Laurent Papazian

Effect of Statin Therapy on Mortality in Patients With Ventilator-AssociatedPneumonia: A Randomized Clinical Trial

IMPORTANCEnObservational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.nnnOBJECTIVEnTo determine whether statin therapy can decrease day-28 mortality in patients with VAP.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.nnnINTERVENTIONSnParticipants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.nnnMAIN OUTCOMES AND MEASURESnPrimary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.nnnRESULTSnThe study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; Pu2009=u2009.10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (Pu2009=u2009.054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.nnnCONCLUSIONS AND RELEVANCEnIn adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01057758.

De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial

BackgroundIn patients with severe sepsis, no randomized clinical trial has tested the concept of de-escalation of empirical antimicrobial therapy. This study aimed to compare the de-escalation strategy with the continuation of an appropriate empirical treatment in those patients.MethodsThis was a multicenter non-blinded randomized noninferiority trial of patients with severe sepsis who were randomly assigned to de-escalation or continuation of empirical antimicrobial treatment. Recruitment began in February 2012 and ended in April 2013 in nine intensive care units (ICUs) in France. Patients with severe sepsis were assigned to de-escalation (nxa0=xa059) or continuation of empirical antimicrobial treatment (nxa0=xa057). The primary outcome was to measure the duration of ICU stay. We defined a noninferiority margin of 2xa0days. If the lower boundary of the 95xa0% confidence interval (CI) for the difference in patients assigned to the de-escalation group was less than 2xa0days, as compared with that of patients assigned to the continuation group, de-escalation was considered to be noninferior to the continuation strategy. Secondary outcomes included mortality at 90xa0days, occurrence of organ failure, number of superinfections, and number of days with antibiotics during the ICU stay.ResultsThe median duration of ICU stay was 9 [interquartile range (IQR) 5–22] days in the de-escalation group and 8 [IQR 4–15] days in the continuation group, respectively (Pxa0=xa00.71). The mean difference was 3.4 (95xa0% CI −1.7 to 8.5). A superinfection occurred in 16 (27xa0%) patients in the de-escalation group and six (11xa0%) patients in the continuation group (Pxa0=xa00.03). The numbers of antibiotic days were 9 [7–15] and 7.5 [6–13] in the de-escalation group and continuation group, respectively (Pxa0=xa00.03). Mortality was similar in both groups.ConclusionAs compared to the continuation of the empirical antimicrobial treatment, a strategy based on de-escalation of antibiotics resulted in prolonged duration of ICU stay. However, it did not affect the mortality rate.

Acinetobacter baumannii Resistant to Colistin With Impaired Virulence: A Case Report From France

To the Editor—In an article recently published in the Journal, Lopez-Rojas et al [1] demonstrated that an in vitro mutant of Acinetobacter baumannii resistant to colistin had reduced in vivo fitness and decreased virulence, in terms of both mortality and survival, in a mouse model of peritoneal sepsis. They suggest that the lower in vivo bacterial fitness and decreased virulence of this mutant may explain the low incidence of colistin resistance in the clinical setting. We report herein the clinical case of a French patient colonized with an A. baumannii colistin-resistant isolate after colistin therapy without clinical signs of infection. A 58-year-old patient presented with an influenzalike illness on 16 December 2010 and was treated at home with ampicillin-clavulanic acid. On day 3, he was admitted at Salon de Provence hospital for dyspnea, fever, and right lobar pneumonia on chest x-ray. On day 7, the patient required mechanical ventilation after endotracheal intubation for acute respiratory failure. Antibiotherapy was switched to piperacillin-tazobactam and spiramycin. A bronchoalveolar lavage (BAL) sampled at that time was sterile, and influenza virus detection was negative. Treatment was switched to imipenem-amikacin on day 15 for acute respiratory distress syndrome and septic shock. On day 19, extracorporeal membrane oxy-genation (ECMO) was started for re-fractory hypoxemia, and the patient was referred to an intensive care unit (ICU) in Marseille. On day 21, a colistin-susceptible A. baumannii isolate was recovered from BAL, as well as from 3 blood cultures. Treatment was switched to intravenous colistin and rifampin. ECMO was weaned and sedation was stopped on day 27. Colistin and rifampin were stopped on day 35 but a treatment using imipenem-amikacin-colistin was started on day 37 for a new septic shock episode and stopped on day 41, based on negative BAL and blood cultures. While respiratory status improved, tracheal colonization with colistin-resistant A. baumannii was detected from day 50 to day 60 on biweekly endotracheal aspirate cultures. No clinical sign of infection was present during this period. Asymptomatic bacteri-uria to colistin-sensitive A. baumannii was also present by day 50 and was treated with bladder instillations of colistin from day 57. Treatment was stopped on day 67 when colistin-resistant A. baumannii was isolated from urine samples. The patient was discharged alive from the ICU on day 70. Our case report confirms that colistin-resistant A. baumannii strains may be selected in vivo by the use of colistin but that colistin-resistant strains may be …

Effects of norepinephrine on right ventricular function in septic shock patients.

ObjectiveTo study the effects of norepinephrine on right ventricular function in patients with hyperdynamic septic shock.DesignProspective, open study.SettingA 15 bed ICU in a university hospital.Patients9 patients with hyperdynamic septic shock (SBP<90 mmHg, Cl≥4l·min−1·m−2, SVRI≤850 dynes·s·cm−5m−2 and oliguria).InterventionsPlasma volume expansion was used to correct a suspected volume deficit and then, norepinephrine infusion was started and titrated to restore systemic blood pressure to the normal range (mean infusion rate: 1.1±0.2 mcg·kg−1·min−1). Norepinephrine was the only vasoactive agent used in these patients.Measurements and resultsA modified Swan-Ganz catheter mounted with a fast response thermistor was inserted in each patient, allowing repeated measurements of RVEDVI and RVEF. At time of inclusion to the study, all but one patient had elevated MPAP (23±4 mmHg) and RVEF≤50%, and all patients had RVEDVI≥90 ml·m−2. During norepinephrine infusion, MAP increased from 51±9 to 89±10 mmHg (p<0.0001), PVRI increased from 204±35 to 286±63 dynes·s·cm−5·m−2 (p<0.05), and despite this increase in right ventricular afterload, no detrimental effect in RVEF (36±11 to 36±10%) or in RVEDVI (116±30 to 127±40 ml·m−2) was observed. A Frank-Starling relationship for the right ventricle was constructed by plotting an index of ventricular performance (RVSWI) against an index of ventricular preload (RVEDVI). A significant upward shift to the right of the relationship was observed during norepinephrine infusion.ConclusionIt was concluded that norepinephrine exerted a favourable effect on right ventricular function.

Ventilator-associated pneumonia and ICU mortality in severe ARDS patients ventilated according to a lung-protective strategy

IntroductionVentilator-associated pneumonia (VAP) may contribute to the mortality associated with acute respiratory distress syndrome (ARDS). We aimed to determine the incidence, outcome, and risk factors of bacterial VAP complicating severe ARDS in patients ventilated by using a strictly standardized lung-protective strategy.MethodsThis prospective epidemiologic study was done in all the 339 patients with severe ARDS included in a multicenter randomized, placebo-controlled double-blind trial of cisatracurium besylate in severe ARDS patients. Patients with suspected VAP underwent bronchoalveolar lavage to confirm the diagnosis.ResultsNinety-eight (28.9%) patients had at least one episode of microbiologically documented bacterial VAP, including 41 (41.8%) who died in the ICU, compared with 74 (30.7%) of the 241 patients without VAP (P = 0.05). After adjustment, age and severity at baseline, but not VAP, were associated with ICU death. Cisatracurium besylate therapy within 2 days of ARDS onset decreased the risk of ICU death. Factors independently associated with an increased risk to develop a VAP were male sex and worse admission Glasgow Coma Scale score. Tracheostomy, enteral nutrition, and the use of a subglottic secretion-drainage device were protective.ConclusionsIn patients with severe ARDS receiving lung-protective ventilation, VAP was associated with an increased crude ICU mortality which did not remain significant after adjustment.

Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment.

Purpose The optimal treatment duration for ventilator-associated pneumonia is based on one study dealing with late-onset of the condition. Shortening the length of antibiotic treatment remains a major prevention factor for the emergence of multiresistant bacteria. Objective To demonstrate that 2 different antibiotic treatment durations (8 versus 15 days) are equivalent in terms of clinical cure for early-onset ventilator-associated pneumonia. Methods Randomized, prospective, open, multicenter trial carried out from 1998 to 2002. Measurements The primary endpoint was the clinical cure rate at day 21. The mortality rate was evaluated on days 21 and 90. Results 225 patients were included in 13 centers. 191 (84.9%) patients were cured: 92 out of 109 (84.4%) in the 15 day cohort and 99 out of 116 (85.3%) in the 8 day cohort (differenceu200a=u200a0.9%, odds ratiou200a=u200a0.929). 95% two-sided confidence intervals for difference and odds ratio were [−8.4% to 10.3%] and [0.448 to 1.928] respectively. Taking into account the limits of equivalence (10% for difference and 2.25 for odds ratio), the objective of demonstrative equivalence between the 2 treatment durations was fulfilled. Although the rate of secondary infection was greater in the 8 day than the 15 day cohort, the number of days of antibiotic treatment remained lower in the 8 day cohort. There was no difference in mortality rate between the 2 groups on days 21 and 90. Conclusion Our results suggest that an 8-day course of antibiotic therapy is safe for early-onset ventilator-associated pneumonia in intubated patients. Trial Registration ClinicalTrials.gov NCT01559753

Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and administration of buffer therapy. A prospective, multiple-center study.

IntroductionIn this study, we sought describe the incidence and outcomes of severe metabolic or mixed acidemia in critically ill patients as well as the use of sodium bicarbonate therapy to treat these illnesses.MethodsWe conducted a prospective, observational, multiple-center study. Consecutive patients who presented with severe acidemia, defined herein as plasma pH below 7.20, were screened. The incidence, sodium bicarbonate prescription and outcomes of either metabolic or mixed severe acidemia were analyzed.ResultsAmong 2, 550 critically ill patients, 200 (8%) presented with severe acidemia, and 155 (6% of the total admissions) met the inclusion criteria. Almost all patients needed mechanical ventilation and vasopressors during their ICU stay, and 20% of them required renal replacement therapy within the first 24 hours of their ICU stay. Severe metabolic or mixed acidemia was associated with a mortality rate of 57% in the ICU. Delay of acidemia recovery as opposed to initial pH value was associated with increased mortality in the ICU. The type of acidemia did not influence the decision to administer sodium bicarbonate.ConclusionsThe incidence of severe metabolic or mixed acidemia in critically ill patients was 6% in the present study, and it was associated with a 57% mortality rate in the ICU. In contradistinction with the initial acid-base parameters, the rapidity of acidemia recovery was an independent risk factor for mortality. Sodium bicarbonate prescription was very heterogeneous between ICUs. Further studies assessing specific treatments may be of interest in this population.

High or low doses of almitrine bismesylate in ARDS patients responding to inhaled NO and receiving norepinephrine

Abstract.Objective: To evaluate the effects on oxygenation and pulmonary haemodynamics of almitrine bismesylate (AB) 5xa0µg/kg per minute and 16xa0µg/kg per minute in ARDS patients responding to and receiving inhaled NO (iNO) and presenting septic shock requiring norepinephrine, while no difference was observed in a previous trial including iNO responders and nonresponders. Design: Prospective, cohort study. Setting: Adult medico-surgical intensive care unit of a university hospital. Patients: Fifteen patients with ARDS receiving and responding to iNO (10xa0ppm) and presenting septic shock requiring norepinephrine (mean 0.5±0.45 µg/kg per minute, range 0.08– 2.08). Interventions: The protocol consisted of two consecutive phases in a fixed order: continuous intravenous infusion of AB 5xa0µg/kg per minute for 30xa0min, and continuous intravenous infusion of AB 16xa0µg/kg per minute for 30xa0min. Measurements and main results: AB 5xa0µg/kg per minute significantly increased PaO2/FiO2 (P<0.05) compared with iNO alone [160 (range 77–450) mmHg vs 122 (range 70–225) mmHg]. AB 16xa0µg/kg per minute produced a greater increase of PaO2/FiO2 (P<0.05) when compared with 5xa0µg/kg per minute [227 (range 84–501) mmHg]. AB did not improve shunt at any dose regimen. AB produced an increase in mean pulmonary arterial pressure (MPAP) from 22±5 to 25±4xa0mmHg (P<0.03). MPAP did not significantly increase between the two doses. Pulmonary vascular resistances and other haemodynamic and respiratory parameters were not affected by almitrine bismesylate. Conclusions: These results suggest that it is possible to obtain a further improvement in oxygenation by increasing AB infusion rate in ARDS patients iNO responders receiving norepinephrine. Due to the potential deleterious effects of AB, this strategy should be used in the most severely hypoxaemic patients.

High-Flow Nasal Cannula Oxygenation in Immunocompromised Patients With Acute Hypoxemic Respiratory Failure: A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique Study.

Objective: In immunocompromised patients with acute respiratory failure, invasive mechanical ventilation remains associated with high mortality. Choosing the adequate oxygenation strategy is of the utmost importance in that setting. High-flow nasal oxygen has recently shown survival benefits in unselected patients with acute respiratory failure. The objective was to assess outcomes of immunocompromised patients with hypoxemic acute respiratory failure treated with high-flow nasal oxygen. Design: We performed a post hoc analysis of a randomized controlled trial of noninvasive ventilation in critically ill immunocompromised patients with hypoxemic acute respiratory failure. Setting: Twenty-nine ICUs in France and Belgium. Patients: Critically ill immunocompromised patients with hypoxemic acute respiratory failure. Intervention: A propensity score–based approach was used to assess the impact of high-flow nasal oxygen compared with standard oxygen on day 28 mortality. Measurements and Main Results: Among 374 patients included in the study, 353 met inclusion criteria. Underlying disease included mostly malignancies (n = 296; 84%). Acute respiratory failure etiologies were mostly pneumonia (n = 157; 44.4%) or opportunistic infection (n = 76; 21.5%). Noninvasive ventilation was administered to 180 patients (51%). Invasive mechanical ventilation was ultimately needed in 142 patients (40.2%). Day 28 mortality was 22.6% (80 deaths). Throughout the ICU stay, 127 patients (36%) received high-flow nasal oxygen whereas 226 patients received standard oxygen. Ninety patients in each group (high-flow nasal oxygen or standard oxygen) were matched according to the propensity score, including 91 of 180 (51%) who received noninvasive ventilation. High-flow nasal oxygen was neither associated with a lower intubation rate (hazard ratio, 0.42; 95% CI, 0.11–1.61; p = 0.2) nor day 28 mortality (hazard ratio, 0.80; 95% CI, 0.45–1.42; p = 0.45). Conclusions: In immunocompromised patients with hypoxemic acute respiratory failure, high-flow nasal oxygen when compared with standard oxygen did not reduce intubation or survival rates. However, these results could be due to low statistical power or unknown confounders associated with the subgroup analysis. A randomized trial is needed.

Advances in mimivirus pathogenicity.

Viral diseases in the clinical setting have been extensively investigated. Viruses are now considered as potentially responsible for nosocomial infections, especially in intensive care unit (ICU) patients. Mimivirus is the largest virus known to date. Recent studies have suggested that Mimivirus could be responsible for both community-acquired and nosocomial pneumonia. These studies were mainly based on serologic diagnosis, which showed patients with community-acquired pneumonia have more antibodies to Mimivirus than healthy controls. Serologic evidence of Mimivirus pneumonia was also found in mechanically ventilated ICU patients. In a matched-cohort study in which ICU patients with serologic evidence of Mimivirus pneumonia were matched to ICU patients remaining seronegative for Mimivirus, positive serology was associated with an increased duration of both mechanical ventilation and ICU stay. Identification by PCR techniques remains difficult, probably because of the high level of polymorphism of nucleotide sequences of giant viruses. More studies are needed to confirm the clinical impact of Mimivirus in humans.