) and 854 ng/L (190 to 3,560) in patients with and without cardiac dysfunction, respectively (P < 0.0001). In addition, NT-proBNP concentrations were correlated with age (ρ = 0.43, P < 0.0001) and inversely correlated with creatinine clearance (ρ = -0.58, P < 0.0001). When evaluating the performance of NT-proBNP concentrations to detect cardiac dysfunction, the area under the receiver operating characteristic (ROC) curve was 0.76 (95% confidence interval (CI) 0.69 to 0.83). In addition, a stepwise logistic regression model revealed that NT-proBNP (odds ratio (OR) = 1.01 per 100 ng/L, 95% CI 1.002 to 1.02), electrocardiogram modifications (OR = 11.03, 95% CI 5.19 to 23.41), and severity assessed by organ system failure score (OR = 1.63 per point, 95% CI 1.17 to 2.41) adequately predicted cardiac dysfunction. The area under the ROC curve of this model was 0.83 (95% CI 0.77 to 0.90).
NT-proBNP measured at ICU admission might represent a useful marker to exclude cardiac dysfunction in critically ill patients.
PMCID: PMC2646347  PMID: 18990203
21.  Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either gram negative or gram positive bacteria 
In the ICU, bacteremia is a life-threatening infection whose prognosis is highly dependent on early recognition and treatment with appropriate antibiotics. Procalcitonin levels have been shown to distinguish between bacteremia and noninfectious inflammatory states accurately and quickly in critically ill patients. However, we still do not know to what extent the magnitude of PCT elevation at the onset of bacteremia varies according to the Gram stain result.
Review of the medical records of every patient treated between May, 2004 and December, 2006 who had bacteremia caused by either Gram positive (GP) or Gram negative (GN) bacteria, and whose PCT dosage at the onset of infection was available.
97 episodes of either GN bacteremia (n = 52) or GP bacteremia (n = 45) were included. Procalcitonin levels were found to be markedly higher in patients with GN bacteremia than in those with GP bacteremia, whereas the SOFA score value in the two groups was similar. Moreover, in the study population, a high PCT value was found to be independently associated with GN bacteremia. A PCT level of 16.0 ng/mL yielded an 83.0% positive predictive value and a 74.0% negative predictive value for GN-related bacteremia in the study cohort (AUROCC = 0.79; 95% CI, 0.71–0.88).
In a critically ill patient with clinical sepsis, GN bacteremia could be associated with higher PCT values than those found in GP bacteremia, regardless of the severity of the disease.
PMCID: PMC2289831  PMID: 18366777
22.  Incidence and Predictors of New-Onset Atrial Fibrillation in Septic Shock Patients in a Medical ICU: Data from 7-Day Holter ECG Monitoring 
PLoS ONE  2015;10(5):e0127168.
We investigated incidence, risk factors for new-onset atrial fibrillation (NAF), and prognostic impact during septic shock in medical Intensive Care Unit (ICU) patients.
Prospective, observational study in a university hospital. Consecutive patients from 03/2011 to 05/2013 with septic shock were eligible. Exclusion criteria were age <18 years, history of AF, transfer with prior septic shock. Included patients were equipped with long-duration (7 days) Holter ECG monitoring. NAF was defined as an AF episode lasting >30 seconds. Patient characteristics, infection criteria, cardiovascular parameters, severity of illness, support therapies were recorded.
Among 66 patients, 29(44%) developed NAF; 10 (34%) would not have been diagnosed without Holter ECG monitoring. NAF patients were older, with more markers of heart failure (troponin and NT-pro-BNP), lower left ventricular ejection fraction (LVEF), longer QRS duration and more nonsustained supra ventricular arrhythmias (<30s) on day 1 than patients who maintained sinus rhythm. By multivariate analysis, age (OR: 1.06; p = 0.01) and LVEF<45% (OR: 13.01, p = 0.03) were associated with NAF. NAF did not predict 28 or 90 day mortality.
NAF is common, especially in older patients, and is associated with low ejection fraction. We did not find NAF to be independently associated with higher mortality.
PMCID: PMC4428753  PMID: 25965915
23.  A Leukocyte Score to Improve Clinical Outcome Predictions in Bacteremic Pneumococcal Pneumonia in Adults 
Open Forum Infectious Diseases  2014;1(2):ofu075.
In multivariate analysis, a leukocyte score that adds 1 point each for neutropenia, lymphopenia and monocytopenia was associated with 30-day mortality in 192 patients with bacteremic pneumococcal pneumonia. By reflecting immunoparalysis, this score could improve clinical outcome predictions in BPP.
 Bacteremic pneumococcal pneumonia (BPP) is associated with high and early mortality. A simple procedure to predict mortality is crucial.
 All adult patients with BPP admitted from 2005 through 2013 to the University Hospital of Dijon, France, were enrolled to study 30-day mortality and associated factors, particularly leukocyte counts. A simple leukocyte score was created by adding 1 point each for neutropenia (<1500 cells/mm3), lymphopenia (<400), and monocytopenia (<200).
 One hundred and ninety-two adult patients (mean age, 69 years; standard deviation [SD], 19 years) who had developed and were hospitalized for BPP (58% community-acquired) were included. The 30-day crude mortality rate was 21%. The mean Pneumonia Severity Index score was high at 127.3 (SD = 41.3). Among the 182 patients who had a white blood cell count, 34 (19%) had a high leukocyte score (≥2). Multivariate analysis revealed that mortality was significantly associated with a high leukocyte score (odds ratio, 6.28; 95% confidence interval, 2.35–16.78), a high respiratory rate, a low serum bicarbonate level, and an altered mental status (all P < .05). The leukocyte score was not significantly dependent on the previous state of immunosuppression, alcoholism, or viral coinfection, but it did correlate with an acute respiratory distress syndrome and a low serum bicarbonate level.
 This new leukocyte score, in combination with the well known predictive factors, seems of interest in predicting the risk of death in BPP. A high score correlated with organ dysfunction and probably reflects the level of immunoparalysis. Its predictive value has to be confirmed in other cohorts.
PMCID: PMC4281790  PMID: 25734145
bacteremia; leukocyte; mortality; pneumonia; Streptococcus pneumonia
24.  Post mortem scientific sampling and the search for causes of death in intensive care: what information should be given and what consent should be obtained? 
Journal of Medical Ethics  2010;37(3):132-136.
The search for cause of death is important to improve knowledge and provide answers for the deceased’s relatives. Medical autopsy following unexplained death in hospital is one way to identify cause of death, but difficult to carry out routinely. Post mortem sampling (PMS) of tissues via thin biopsy needle or “mini incisions” in the skin may be a useful alternative. We aimed to assess how this approach is perceived by intensive care doctors, and secondarily, to evaluate how this practice is considered in ethical terms in France.
Study of PMS practices immediately after death in 10 intensive care departments. The medical director of each centre was interviewed by phone and asked to describe practices in their unit and identify questions raised concerning this practice.
PMS is routinely performed in 70% of units, without obtaining formal consent and without precise rules for communicating results. Approaches to PMS differed between centres, but all physicians felt that PMS is useful, firstly for the scientific information provided, but also for the information it provides for relatives. All physicians regret the lack of standards to structure PMS practices.
Information from post-mortem examination is important for society, to inform about causes of death; for doctors, to improve practices; and for decision-makers responsible for organising care. Debate persists regarding the balance between individual rights and community interests. We purport that an approach for identifying cause of death could easily be integrated into the relationship between carers and relatives, provided full transparency is maintained.
PMCID: PMC3317884  PMID: 21186206
Adult; Autopsy; ethics; psychology; statistics & numerical data; Cause of Death; Family; psychology; France; Hospital Mortality; Humans; Informed Consent; ethics; psychology; Intensive Care; Middle Aged; Tissue and Organ Harvesting; ethics; Post mortem sampling; autopsy; intensive care; ethics

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