Publications by authors named "Julio Badie"

26 Publications

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Systematic Review and Subgroup Meta-analysis of Randomized Trials to Determine Tocilizumab's Place in COVID-19 Pneumonia.

Infect Dis Ther 2021 Sep 11;10(3):1195-1213. Epub 2021 Jul 11.

Infectious Disease Department, Nord Franche-Comté Hospital, 90400, Trevenans, France.

Introduction: Tocilizumab randomized clinical trial results are heterogeneous because of the heterogenous population included in them.

Methods: We conducted a meta-analysis with subgroup meta-analysis (PRISMA guidelines) between severe and non-severe COVID-19.

Results: We included nine trials. Overall, the mortality rate was 24.5% (821/3357) in the tocilizumab group and 29.1% (908/3125) in the control group at day 28-30 (pooled OR, 0.85; 95% CI 0.76-0.96; p = 0.006). Considering the subgroup analysis, this benefit on mortality was confirmed and amplified in the severe COVID-19 group (pooled OR, 0.82; 95% CI 0.73-0.93; p = 0.001) but not in the non-severe COVID-19 group (pooled OR, 1.46; 95% CI 0.91-2.34; p = 0.12). For patients who were not mechanically ventilated at baseline (5523/6482), the pooled OR (0.74; 95% CI 0.64-0.85; p < 0.0001) for mechanical ventilation incidence at day 28-30 was in favor of tocilizumab (cumulative incidence of 14.8% versus 19.4% in tocilizumab and control arm, respectively). This benefit was confirmed in both subgroups, i.e., severe and non-severe COVID-19.

Conclusion: Tocilizumab is an effective treatment in hospitalized patients with COVID-19 and hypoxemia by improving survival and decreasing mechanical ventilation requirement. The greatest benefit is observed in severe COVID-19.
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http://dx.doi.org/10.1007/s40121-021-00488-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272840PMC
September 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

Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BMJ Open 2021 05 11;11(5):e045041. Epub 2021 May 11.

Service de Médecine Intensive Réanimation, Centre Hospitalier de Valenciennes, Valenciennes, France.

Introduction: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets.

Methods And Analysis: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes.

Ethics And Dissemination: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals.

Trial Registration Number: NCT03573739.
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http://dx.doi.org/10.1136/bmjopen-2020-045041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117996PMC
May 2021

Image of a pacemaker that was externally manipulated by the patient.

Arch Cardiol Mex 2021 ;91(2):238-239

Unidad de Terapia Intensiva, Hôpital Nord Franche-Comté, Trevenans, Francia.

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http://dx.doi.org/10.24875/ACM.20000102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295862PMC
January 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

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

JAMA 2020 10;324(13):1317-1329

School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

JAMA 2020 10;324(13):1298-1306

INSERM CIC1415, CHU de Tours, Tours, France.

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.

Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.

Design, Setting, And Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.

Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).

Main Outcomes And Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.

Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.

Conclusions And Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.
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http://dx.doi.org/10.1001/jama.2020.16761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489432PMC
October 2020

Predictive factors of mortality in patients treated with tocilizumab for acute respiratory distress syndrome related to coronavirus disease 2019 (COVID-19).

Microbes Infect 2020 10 20;22(9):500-503. Epub 2020 Jun 20.

Department of Infectious Diseases, Nord Franche-Comté Hospital, Belfort, France. Electronic address:

COVID-19 patients (n = 34) suffering from ARDS were treated with tocilizumab (TCZ). Outcome was classified in two groups: "Death" and "Recovery". Predictive factors of mortality were studied. Mean age was 75.3, mean oxygen (O) requirements 10.4 l/min. At baseline, all patients had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer and liver enzymes). 24 patients (70.5%) recovered after TCZ therapy and 10 died (29.5%). Deceased subjects differed from patients in whom treatment was effective with regard to more pronounced lymphopenia (0.6 vs 1.0 G/l; p = 0.037), lower platelet number (156 vs 314 G/l; p = 0.0001), lower fibrinogen serum level (0.6 vs 1.0 G/l; p = 0.03), higher aspartate-amino-transferase (108 vs 57 UI/l; p = 0.05) and greater O requirements (11 vs 8 l/min; p = 0.003).
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http://dx.doi.org/10.1016/j.micinf.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305501PMC
October 2020

Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration.

Clin Exp Rheumatol 2020 Jul-Aug;38(4):742-747. Epub 2020 Jun 23.

Department of Infectious Diseases, Nord Franche-Comté Hospital, Belfort, France.

Objectives: Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 is likely due to a cytokine storm characterised by a major release of pro-inflammatory cytokines, including interleukin-6 (IL-6). Blocking excessive IL-6 production might be the key to the COVID-19-ARDS treatment. Beneficial effects of IL-6 blockade using a humanised anti-IL-6 receptor antibody, tocilizumab (TCZ) were previously reported in patients with COVID-19 related ARDS. The aim of the study was to study the variation over time of several biomarkers, demonstrated to be predictors of poor prognostic, in subjects successfully treated with TCZ for severe COVID-19.

Methods: Retrospective analysis of a case series of patients with COVID-19-ARDS, evidenced by RT-PCR and lung CT-scan. Patients with increasing O2 requirements, within the window of opportunity for TCZ treatment (Day 7 to Day 17 after onset of symptoms) were treated with TCZ (2 infusions of 8 mg/kg). Demographic, biological and clinical data were collected from the patients' files. Serum levels of CRP, ferritin, fibrinogen, lymphocytes, platelets, creatinine, D-dimer and liver enzymes were assayed at the time of the first TCZ administration, then every two days for 8 days.

Results: 40 patients were treated with TCZ. Most of them had several comorbidities, and all had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer, liver enzymes). 30 patients (75%) benefited from TCZ and 10 patients died. In the survivors, following TCZ administration CRP decreased dramatically as early as day 4 (-86.7%, p<0.0001) and returned to normal at day 6. Fibrinogen and lymphocyte count returned to normal values at day 6. Ferritin also decreased significantly. No significant change was observed for D-dimer (p=0.68) and other studied biomarkers (haemoglobin, leucocyte count, AST).

Conclusions: In patients with COVID-19 acute respiratory distress syndrome, treatment with TCZ resulted in favourable evolution in 75% of the cases. Biomarkers of inflammation (CRP, ferritin, fibrinogen) decreased dramatically as early as the 4th day after TCZ injection. Lymphopenia, a predictor of poor prognostic, was reversed 6 days after TCZ injection.
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July 2020

Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome.

N Engl J Med 2020 03;382(11):999-1008

From the Medical Intensive Care Unit (L.B., H.W., L.V., G.C.), the Anesthesia and Intensive Care Unit (L.B., S.P.-F.), Unité de Méthodologie, INSERM Clinical Investigation Center 1431, University Hospital (F. Mauny, M.P.), and Research Unit EA3920, Université de Franche Comté (L.B., H.W. S.P.-F., G.C.), Besançon, the Medical Intensive Care Unit, University Hospital of Angers, Angers (P.A.), the Intensive Care Unit, General Hospital of Avignon, Avignon (F. Montini), the Intensive Care Unit, General Hospital of Nord Franche-Comté, Trévenans (J.B.), the Medical Intensive Care Unit (J.-P.Q.) and the Anesthesia and Intensive Care Unit (B.B.), University Hospital of Dijon, Dijon, the Intensive Care Unit, General Hospital of Metz-Thionville, Metz (G.L.), the Medical Intensive Care Unit (B.S.) and the Anesthesia and Intensive Care Unit (J.-M.C.), University Hospital of Clermont-Ferrand, Clermont-Ferrand, the Anesthesia and Intensive Care Unit, University Hospital of Strasbourg, Strasbourg (O.C., J.P.), and the Medical Intensive Care Unit, University Hospital of Nancy, Nancy (B.L.) - all in France; and the Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia (G.C.).

Background: In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao) between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS.

Methods: In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry [Spo], 88 to 92%) or liberal oxygen therapy (target Pao, 90 to 105 mm Hg; Spo, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.

Results: After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval [CI], -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group.

Conclusions: Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO ClinicalTrials.gov number, NCT02713451.).
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http://dx.doi.org/10.1056/NEJMoa1916431DOI Listing
March 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

Effect of an ICU Diary on Posttraumatic Stress Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

JAMA 2019 07;322(3):229-239

Infection, Antimicrobials, Modelling, Evolution (IAME), UMR 1137, INSERM, Paris Diderot University, Department of Biostatistics - HUPNVS. - AP-HP, UFR de Médecine - Bichat University Hospital, Paris, France.

Importance: Keeping a diary for patients while they are in the intensive care unit (ICU) might reduce their posttraumatic stress disorder (PTSD) symptoms.

Objectives: To assess the effect of an ICU diary on the psychological consequences of an ICU hospitalization.

Design, Setting, And Participants: Assessor-blinded, multicenter, randomized clinical trial in 35 French ICUs from October 2015 to January 2017, with follow-up until July 2017. Among 2631 approached patients, 709 adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days were eligible, 657 were randomized, and 339 were assessed 3 months after ICU discharge.

Interventions: Patients in the intervention group (n = 355) had an ICU diary filled in by clinicians and family members. Patients in the control group (n = 354) had usual ICU care without an ICU diary.

Main Outcomes And Measures: The primary outcome was significant PTSD symptoms, defined as an Impact Event Scale-Revised (IES-R) score greater than 22 (range, 0-88; a higher score indicates more severe symptoms), measured in patients 3 months after ICU discharge. Secondary outcomes, also measured at 3 months and compared between groups, included significant PTSD symptoms in family members; significant anxiety and depression symptoms in patients and family members, based on a Hospital Anxiety and Depression Scale score greater than 8 for each subscale (range, 0-42; higher scores indicate more severe symptoms; minimal clinically important difference, 2.5); and patient memories of the ICU stay, reported with the ICU memory tool.

Results: Among 657 patients who were randomized (median [interquartile range] age, 62 [51-70] years; 126 women [37.2%]), 339 (51.6%) completed the trial. At 3 months, significant PTSD symptoms were reported by 49 of 164 patients (29.9%) in the intervention group vs 60 of 175 (34.3%) in the control group (risk difference, -4% [95% CI, -15% to 6%]; P = .39). The median (interquartile range) IES-R score was 12 (5-25) in the intervention group vs 13 (6-27) in the control group (difference, -1.47 [95% CI, -1.93 to 4.87]; P = .38). There were no significant differences in any of the 6 prespecified comparative secondary outcomes.

Conclusions And Relevance: Among patients who received mechanical ventilation in the ICU, the use of an ICU diary filled in by clinicians and family members did not significantly reduce the number of patients who reported significant PTSD symptoms at 3 months. These findings do not support the use of ICU diaries for preventing PTSD symptoms.

Trial Registration: ClinicalTrials.gov Identifier: NCT02519725.
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http://dx.doi.org/10.1001/jama.2019.9058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635906PMC
July 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

Effect of fluid balance control in critically ill patients: Design of the stepped wedge trial POINCARE-2.

Contemp Clin Trials 2019 08 29;83:109-116. Epub 2019 Jun 29.

Université de Lorraine, CHRU-Nancy, Service de Médecine Intensive Réanimation, F-54000 Nancy, France.

A high number of recent studies have shown that a positive fluid balance is independently associated with impaired prognosis in specific populations of patients hospitalized in intensive care unit (ICU): acute kidney injury, acute respiratory distress syndrome (ARDS), sepsis, high risk surgery. However, to date, there is no evidence that control of fluid overload reduces mortality in critically ill patients. The main objective is to assess the efficacy of a strategy limiting fluid overload on mortality in unselected critically ill patients hospitalized in ICU. We hypothesized that a strategy based on a weight-driven recommendation of restricted fluid intake, diuretics, and ultrafiltration initiated from 48 h up to 14 days after admission in critically ill patients would reduce all-cause mortality as compared to usual care. We use a stepped wedge cluster randomized controlled trial combined with a quasi-experimental (before-and-after) study. Patients under mechanical ventilation, admitted since >48 h and < 72 h in ICU, and with no discharge planned for the next 24 h are eligible. A total of 1440 patients are expected to be enrolled in 12 ICUs. Sociodemographic and clinical data are collected at inclusion, and outcomes are collected during the follow-up. Primary outcome is all-cause mortality at 60 days after admission. Secondary outcomes are patients weight differences between admission and day7 (or day 14), 28-day, in-hospital, and 1-year mortality, end-organ damages, and unintended harmful events. Analyses will be held in intention-to-treat. If POINCARE-2 strategy proves effective, then guidelines on fluid balance control might be extended to all critically ill patients. Trial registration: ClinicalTrials.govNCT02765009.
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http://dx.doi.org/10.1016/j.cct.2019.06.020DOI Listing
August 2019

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

The ICU-Diary study: prospective, multicenter comparative study of the impact of an ICU diary on the wellbeing of patients and families in French ICUs.

Trials 2017 Nov 15;18(1):542. Epub 2017 Nov 15.

Department of Intensive Care, Dieppe General Hôpital, Dieppe, France.

Background: Post-intensive care syndrome includes the multiple consequences of an intensive care unit (ICU) stay for patients and families. It has become a new challenge for intensivists. Prevention programs have been disappointing, except for ICU diaries, which report the patient's story in the ICU. However, the effectiveness of ICU diaries for patients and families is still controversial, as the interpretation of the results of previous studies was open to criticism hampering an expanded use of the diary. The primary objective of the study is to evaluate the post-traumatic stress syndrome in patients. The secondary objectives are to evaluate the post-traumatic stress syndrome in families, anxiety and depression symptoms in patients and families, and the recollected memories of patients. Endpoints will be evaluated 3 months after ICU discharge or death.

Methods: A prospective, multicenter, randomized, assessor-blind comparative study of the effect of an ICU diary on patients and families. We will compare two groups: one group with an ICU diary written by staff and family and given to the patient at ICU discharge or to the family in case of death, and a control group without any ICU diary. Each of the 35 participating centers will include 20 patients having at least one family member who will likely visit the patient during their ICU stay. Patients must be ventilated within 48 h after ICU admission and not have any previous chronic neurologic or acute condition responsible for cognitive impairments that would hamper their participation in a phone interview. Three months after ICU discharge or death of the patient, a psychologist will contact the patient and family by phone. Post-traumatic stress syndrome will be evaluated using the Impact of Events Scale-Revised questionnaire, anxiety and depression symptoms using the Hospital Anxiety and Depression Scale questionnaire, both in patients and families, and memory recollection using the ICU Memory Tool Questionnaire in patients. The content of a randomized sample of diaries of each center will be analyzed using a grid. An interview of the patients in the intervention arm will be conducted 6 months after ICU discharge to analyze in depth how they use the diary.

Discussion: This study will provide new insights on the impact of ICU diaries on post-traumatic stress disorders in patients and families after an ICU stay.

Trial Registration: ClinicalTrial.gov, ID: NCT02519725 . Registered on 13 July 2015.
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http://dx.doi.org/10.1186/s13063-017-2283-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688734PMC
November 2017

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 30;10(6):e0130489. Epub 2015 Jun 30.

Service de Réanimation Médicale, Centre Hospitalier Universitaire de Dijon, Bocage Central, Dijon, France; INSERM Centre de Recherche UMR1347, Université de Bourgogne, Dijon, France.

Background: 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.

Methods: 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 500 ml 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.

Results: 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).

Conclusion: We show strong correlation esCCO and echocardiography for measuring CO, and change in CO after fluid infusion in ICU patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488420PMC
April 2016

Fatal thrombotic thrombocytopenic purpura in a psoriasis patient treated with ustekinumab and methotrexate.

Acta Derm Venereol 2015 Apr;95(4):495-6

Service d'Hématologie, Centre Hospitalier Universitaire, Besançon, France.

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http://dx.doi.org/10.2340/00015555-1987DOI Listing
April 2015

Profile of the risk of death after septic shock in the present era: an epidemiologic study.

Crit Care Med 2013 Nov;41(11):2600-9

1Service de réanimation médicale, Centre Hospitalier Universitaire, Dijon, France. 2CHU de Dijon, Centre d'Investigation Clinique-Epidémiologie Clinique/Essais Cliniques, Dijon, France. 3Service de réanimation polyvalente, Centre Hospitalier, Haguenau, France. 4Service de réanimation Médicale, Centre Hospitalier Universitaire Hôpital Civil, Strasbourg, France. 5Service de réanimation médicale, Centre Hospitalier Universitaire, Besançon, France. 6Service de réanimation médicale, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France. 7Service de réanimation médicale, Centre Hospitalier Universitaire Hôpital Central, Nancy, France. 8Service de réanimation médicale, Centre Hospitalier Universitaire, Reims, France. 9Service de réanimation polyvalente, Centre Hospitalier, Metz, France. 10Service de réanimation médicale, Centre Hospitalier Universitaire Brabois, Nancy, France. 11Service de réanimation médicale, Centre Hospitalier, Mulhouse, France. 12Service de réanimation médicale, Centre Hospitalier, Vesoul, France. 13Service de réanimation polyvalente, Centre Hospitalier, Belfort, France. 14Service de réanimation polyvalente, Centre Hospitalier, Montbéliard, France. 15Service de réanimation polyvalente, Centre Hospitalier, Colmar, France. 16Institut National de la Santé et de la Recherche Médicale, U866, Dijon, France. 17Service de Biostatistique et d'Informatique Médicale (DIM), Centre Hospitalier Universitaire, Dijon, France. 18Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada. 19Université de l'Océan Indien, St. Denis, Ile de la Réunion, France.

Objectives: To investigate mortality of ICU patients over a 3-month period after an initial episode of septic shock and to identify factors associated with mortality.

Design: Prospective multicenter observational cohort study.

Setting: Fourteen ICUs from 10 French nonacademic and university teaching hospitals.

Patients: All consecutive adult patients with septic shock admitted between October 2009 and September 2011 were eligible.

Intervention: None.

Measurements And Main Results: Multivariable analyses were performed using a Cox proportional hazard model and a flexible extension of the Cox model. In total, 1,495 of 10,941 patients (13.7%) had septic shock and 1,488 patients (99.5%) were included. Median age was 68 years (range, 58-78 yr). The majority of admissions (84%) were medical. Median (interquartile range) Simplified Acute Physiological Score II and Sequential Organ Failure Assessment were, respectively, 56 (45-70) and 11 (9-14). ICU and hospital mortality were, respectively, 39.4% and 48.6%. At 3 months, 776 patients (52.2%) had died. Factors significantly associated with increased risk of death in the multivariable Cox model were older age, male sex, comorbidities (immune deficiency, cirrhosis), Knaus C/D score, and high Sequential Organ Failure Assessment score. Flexible analyses indicated that the impact of Sequential Organ Failure Assessment score was greatest early after septic shock, while the onset of the effect of age, nosocomial infection, and cirrhosis was later.

Conclusions: This is the most recent large-scale epidemiological study to investigate medium-term mortality in nonselected patients hospitalized in the ICU for septic shock. Advances in early management have improved survival at the initial phase, but risk of death persists in the medium term. Flexible modeling techniques yield insights into the profile of the risk of death in the first 3 months.
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http://dx.doi.org/10.1097/CCM.0b013e31829a6e89DOI Listing
November 2013

Plethysmographic variation index predicts fluid responsiveness in ventilated patients in the early phase of septic shock in the emergency department: a pilot study.

J Crit Care 2013 Oct 15;28(5):634-9. Epub 2013 May 15.

Service de Réanimation, Maladies Infectieuses, Centre Hospitalier de Belfort-Montbéliard, Hôpital de Belfort, Belfort, France.

Purpose: Feasibility study examining whether plethysmographic variability index (PVI) can predict fluid responsiveness in mechanically ventilated patients in the early phase of septic shock in the emergency department.

Materials And Methods: Monocentric, prospective, observational study that included 31 mechanically ventilated and sedated patients with septic shock in whom volume expansion was planned. The patients were equipped with a pulse oximeter that automatically calculated and displayed PVI. The intervention consisted in infusing 8 mL/kg of hydroxylethyl starch over a 20-minute period. Before and after intervention, we recorded PVI and measured the aortic velocity-time integral (VTIao) using transthoracic echocardiography. Responders were defined as patients who increased their VTIao by 15% or higher after fluid infusion.

Results: Sixteen patients were classified as responders, and 15 as nonresponders. Mean PVI values before intervention were significantly higher in responders vs nonresponders (30%±9% vs 8%±5%, P<.001). Plethysmographic variability index values before intervention were correlated with percent changes in VTIao induced by intervention (R2=0.67; P<.001). A PVI threshold value of 19% discriminates responders from nonresponders with a sensitivity of 94% and a specificity of 87% (area under the curve, 0.97; P<.001).

Conclusion: Our study suggests that PVI is a feasible and interesting method to predict fluid responsiveness in early phase septic shock patients in the emergency department.
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http://dx.doi.org/10.1016/j.jcrc.2013.03.011DOI Listing
October 2013

The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study.

Crit Care 2013 Apr 25;17(2):R65. Epub 2013 Apr 25.

Introduction: 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).

Methods: 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1186/cc12598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056892PMC
April 2013

Clinical relevance of echocardiography in acute severe dyspnea.

J Am Soc Echocardiogr 2009 Oct;22(10):1159-64

Unité de Réanimation Polyvalente, Centre Hospitalier de Belfort-Montbéliard, Site de Belfort, Belfort, France.

Background: The aim of this study was to assess the most relevant echocardiographic parameter for the clinical diagnosis of acute dyspnea due to left-heart dysfunction.

Methods: Transthoracic echocardiography was performed in 88 patients in sinus rhythm admitted for respiratory distress. Two experts determined the cause of dyspnea as cardiogenic (26 patients) or noncardiogenic (62 patients).

Results: The feasibility was 100% for the E/A ratio and the E/E deceleration time (EDT) ratio but 97%, 89%, and 85% for the E/Ea ratio, left ventricular ejection fraction (LVEF), and the E/propagation velocity (Vp) ratio, respectively. The area under the receiver operating characteristic curve for E/EDT (0.947 +/- 0.035) was statistically significantly greater than that for E/A (0.753 +/- 0.068) (P = .004). The areas under the curves for all other parameters were not statistically significantly different. In the subpopulation of patients with LVEFs > 45%, the area under the curve for LVEF was significantly smaller than those for E/Ea, E/EDT, and E/Vp.

Conclusion: E/EDT, E/Ea, and E/Vp appear equally useful to distinguish acute dyspnea due to left-heart dysfunction from that of pulmonary origin. However, E/EDT and E/Ea can be considered the best indices with regard to feasibility.
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http://dx.doi.org/10.1016/j.echo.2009.06.022DOI Listing
October 2009

Plethysmographic dynamic indices predict fluid responsiveness in septic ventilated patients.

Intensive Care Med 2007 Jun 29;33(6):993-9. Epub 2007 Mar 29.

Medical Intensive Care Unit, Centre Hospitalier, Belfort, France.

Objectives: In septic patients, reliable non-invasive predictors of fluid responsiveness are needed. We hypothesised that the respiratory changes in the amplitude of the plethysmographic pulse wave (DeltaP(PLET)) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients.

Design: Prospective clinical investigation.

Setting: An 11-bed hospital medical intensive care unit.

Patients: Twenty-three deeply sedated septic patients mechanically ventilated with tidal volume >or=8 ml/kg and equipped with an arterial catheter and a pulse oximetry plethysmographic sensor.

Interventions: Respiratory changes in pulse pressure (DeltaPP), DeltaP(PLET) and cardiac index (transthoracic Doppler echocardiography) were determined before and after volume infusion of colloids (8 ml/kg).

Measurements And Main Results: Twenty-eight volume challenges were performed in 23 patients. Before volume expansion, DeltaPP correlated with DeltaP(PLET) (r2 = 0.71, p<0.001). Changes in cardiac index after volume expansion significantly (p<0.001) correlated with baseline DeltaPP (r2 = 0.76) and DeltaP(PLET) (r2 = 0.50). The patients were defined as responders to fluid challenge when cardiac index increased by at least 15% after the fluid challenge. Such an event occurred 18 times. Before volume challenge, a DeltaPP value of 12% and a DeltaP(PLET) value of 14% allowed discrimination between responders and non-responders with sensitivity of 100% and 94% respectively and specificity of 70% and 80% respectively. Comparison of areas under the receiver operator characteristic curves showed that DeltaPP and DeltaP(PLET) predicted similarly fluid responsiveness.

Conclusion: The present study found DeltaP(PLET) to be as accurate as DeltaPP for predicting fluid responsiveness in mechanically ventilated septic patients.
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http://dx.doi.org/10.1007/s00134-007-0602-6DOI Listing
June 2007

Pre-ejection period variations predict the fluid responsiveness of septic ventilated patients.

Crit Care Med 2005 Nov;33(11):2534-9

Intensive Care Unit, Centre Hospitalier, Belfort, France.

Objectives: In septic patients with acute circulatory failure, reliable predictors of fluid responsiveness are needed at the bedside. We hypothesized that the respiratory change in pre-ejection period (DeltaPEP) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients.

Design: Prospective clinical investigation.

Setting: A ten-bed hospital intensive care unit.

Patients: Patients admitted after septic shock equipped with an arterial catheter.

Interventions: Pre-ejection period (PEP)--defined as the time interval between the beginning of the R wave on the electrocardiogram and the upstroke of the radial arterial pressure curve (PEPKT) or the pulse plethysmographic waveforms (PEPPLET)--and cardiac index (transthoracic echocardiography-Doppler) were determined before and after volume infusion of colloid (8 mL x kg). DeltaPEP (%) was defined as the difference between expiratory and inspiratory PEP divided by the mean of expiratory and inspiratory values. Respiratory changes in pulse pressure (DeltaPP) was also measured.

Measurements And Main Results: : Twenty-two volume challenges were done in 20 deeply sedated patients. DeltaPEPKT, DeltaPEPPLET, and DeltaPP (measured in all patients) before volume expansion were correlated with cardiac index change after fluid challenge (r = .73, r = .67, and r = .70, respectively, p < .0001). Patients with a cardiac index increase induced by volume expansion > or = 15% and <15% were classified as responders and nonresponders, respectively. Receiver operating characteristic curves showed that the threshold DeltaPP value of 17% allowed discrimination between responder/nonresponder patients with a sensitivity of 85% and a specificity of 100%. For both DeltaPEPKT and DeltaPEPPLET, the best threshold value was 4% with a sensitivity-specificity of 92%-89% and 100%-67%, respectively.

Conclusions: The present study found DeltaPEPKT and DeltaPEPPLET to be as accurate as DeltaPP in the prediction of fluid responsiveness in mechanically ventilated septic patients.
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http://dx.doi.org/10.1097/01.ccm.0000186415.43713.2fDOI Listing
November 2005

Increased blood flow prevents intramucosal acidosis in sheep endotoxemia: a controlled study.

Crit Care 2005 Apr 11;9(2):R66-73. Epub 2005 Jan 11.

Intensive Care Unit, Sanatorio Otamendi y Miroli, Buenos Aires, Argentina.

Introduction: Increased intramucosal-arterial carbon dioxide tension (PCO2) difference (DeltaPCO2) is common in experimental endotoxemia. However, its meaning remains controversial because it has been ascribed to hypoperfusion of intestinal villi or to cytopathic hypoxia. Our hypothesis was that increased blood flow could prevent the increase in DeltaPCO2.

Methods: In 19 anesthetized and mechanically ventilated sheep, we measured cardiac output, superior mesenteric blood flow, lactate, gases, hemoglobin and oxygen saturations in arterial, mixed venous and mesenteric venous blood, and ileal intramucosal PCO2 by saline tonometry. Intestinal oxygen transport and consumption were calculated. After basal measurements, sheep were assigned to the following groups, for 120 min: (1) sham (n = 6), (2) normal blood flow (n = 7) and (3) increased blood flow (n = 6). Escherichia coli lipopolysaccharide (5 microg/kg) was injected in the last two groups. Saline solution was used to maintain blood flood at basal levels in the sham and normal blood flow groups, or to increase it to about 50% of basal in the increased blood flow group.

Results: In the normal blood flow group, systemic and intestinal oxygen transport and consumption were preserved, but DeltaPCO2 increased (basal versus 120 min endotoxemia, 7 +/- 4 versus 19 +/- 4 mmHg; P < 0.001) and metabolic acidosis with a high anion gap ensued (arterial pH 7.39 versus 7.35; anion gap 15 +/- 3 versus 18 +/- 2 mmol/l; P < 0.001 for both). Increased blood flow prevented the elevation in DeltaPCO2 (5 +/- 7 versus 9 +/- 6 mmHg; P = not significant). However, anion-gap metabolic acidosis was deeper (7.42 versus 7.25; 16 +/- 3 versus 22 +/- 3 mmol/l; P < 0.001 for both).

Conclusions: In this model of endotoxemia, intramucosal acidosis was corrected by increased blood flow and so might follow tissue hypoperfusion. In contrast, anion-gap metabolic acidosis was left uncorrected and even worsened with aggressive volume expansion. These results point to different mechanisms generating both alterations.
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http://dx.doi.org/10.1186/cc3021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1175914PMC
April 2005

Intramucosal-arterial PCO2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia.

Crit Care 2002 Dec 28;6(6):514-20. Epub 2002 Aug 28.

Cátedra de Farmacologia, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina.

Introduction: An elevation in intramucosal-arterial PCO2 gradient (DeltaPCO2) could be determined either by tissue hypoxia or by reduced blood flow. Our hypothesis was that in hypoxic hypoxia with preserved blood flow, DeltaPCO2 should not be altered.

Methods: In 17 anesthetized and mechanically ventilated sheep, oxygen delivery was reduced by decreasing flow (ischemic hypoxia, IH) or arterial oxygen saturation (hypoxic hypoxia, HH), or no intervention was made (sham). In the IH group (n = 6), blood flow was lowered by stepwise hemorrhage; in the HH group (n = 6), hydrochloric acid was instilled intratracheally. We measured cardiac output, superior mesenteric blood flow, gases, hemoglobin, and oxygen saturations in arterial blood, mixed venous blood, and mesenteric venous blood, and ileal intramucosal PCO2 by tonometry. Systemic and intestinal oxygen transport and consumption were calculated, as was DeltaPCO2. After basal measurements, measurements were repeated at 30, 60, and 90 minutes.

Results: Both progressive bleeding and hydrochloric acid aspiration provoked critical reductions in systemic and intestinal oxygen delivery and consumption. No changes occurred in the sham group. DeltaPCO2 increased in the IH group (12 +/- 10 [mean +/- SD] versus 40 +/- 13 mmHg; P < 0.001), but remained unchanged in HH and in the sham group (13 +/- 6 versus 10 +/- 13 mmHg and 8 +/- 5 versus 9 +/- 6 mmHg; not significant).

Discussion: In this experimental model of hypoxic hypoxia with preserved blood flow, DeltaPCO2 was not modified during dependence of oxygen uptake on oxygen transport. These results suggest that DeltaPCO2 might be determined primarily by blood flow.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC153432PMC
http://dx.doi.org/10.1186/cc1813DOI Listing
December 2002
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