Publications by authors named "Saber Barbar"

30 Publications

  • Page 1 of 1

Renal Replacement Therapy for Acute Kidney Injury in French Intensive Care Units: A Nationwide Survey of Practices.

Blood Purif 2021 Nov 4:1-10. Epub 2021 Nov 4.

BoReal Study Group, Intensive Care Unit, Hôpital de Bethune, Bethune, France.

Background: The frequency of acute kidney injury (AKI) can be as high as 50% in the intensive care unit (ICU). Despite the publication of national guidelines in France in 2015 for the use of RRT, there are no data describing the implementation of these recommendations in real-life.

Methods: We performed a nationwide survey of practices from November 15, 2019, to January 24, 2020, in France. An electronic questionnaire based on the items recommended in the national guidelines was sent using an online survey platform, to the chiefs of all ICUs in France. The questionnaire comprised a section for the Department Chief about local organization and facilities, and a second section destined for individual physicians about their personal practices.

Results: We contacted the Department Chief in 356 eligible ICUs, of whom 88 (24.7%) responded regarding their ICU organization. From these 88 ICUs, 232/285 physicians (82%) completed the questionnaire regarding individual practices. The practices reported by respondent physicians were as follows: intermittent RRT was first-line choice in >75% in a patient with single organ (kidney) failure at the acute phase, whereas continuous RRT was predominant (>75%) in patients with septic shock or multi-organ failure. Blood and dialysate flow for intermittent RRT were 200-300 mL/min and 400-600 mL/min, respectively. The dose of dialysis for continuous RRT was 25-35 mL/kg/h (65%). Insertion of the dialysis catheter was mainly performed by the resident under echographic guidance, in the right internal jugular vein. The most commonly used catheter lock was citrate (53%). The most frequently cited criterion for weaning from RRT was diuresis, followed by a drop in urinary markers (urea and creatinine).

Conclusion: This study shows a satisfactory level of reported compliance with French guidelines and recent scientific evidence among ICU physicians regarding initiation of RRT for AKI in the ICU.
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http://dx.doi.org/10.1159/000518919DOI Listing
November 2021

Mental health and stress among ICU healthcare professionals in France according to intensity of the COVID-19 epidemic.

Ann Intensive Care 2021 Jun 4;11(1):90. Epub 2021 Jun 4.

Service de Médecine Intensive Réanimation-Unité de Sevrage Ventilatoire et Réhabilitation, CH de Bethune, Bethune, France.

Background: We investigated the impact of the COVID-19 crisis on mental health of professionals working in the intensive care unit (ICU) according to the intensity of the epidemic in France.

Methods: This cross-sectional survey was conducted in 77 French hospitals from April 22 to May 13 2020. All ICU frontline healthcare workers were eligible. The primary endpoint was the mental health, assessed using the 12-item General Health Questionnaire. Sources of stress during the crisis were assessed using the Perceived Stressors in Intensive Care Units (PS-ICU) scale. Epidemic intensity was defined as high or low for each region based on publicly available data from Santé Publique France. Effects were assessed using linear mixed models, moderation and mediation analyses.

Results: In total, 2643 health professionals participated; 64.36% in high-intensity zones. Professionals in areas with greater epidemic intensity were at higher risk of mental health issues (p < 0.001), and higher levels of overall perceived stress (p < 0.001), compared to low-intensity zones. Factors associated with higher overall perceived stress were female sex (B = 0.13; 95% confidence interval [CI] = 0.08-0.17), having a relative at risk of COVID-19 (B = 0.14; 95%-CI = 0.09-0.18) and working in high-intensity zones (B = 0.11; 95%-CI = 0.02-0.20). Perceived stress mediated the impact of the crisis context on mental health (B = 0.23, 95%-CI = 0.05, 0.41) and the impact of stress on mental health was moderated by positive thinking, b = - 0.32, 95% CI = - 0.54, - 0.11.

Conclusion: COVID-19 negatively impacted the mental health of ICU professionals. Professionals working in zones where the epidemic was of high intensity were significantly more affected, with higher levels of perceived stress. This study is supported by a grant from the French Ministry of Health (PHRC-COVID 2020).
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http://dx.doi.org/10.1186/s13613-021-00880-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177250PMC
June 2021

Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial.

Lancet 2021 04;397(10281):1293-1300

Réanimation médicale, CHRU de Lille, Hôpital Roger Salengro, Lille, France.

Background: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy.

Methods: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed.

Findings: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups.

Interpretation: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm.

Funding: Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.1016/S0140-6736(21)00350-0DOI Listing
April 2021

Prevalence of pressure injuries among critically ill patients and factors associated with their occurrence in the intensive care unit: The PRESSURE study.

Aust Crit Care 2021 09 20;34(5):411-418. Epub 2021 Jan 20.

CERC, SRLF, France. Electronic address:

Background: The prevalence of pressure injuries (PIs) in critically ill patients has been extensively studied, but there is uncertainty regarding the risk factors. The main objective of this study was to describe the prevalence of PIs in critically ill patients. Secondary objectives were to describe PI, use of preventive measures for PI, and factors associated with occurrence of PI in the intensive care unit (ICU).

Material And Methods: This was a 1-day point-prevalence study performed on a weekday in June 2017 in ICUs in France. On the same day, we noted the presence or absence of PI in all hospitalised patients of the participating ICUs, data on the ICUs, and the characteristics of patients and of PI.

Results: Eighty-six participating ICUs allowed the inclusion of 1228 patients. The prevalence of PI on the study day was 18.7% (95% confidence interval: 16.6-21.0). PIs acquired in the ICU were observed in 12.5% (95% confidence interval: 10.6-14.3) of critically ill patients on the study day. The most frequent locations of PI were the sacrum (57.4%), heel (35.2%), and face (8.7%). Severe forms of PI accounted for 40.8% of all PIs. Antiulcer mattresses were used in 91.5% of the patients, and active and/or passive mobilisation was performed for all the patients. Multiple logistic regression analysis identified longer length of stay in the ICU, a higher Simplified Acute Physiology Score, higher body weight, motor neurological disorder, high-dose steroids, and absence of oral nutrition on the study day as factors independently associated with occurrence of PI in the ICU.

Conclusion: This large point-prevalence study shows that PIs are found in about one of five critically ill patients despite extensive use of devices for preventing PI. Acquisition of PI in the ICU is strongly related to the patient's severity of illness on admission to the ICU and length of stay in the ICU.
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http://dx.doi.org/10.1016/j.aucc.2020.12.001DOI Listing
September 2021

Vancomycin Serum Concentration after 48 h of Administration: A 3-Years Survey in an Intensive Care Unit.

Antibiotics (Basel) 2020 Nov 10;9(11). Epub 2020 Nov 10.

Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, 30029 Nîmes, France.

The present study assessed the proportion of intensive care unit (ICU) patients who had a vancomycin serum concentration between 20 and 25 mg/L after 24-48 h of intravenous vancomycin administration. From 2016 to 2018, adult ICU patients with vancomycin continuous infusion (CI) for any indication were included. The primary outcome was the proportion of patients with a first-available vancomycin serum concentration between 20-25 mg/L at 24 h (D2) or 48 h (D3). Of 3894 admitted ICU patients, 179 were included. A median loading dose of 15.6 (interquartile range (IQR) = (12.5-20.8) mg/kg) was given in 151/179 patients (84%). The median daily doses of vancomycin infusion for D1 and D2 were 2000 [(IQR (1600-2000)) and 2000 (IQR (2000-2500)) mg/d], respectively. The median duration of treatment was 4 (2-7) days. At D2 or D3, the median value of first serum vancomycin concentration was 19.8 (IQR (16.0-25.1)) with serum vancomycin concentration between 20-25 mg/L reported in 43 patients (24%). Time spent in the ICU before vancomycin initiation was the only risk factor of non-therapeutic concentration at D2 or D3. Acute kidney injury occurred significantly more when vancomycin concentration was supra therapeutic at D2 or D3. At D28, 44 (26%) patients had died. These results emphasize the need of appropriate loading dose and regular monitoring to improve vancomycin efficacy and avoid renal toxicity.
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http://dx.doi.org/10.3390/antibiotics9110793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698174PMC
November 2020

Short- and Long-Term Outcome of Chronic Dialyzed Patients Admitted to the ICU and Assessment of Prognosis Factors: Results of a 6-Year Cohort Study.

Crit Care Med 2020 08;48(8):e666-e674

Department of Intensive Care Medicine, Lapeyronie University Hospital, Montpellier, France.

Objectives: Data about end-stage kidney disease patients admitted to the ICU are scarce, dated, and mostly limited to short-term survival. The aim of this study was to assess the short- and long-term outcome and to determine the prognostic factors for end-stage kidney disease patients admitted to the ICU.

Design: Prospective observational study.

Setting: Medical ICUs in two university hospitals.

Patients: Consecutive end-stage kidney disease patients admitted in two ICUs between 2012 and 2017.

Intervention: None.

Measurements And Main Results: Renal replacement therapy variables, demographic, clinical, and biological data were collected. The requirement of mechanical ventilation and vasopressive drugs were also collected. In-ICU and one-year mortality were estimated and all data were analyzed in order to identify predictive factors of short and long-term mortality. A total of 140 patients were included, representing 1.7% of total admissions over the study period. Septic shock was the main reason for admission mostly of pulmonary origin. Median Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score were at 63 and 6.7, respectively. In-ICU, hospital, and 1-year mortality were 41.4%, 46.4%, and 63%, respectively. ICU mortality was significantly higher as compared with ICU control group non-end-stage kidney disease (25% vs 41.4%; p = 0.005). By multivariate analysis, the short-term outcome was significantly associated with nonrenal Sequential Organ Failure Assessment score, and with the requirement of mechanical ventilation or/and vasoconstrictive agents during ICU stay. One-year mortality was associated with increased dialysis duration (> 3 yr) and phosphatemia (> 2.5 mmol/L), with lower albuminemia (< 30 g/L) and nonrenal Sequential Organ Failure Assessment greater than 8.

Conclusions: End-stage kidney disease patients presented frequently severe complications requiring critical care that induced significant short- and long-term mortality. ICU and hospital mortality depended mainly on the severity of the critical event reflected by Sequential Organ Failure Assessment score and the need of mechanical ventilation and/or catecholamines. One-year mortality was associated with both albuminemia and phosphatemia and with prior duration of chronic dialysis treatment, and with organ failure at ICU admission.
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http://dx.doi.org/10.1097/CCM.0000000000004412DOI Listing
August 2020

Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.

Lancet 2020 05 23;395(10235):1506-1515. Epub 2020 Apr 23.

Common and Rare Kidney Diseases, Sorbonne Université, INSERM, UMR-S 1155, Paris, France; Médecine Intensive-Réanimation, Université de Paris, AP-HP Hôpital Louis Mourier, Colombes, France. Electronic address:

Background: The timing of renal replacement therapy (RRT) for severe acute kidney injury is highly debated when no life-threatening complications are present. We assessed whether a strategy of delayed versus early RRT initiation affects 28-day survival in critically ill adults with severe acute kidney injury.

Methods: In this systematic review and individual patient data meta-analysis, we searched MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials for randomised trials published from April 1, 2008, to Dec 20, 2019, that compared delayed and early RRT initiation strategies in patients with severe acute kidney injury. Trials were eligible for inclusion if they included critically ill patients aged 18 years or older with acute kidney injury (defined as a Kidney Disease: Improving Global Outcomes [KDIGO] acute kidney injury stage 2 or 3, or, where KDIGO was unavailable, a renal Sequential Organ Failure Assessment score of 3 or higher). We contacted the principal investigator of each eligible trial to request individual patient data. From the included trials, any patients without acute kidney injury or who were not randomly allocated were not included in the individual patient data meta-analysis. The primary outcome was all-cause mortality at day 28 after randomisation. This study is registered with PROSPERO (CRD42019125025).

Findings: Among the 1031 studies identified, one study that met the eligibility criteria was excluded because the recruitment period was not recent enough, and ten (including 2143 patients) were included in the analysis. Individual patient data were available for nine studies (2083 patients), from which 1879 patients had severe acute kidney injury and were randomly allocated: 946 (50%) to the delayed RRT group and 933 (50%) to the early RRT group. 390 (42%) of 929 patients allocated to the delayed RRT group and who had available data did not receive RRT. The proportion of patients who died by day 28 did not significantly differ between the delayed RRT group (366 [44%] of 837) and the early RRT group (355 [43%] of 827; risk ratio 1·01 [95% CI 0·91 to 1·13], p=0·80), corresponding to an overall risk difference of 0·01 (95% CI -0·04 to 0·06). There was no heterogeneity across studies (I=0%; τ=0), and most studies had a low risk of bias.

Interpretation: The timing of RRT initiation does not affect survival in critically ill patients with severe acute kidney injury in the absence of urgent indications for RRT. Delaying RRT initiation, with close patient monitoring, might lead to a reduced use of RRT, thereby saving health resources.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)30531-6DOI Listing
May 2020

The Artificial Kidney Initiation in Kidney Injury 2 (AKIKI2): study protocol for a randomized controlled trial.

Trials 2019 Dec 16;20(1):726. Epub 2019 Dec 16.

Réanimation médicale, CHRU de Lille, Hôpital Roger Salengro, 59037, Lille, France.

Background: The Artificial Kidney Initiation in Kidney Injury (AKIKI) trial showed that a delayed renal replacement therapy (RRT) strategy for severe acute kidney injury (AKI) in critically ill patients was safe and associated with major reduction in RRT initiation compared with an early strategy. The five criteria which mandated RRT initiation in the delayed arm were: severe hyperkalemia, severe acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia, serum urea concentration > 40 mmol/l and oliguria/anuria > 72 h. However, duration of anuria/oliguria and level of blood urea are still criteria open to debate. The objective of the study is to compare the delayed strategy used in AKIKI (now termed "standard") with another in which RRT is further delayed for a longer period (termed "delayed strategy").

Methods/design: This is a prospective, multicenter, open-label, two-arm randomized trial. The study is composed of two stages (observational and randomization stages). At any time, the occurrence of a potentially severe condition (severe hyperkalemia, severe metabolic or mixed acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia) suggests immediate RRT initiation. Patients receiving (or who have received) intravenously administered catecholamines and/or invasive mechanical ventilation and presenting with AKI stage 3 of the KDIGO classification and with no potentially severe condition are included in the observational stage. Patients presenting a serum urea concentration > 40 mmol/l and/or an oliguria/anuria for more than 72 h are randomly allocated to a standard (RRT is initiated within 12 h) or a delayed RRT strategy (RRT is initiated only if an above-mentioned potentially severe condition occurs or if the serum urea concentration reaches 50 mmol/l). The primary outcome will be the number of RRT-free days at day 28. One interim analysis is planned. It is expected to include 810 patients in the observational stage and to randomize 270 subjects.

Discussion: The AKIKI2 study should improve the knowledge of RRT initiation criteria in critically ill patients. The potential reduction in RRT use allowed by a delayed RRT strategy might be associated with less invasive care and decreased costs. Enrollment is ongoing. Inclusions are expected to be completed by November 2019.

Trial Registration: ClinicalTrials.gov, ID: NCT03396757. Registered on 11 January 2018.
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http://dx.doi.org/10.1186/s13063-019-3774-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915917PMC
December 2019

Trisodium citrate 4% versus heparin as a catheter lock for non-tunneled hemodialysis catheters in critically ill patients: a multicenter, randomized clinical trial.

Ann Intensive Care 2019 Jul 1;9(1):75. Epub 2019 Jul 1.

CH de Bourg en Bresse, Service de Réanimation polyvalente, 01000, Bourg en Bresse, France.

Background: Non-tunneled hemodialysis catheters are currently used for critically ill patients with acute kidney injury requiring extracorporeal renal replacement therapy. Strategies to prevent catheter dysfunction and infection with catheter locks remain controversial.

Methods: In a multicenter, randomized, controlled, double-blind trial, we compared two strategies for catheter locking of non-tunneled hemodialysis catheters, namely trisodium citrate at 4% (intervention group) versus unfractionated heparin (control group), in patients aged 18 years or older admitted to the intensive care unit and in whom a first non-tunneled hemodialysis catheter was to be inserted by the jugular or femoral vein. The primary endpoint was length of event-free survival of the first non-tunneled hemodialysis catheter. Secondary endpoints were: rate of fibrinolysis, incidence of catheter dysfunction and incidence of catheter-related bloodstream infection (CRBSI), all per 1000 catheter-days; number of hemorrhagic events requiring transfusion, length of stay in intensive care and in hospital; 28-day mortality.

Results: Overall, 396 randomized patients completed the trial: 199 in the citrate group and 197 in the heparin group. There was no significant difference in baseline characteristics between groups. The duration of event-free survival of the first non-tunneled hemodialysis catheter was not significantly different between groups: 7 days (IQR 3-10) in the citrate group and 5 days (IQR 3-11) in the heparin group (p = 0.51). Rates of catheter thrombosis, CRBSI, and adverse events were not statistically different between groups.

Conclusions: In critically ill patients, there was no significant difference in the duration of event-free survival of the first non-tunneled hemodialysis catheter between trisodium citrate 4% and heparin as a locking solution. Catheter thrombosis, catheter-related infection, and adverse events were not statistically different between the two groups. Trial registration Registered with Clinicaltrials.gov under the number NCT01962116. Registered 14 October 2013.
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http://dx.doi.org/10.1186/s13613-019-0553-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603108PMC
July 2019

Strategy focused on clinical parameters of microcirculation to resuscitate patients in septic shock: Do not forget any tools.

Anaesth Crit Care Pain Med 2019 06;38(3):209-210

Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK.

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http://dx.doi.org/10.1016/j.accpm.2019.04.011DOI Listing
June 2019

WITHDRAWN: Strategy focused on clinical parameters of microcirculation to resuscitate patients in septic shock: do not forget any tools.

Anaesth Crit Care Pain Med 2019 04 21. Epub 2019 Apr 21.

Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK.

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http://dx.doi.org/10.1016/j.accpm.2019.04.009DOI Listing
April 2019

Timing of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients.

Am J Respir Crit Care Med 2019 05;199(9):1066-1075

2 INSERM UMR S 1155 "Common and Rare Kidney Diseases: from Molecular Events to Precision Medicine," and.

Acute kidney injury (AKI) affects many ICU patients and is responsible for increased morbidity and mortality. Although lifesaving in many situations, renal replacement therapy (RRT) may be associated with complications, and the appropriate timing of its initiation is still the subject of intense debate. An early initiation strategy can prevent some metabolic complications, whereas a delayed one may allow for renal function recovery in some patients without need for this costly and potentially dangerous technique. For years, most of the knowledge on this issue stemmed from observational studies or small randomized controlled trials. Recent randomized controlled trials have indicated that a watchful waiting strategy (in the absence of life-threatening conditions such as severe hyperkalemia or pulmonary edema) during severe AKI allowed many patients to escape RRT and did not seem to adversely affect survival compared with a strategy of immediate RRT. In addition, data suggest that a delayed strategy may reduce the rate of complications (such as catheter infection) and favor renal function recovery. Ongoing studies will have to both confirm these conclusions and clarify to what extent the delay in initiating RRT can be prolonged. Pending those results, the bulk of evidence suggests that, in the absence of potential severe complications of AKI, delaying RRT is a valid and safe strategy that may also allow for considerable cost savings.
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http://dx.doi.org/10.1164/rccm.201810-1906CPDOI Listing
May 2019

Timing of Renal-Replacement Therapy in Acute Kidney Injury and Sepsis.

N Engl J Med 2019 01;380(4):399

CHU Dijon Bourgogne, Dijon, France

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http://dx.doi.org/10.1056/NEJMc1815142DOI Listing
January 2019

Renal replacement therapy: Time to give up on early initiation? Yes.

Anaesth Crit Care Pain Med 2018 12;37(6):501-503

Department of intensive care medicine, Dijon Bourgogne university hospital, 14, rue Paul-Gaffarel, 21000 Dijon, France; Bourgogne Franche-Comté university, Lipness Team UMR 1231 et LabExLipSTIC, 21000 Dijon, France; Inserm CIC 1432 Clinical Epidemiology and clinical trial, Dijon Bourgogne university hospital, 21000 Dijon, France.

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http://dx.doi.org/10.1016/j.accpm.2018.11.008DOI Listing
December 2018

Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.

N Engl J Med 2018 Oct;379(15):1431-1442

From Réanimation Médicale, Centre Hospitalier Universitaire (CHU) de Nîmes (S.D.B., B. Louart, R.T.), and Saint Eloi, CHU de Montpellier, Université de Montpellier, and INSERM Unité 1046 (S.J.), Service de Réanimation Médicale, CHU Lapeyronie (K.K.), Montpellier, Université de Strasbourg, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg (R.C.-J., F. Meziani, J.H.), Service de Médecine Intensive Réanimation, Hôpital Universitaire François Mitterrand, and Lipness Team, INSERM Research Center Lipids, Nutrition, Cancer-Unité Mixte de Recherche 1231 and Laboratoire d'Excellence LipSTIC (A.D., J.-P.Q.), and Centre d'Investigation Clinique-Epidemiologie Clinique, CHU Dijon-Bourgogne and INSERM Centre d'Investigation Clinique 1432, Université de Bourgogne, Dijon (A.B., C.B., J.-P.Q.), Réanimation Médicale, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon (R.H.), Réanimation Polyvalente, Centre Hospitalier d'Avignon, Avignon (F. Montini), Réanimation Polyvalente, Centre Hospitalier de Bourg-en-Bresse, Bourg-en-Bresse (R.B.), Service de Médecine Intensive-Réanimation, Centre Hospitalier de La Roche-sur-Yon, La Roche-sur-Yon (C.L.), Intensive Care Unit, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite (J. Bohé), Réanimation Polyvalente, Hôpital Nord Franche-Comté, Belfort (J. Badie), Médecine Intensive Réanimation, Centre Hospitalier de Dieppe, Dieppe (J.-P.E., J.-P.R.), Service de Réanimation Médicale, CHU de Nancy-Brabois, Nancy (B. Levy), Service d'Anesthésie-Réanimation, Centre Hospitalier d'Etampes, Etampes (S.S.), Réanimation Polyvalente, Hôpital Bon Secours, Centre Hospitalier Régional de Metz, Metz (G.L.), Infection, Antimicrobiens, Modélisation, Evolution, Unité 1137, Team Decision Sciences in Infectious Disease Prevention, Control, and Care, Université Paris Diderot, Sorbonne Paris Cité, and Medical and Infectious Diseases ICU, Bichat-Claude-Bernard Hospital, Assistance Publique-Hôpitaux de Paris (L.B.), and Service de Réanimation Médicale, Hôpital Cochin (J.-P.M.), Paris, Pôle de Médecine Péri-Opératoire, GReD, and INSERM Unité 1103, CHU Clermont-Ferrand, Clermont-Ferrand (J.-M.C.), Service de Réanimation Médicale, CHU Régional de Tours, Tours (E.M.), CHU de Caen, Service de Réanimation Médicale, Caen (D.C.), Service de Réanimation Médicale (G.P.) and Service de Réanimation Chirurgicale (G.B.), CHU de Besançon, Besançon, Service de Médecine Intensive et Réanimation, Hôpital Raymond Poincaré, Garches (D.A.), Laboratory of Infection and Inflammation, INSERM Unité 1173, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux (D.A.), Service de Médecine Intensive Réanimation, Groupe des Hôpitaux de l'Institut Catholique de Lille, Université Catholique de Lille, Lille (T.L.), Service de Réanimation Médicale, CHU de Grenoble, Grenoble (C.S.), Service de Réanimation, Centre Hospitalier de Perigueux, Perigueux (L.C.), Service de Réanimation Polyvalente, Centre Hospitalier Général de Mulhouse, Mulhouse (P.G.), Médecine Intensive Réanimation, Centre Hospitalier Régional d'Orléans, Orléans (M.-A.N.), and Réanimation Chirurgicale-CHU de Nîmes, Nîmes (C.R.) - all in France.

Background: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial.

Methods: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days.

Results: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients).

Conclusions: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .).
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http://dx.doi.org/10.1056/NEJMoa1803213DOI Listing
October 2018

Changes in the distribution of colonising and infecting Candida spp. isolates, antifungal drug consumption and susceptibility in a French intensive care unit: A 10-year study.

Mycoses 2017 Dec 31;60(12):770-780. Epub 2017 Jul 31.

Département de Parasitologie-Mycologie, Centre Hospitalo-Universitaire, Montpellier, France.

Monitoring fungal ecology and resistance to antifungal agents within intensive care units (ICU) is essential for the management of invasive fungal infections. Therefore, a retrospective descriptive study was carried in the ICU of Nimes University Hospital, France, from 2007 to 2016. As the majority of invasive fungal infections in ICU are caused by Candida species, the study objectives were to describe Candida species distribution, to assess candidaemia incidence and to monitor the antifungal drug susceptibility of Candida isolates and the consumption of antifungal agents. Among the recorded invasive Candida infections (n=244), 43% were intra-abdominal and 22% bloodstream infections. Candida albicans was the most frequent species (55.8%), followed by Candida glabrata (14.1%), Candida tropicalis (10%), Candida parapsilosis (8%) and Candida krusei (5.3%). Candidaemia incidence was 4.49 per 1000 admissions. The mean consumption of antifungal agents was of 170.5 defined daily doses (DDD) for 1000 hospital days (HD) per year. Changes in antifungal drug consumption were observed, with an increased use of echinocandins (from 17.96 DDD/1000 HD in 2007 to 48.76 DDD/1000 HD in 2016), and the total treatment cost tripled during the study period. No significant change in fungal ecology or in the emergence of resistant species was observed; indeed, only 1.1% of isolates presented an unusual resistance to antifungal agents.
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http://dx.doi.org/10.1111/myc.12661DOI Listing
December 2017

Standard dosing of amikacin and gentamicin in critically ill patients results in variable and subtherapeutic concentrations.

Int J Antimicrob Agents 2015 Jul 19;46(1):21-7. Epub 2015 Mar 19.

Service des reanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Place du Professeur Robert Debré, 30 029 Nîmes Cedex 9, France; EA 2992, Faculté de Médicine Montpellier Nîmes, Avenue JF Kennedy, 30 000 Nîmes, France.

Low peak plasma concentrations (Cmax) of amikacin and gentamicin are reported in intensive care unit (ICU) patients after administration of the first dose. The present study aimed to describe the proportion of ICU patients in whom an adequate Cmax was achieved throughout the course of therapy. Septic ICU patients with an indication for intravenous amikacin or gentamicin were eligible for inclusion in this single-centre observational study. The first and subsequent doses and the corresponding Cmax values were recorded. The target Cmax was ≥60mg/L for amikacin and ≥30mg/L for gentamicin. Amikacin and gentamicin plasma concentrations were available in 66 and 24 patients, respectively (59±17 years; 79±19kg; height 169±12cm; SAPS II score 46±19). Pulmonary, abdominal and urinary tract infections were diagnosed in 64 patients. Culture-positive infection was confirmed in 65 patients (72%). A target first Cmax was achieved in 17/90 patients (19%). For amikacin, the target Cmax was achieved in 16/66 patients (24%) after the initial dose. In the 50 remaining patients, a change in dosing was performed in 14 patients, leading adequate peak plasma level in 2 patients. For gentamicin, the targeted Cmax was achieved in only 1/24 patient (4%) after the initial dose and was never achieved after the third dose. In conclusion, standard dosing of amikacin or gentamicin led to adequate Cmax in only 19% of patients. Subtherapeutic Cmax were not significantly corrected after subsequent doses.
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http://dx.doi.org/10.1016/j.ijantimicag.2015.02.009DOI Listing
July 2015

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 Nov 19;15:449. Epub 2014 Nov 19.

Medical Intensive Care Unit, University Hospital of Dijon, 14 rue Paul Gaffarel, 21079 Dijon, France.

Background: 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.

Methods/design: 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.

Discussion: 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 Clinicaltrials.gov (registration number: NCT01962116) on 27 August 2013.
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http://dx.doi.org/10.1186/1745-6215-15-449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289224PMC
November 2014

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 Jul 7;15:270. Epub 2014 Jul 7.

Service de Réanimation Médicale, CHU de Nîmes - Hôpital Carémeau, Nîmes, France.

Background: 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.

Methods/design: 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.

Discussion: 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: ClinicalTrials.gov identifier NCT01682590, registered on 10 September 2012.
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http://dx.doi.org/10.1186/1745-6215-15-270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226975PMC
July 2014

Arginine reduces bacterial invasion in rats with head injury: an in vivo evaluation by bioluminescence.

Crit Care Med 2012 Jan;40(1):278-80

Laboratory Biologie de la Nutrition EA 4466, Faculté des Sciences Pharmaceutiques et Biologiques de l'Université Paris Descartes, Paris, France.

Objectives: The benefit of arginine in intensive care unit patients with severe sepsis is still controversial. An excessive supply of arginine could lead to an overproduction of nitric oxide and could be responsible for septic shock and multiorgan failure. However, this claim is not supported by any experimental or clinical data. We set out to determine whether an enteral supply of arginine would modulate bacterial invasion in rats with head injury.

Methods: Male Sprague-Dawley rats with head injury were randomized into two groups. Group 1 included rats with head injury fed a standard enteral nutrition (Sondalis HP, n = 10) and group 2 included rats with head injury fed the standard enteral nutrition plus arginine (4 g/kg/d, n = 11). Two days after head injury, the rats received a single enteral bolus of luminescent Escherichia coli Xen 14. Bacterial proliferation was evaluated in vivo at time + 2 hrs and time + 6 hrs after E. coli challenge. Four days after head injury, blood was sampled for arginine and fibrinogen assay. Muscles, intestine, spleen, and thymus were removed and weighed.

Results: There was no mortality in either group. The luminescence signal was similar in the two groups at time +2 hrs (group 1: 414 [5-823] vs. group 2: 496 [0.1-993] (median value[min-max]; not significant) and was significantly lower at time +6 hrs in group 2 (group 1: 71 [0-142] vs. group 2: 8.5 [0-17]; p = .026). Arginine treatment did not improve any nutritional parameters.

Conclusions: Arginine was not responsible for mortality in rats with head injury with infectious complications and reduced the intensity of bacterial invasion.
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http://dx.doi.org/10.1097/CCM.0b013e31822b4ec6DOI Listing
January 2012

Sodium citrate versus saline catheter locks for non-tunneled hemodialysis central venous catheters in critically ill adults: a randomized controlled trial.

Intensive Care Med 2012 Feb 29;38(2):279-85. Epub 2011 Nov 29.

CHU de Dijon, Hôpital du Bocage, Réanimation Traumatologique et Neurochirurgicale, Université de Bourgogne, Dijon, France.

Purpose: Sodium citrate has antibacterial and anticoagulant properties that are confined to the catheter when used as a catheter lock. Studies of its use as a catheter lock in chronic hemodialysis patients suggest it may be efficacious in preventing infection and thrombotic complications. We compared sodium citrate with saline catheter locks for non-tunneled hemodialysis central venous catheters in critically ill adult patients. Primary endpoint was catheter life span without complication.

Methods: This was a randomized, controlled, open-label trial involving intensive care patients with acute renal failure requiring hemodialysis. Events were defined as catheter-related bloodstream infection and catheter malfunction.

Results: Seventy-eight patients were included. Median catheter life span without complication was 6 days (saline group) versus 12 days (citrate group) [hazard ratio (HR) 2.12 (95% CI 1.32-3.4), p = 0.0019]. There was a significantly higher rate of catheter malfunction in the saline group compared with in the citrate group (127 catheter events/1,000 catheter-days, saline group vs. 26 events/1,000 catheter-days, citrate group, p < 0.00001). There was no significant difference in incidence of infections between groups. We observed a significantly longer time to occurrence of infection in the citrate group (20 days vs. 14 days, HR 2.8, 95% CI 1.04-7.6, p = 0.04). By multivariate analysis, age and citrate group were the only independent factors that influenced catheter life span.

Conclusions: This study shows for the first time that citrate lock reduced catheter complications and increased catheter life span as compared to saline lock in critically ill adults requiring hemodialysis.
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http://dx.doi.org/10.1007/s00134-011-2422-yDOI Listing
February 2012

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide.

Crit Care 2011 Jul 27;15(4):R181. Epub 2011 Jul 27.

Laboratoire Interactions Muqueuses Agents Pathogènes, EA562, UFR Médecine, Université de Bourgogne, 7 Bd Jeanne d'Arc, 21000 Dijon, France.

Introduction: Mechanical ventilation (MV) could prime the lung toward an inflammatory response if exposed to another insult such as bacterial invasion. The underlying mechanisms are not so far clear. Toll-like receptors (TLRs) allow the host to recognize selectively bacterial pathogens and in turn to trigger an immune response. We therefore hypothesized that MV modulates TLR2 expression and in turn modifies responsiveness to agonists such as bacterial lipopeptide (BLP).

Method: Both in vitro and in vivo experiments were conducted. First, TLR2 expression and protein were measured in the A549 pulmonary epithelial cell line submitted to 8-hour cyclic stretch (20% elongation; 20/minute rate). After a 24-hour period of cyclic stretch, the inflammatory response of the A549 cells to the synthetic BLP, Pam3CSK4, was tested after 8 hours of exposure. In a second set of experiments, healthy anesthetized and paralyzed rabbits were submitted to 8-hour MV (tidal volume = 12 ml/kg, zero end-expiratory pressure; FIO2 = 50%; respiratory rate = 20/minute) before being sacrificed for TLR2 lung expression assessment. The lung inflammatory response to BLP was then tested in animals submitted to 24-hour MV before being sacrificed 8 hours after the tracheal instillation of Pam3CSK4.

Results: Cyclic stretch of human pulmonary epithelial cell lines increased both TLR2 mRNA and protein expression. Cells submitted to cyclic stretch also increased IL-6 and IL-8 secretion in response to Pam3CSK4, a classical TLR2 ligand. A mild-stretch MV protocol induced a 60-fold increase of TLR2 mRNA expression in lung tissue when compared with spontaneously breathing controls. Moreover, the combination of MV and airway exposure to Pam3CSK4 acted synergistically in causing lung inflammation and injury.

Conclusions: Mild-stretch MV increases lung expression of TLR2 and sensitizes the lung to bacterial TLR2 ligands. This may account for the propensity of mechanically ventilated patients to develop acute lung injury in the context of airway bacterial colonization/infection.
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http://dx.doi.org/10.1186/cc10330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387624PMC
July 2011

When should stress ulcer prophylaxis be used in the ICU?

Curr Opin Crit Care 2009 Apr;15(2):139-43

Service de Réanimation Médicale, Dijon University Hospital, Dijon, France.

Purpose Of Review: To discuss the risk factors and underlying illnesses that play a role in the pathophysiology of stress ulcer, and to evaluate the evidence pertaining to stress ulcer-related bleeding prophylaxis in critically ill patients.

Recent Findings: The use of stress ulcer prophylaxis is common in critical care medicine and is a major challenge to physicians in the ICU. The mechanism of stress ulcer is believed to be multifactorial, yet remains incompletely understood. The most widely used drugs for stress ulcer prophylaxis are intravenous histamine2-receptor antagonists. They raise gastric pH, but are associated with the development of tolerance, possible drug interactions, and neurologic manifestations. Sucralfate, which can be administered by the nasogastric route, can protect the gastric mucosa without raising pH, but may decrease absorption of concomitantly administered oral medications. Proton pump inhibitors are the most potent acid-inhibiting pharmacologic agents available. Proton pump inhibitors are at least as effective as histamine2-receptor antagonists, as a limited number of clinical trials have demonstrated. However, these trials were small, lacked an active comparator, varied in the number of risk factors, and used a different definition of clinically important bleeding than previously established.

Summary: Routine prophylaxis against stress ulcers in the ICU is not well justified by current evidence. Patients at risk of stress ulcer-related bleeding are most likely to benefit from prophylaxis. Thus, healthcare professionals should continue to evaluate risk and assess the need for stress ulcer-related prophylaxis.
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http://dx.doi.org/10.1097/MCC.0b013e32832978e0DOI Listing
April 2009

Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome.

Crit Care 2009 16;13(2):R38. Epub 2009 Mar 16.

Service de Réanimation Médicale, Hôpital Le Bocage, C,H,U, de Dijon, 21000 Dijon, France.

Introduction: 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.

Methods: 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.

Results: Appropriate first-line empirical antibiotic therapy (n = 135) was associated with a significantly greater decrease in PCT between D2 and D3 (DeltaPCT D2-D3) (-3.9 (35.9) vs. +5.0 (29.7), respectively; P < 0.01). In addition, DeltaPCT 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 >or= 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).

Conclusions: 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.
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http://dx.doi.org/10.1186/cc7751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689475PMC
September 2009
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