Yoann Launey

Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury

Issues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations. To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients. The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p<0.001) and VAP onset ≥10 days (p<0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770–0.883) in the learning cohort and 0.805 (95% CI 0.732–0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596–0.751). Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts <48 h. To stop spread of resistant bacteria, we should limit broad antimicrobial therapy in brain-injured pneumonia patients http://ow.ly/UL3pS

Extubation Success Prediction in a Multicentric Cohort of Patients with Severe Brain Injury

BACKGROUND Patients with brain injury are at high risk of extubation failure. METHODS We conducted a prospective observational cohort study in four intensive care units of three university hospitals. The aim of the study was to create a score that could predict extubation success in patients with brain injury. RESULTS A total of 437 consecutive patients with brain injury were included, and 338 patients (77.3%) displayed successful extubation. In the multivariate analysis, four features were associated with success the day of extubation: age less than 40 yr, visual pursuit, swallowing attempts, and a Glasgow coma score greater than 10. In the score, each item counted as one. A score of 3 or greater was associated with 90% extubation success. The area under the receiver-operator curve was 0.75 (95% CI, 0.69 to 0.81). After internal validation by bootstrap, the area under the receiver-operator curve was 0.73 (95% CI, 0.68 to 0.79). Extubation success was significantly associated with shorter duration of mechanical ventilation (11 [95% CI, 5 to 17 days] vs. 22 days [95% CI, 13 to 29 days]; P < 0.0001), shorter intensive care unit length of stay (15 [95% CI, 9 to 23 days] vs. 27 days [95% CI, 21 to 36 days]; P < 0.0001), and lower in-intensive care unit mortality (4 [1.2%] vs. 11 [11.1%]; P < 0.0001). CONCLUSIONS Our score exploring both airway functions and neurologic status may increase the probability of successful extubation in patients with severe brain injury.

Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis.

ABSTRACT Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-&agr;, interleukin (IL)-1&bgr;, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

Liver Dysfunction Is Associated with Long-Term Mortality in Septic Shock

Under septic conditions, the liver plays a pivotal role in regulating a wide range of metabolic, homeostatic, and host-defense activities, and it has been suggested that septic liver dysfunction is involved in the genesis and amplification of multiorgan failure. The incidence of liver dysfunction in severe sepsis is estimated to be between 1 and 47%, depending on the restrictiveness of the definition (1). Septic liver dysfunction might be associated with mortality (2–5), but no studies have evaluated its effect on long-term mortality in septic shock. To explore this issue, we investigated the data collected during the PROWESS-SHOCK (Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock) trial. Using Sequential Organ Failure Assessment (SOFA) scores, we evaluated the associations of liver dysfunction at the time of enrollment, as well as the development of new-onset or worsening liver dysfunction during septic shock, with shortand long-term mortality. Some of the results of these studies have been previously presented in part at the 35th International Symposium of Intensive Care and Emergency Medicine and published in abstract form (6). Complete details regarding the inclusion and exclusion criteria in the PROWESS-SHOCK trial have been previously reported; notably, patients with coexisting illnesses with a high risk of death such as end-stage liver disease and at increased risk of bleeding (e.g., known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites) were excluded (7). SOFA score was evaluated daily from baseline to Day 7, and thereafter at Days 14 and 28. Date of death was recorded for all the patients who died on or before study Day 180. Mortality at Days 28, 90, and 180 was calculated. Septic liver dysfunction at baseline was defined as a hepatic SOFA score higher than 0 (bilirubin, >20 mmol/L) within 24 hours before infusion of the study drug. New-onset liver dysfunction after baseline was defined as any postbaseline increase in the hepatic SOFA score from 0. Worsening liver dysfunction after baseline was defined as any increase in the hepatic SOFA score from the baseline measurement of SOFA higher than 0. The postbaseline period extended from the study drug infusion to Day 28. Cox proportional hazard methodology was used to construct multivariate models for both the new-onset/worsening liver dysfunction and 180-day mortality. A total of 1,697 patients were randomized in the PROWESSSHOCK trial. The baseline liver SOFA score was assessed in 1,565 patients, 522 (33%) of whom had a liver SOFA score higher than 0 at baseline. No significant relationships were found between baseline liver dysfunction status and mortality at Days 28, 90, or 180. A total of 403 (26%) patients developed liver dysfunction or exhibited worsened liver dysfunction in the 28-day postbaseline period. Of the 1,043 patients without baseline liver dysfunction, 257 (25%) developed liver dysfunction. Of the 522 patients with baseline liver dysfunction, 146 (28%) exhibited worsened liver dysfunction. The median time to new-onset liver dysfunction or worsening liver dysfunction was 2 (interquartile range, 1–4) days. After adjusting for the baseline confounders, including the baseline liver status, significant relationships between the postbaseline new-onset or worsening liver dysfunction and mortalities were found at Days 28, 90, and 180 (Table 1 and Figure 1). We observed a significant relationship between the occurrence or worsening of liver dysfunction during the course of septic shock and mortality until 6 months; however, the same relationship was not found for baseline liver dysfunction. Previous studies underscored the potential effect of septic liver dysfunction on mortality but focused on septic liver dysfunction in cases of severe sepsis (including a high proportion of patients without shock) and using varying definitions of liver injury. These studies only evaluated short-term mortality (2, 3). Smaller studies found an association between liver injury assessed early after admission and mortality. However, the restrictive definitions of liver dysfunction that were used led to the inclusion of patients with more severe liver dysfunction (5, 8). We chose to define liver dysfunction as a liver SOFA score higher than 0. The advantage of the broader definition was the inclusion of all patients, even those with an apparently low septic liver injury score, hypothesizing that even a low-grade injury could cause major effects. No specific therapeutics for the treatment of septic liver dysfunction are currently available. General recommendations concerning early goal-directed resuscitation can be made to avoid additional liver hypoperfusion, and hepatotoxic drugs should be avoided. Several strengths of our study should be underscored: liver dysfunction was studied in a large, international, multicenter cohort of patients with septic shock, ensuring good-quality and generalizable data. The inclusion criteria ensured adequate early resuscitation, and patients with end-stage liver disease were not included. The main limitations are the post hoc analysis design and the relative lack of specificity of the bilirubin as a single descriptor of liver dysfunction. Indeed, several factors can promote hyperbilirubinemia in critically ill patients, such as hemolysis, transfusion, parenteral nutrition, or drug toxicity.

Hospital-acquired pneumonia in ICU

The French Society of Anesthesia and Intensive Care Medicine and the French Society of Intensive Care edited guidelines focused on hospital-acquired pneumonia (HAP) in intensive care unit (ICU). The goal of 16 French-speaking experts was to produce a framework enabling an easier decision-making process for intensivists. The guidelines were related to 3 specific areas related to HAP (prevention, diagnosis and treatment) in 4 identified patient populations (COPD, neutropenia, postoperative and pediatric). The literature analysis and the formulation of the guidelines were conducted according to the Grade of Recommendation Assessment, Development and Evaluation methodology. An extensive literature research over the last 10 years was conducted based on publications indexed in PubMed™ and Cochrane™ databases. HAP should be prevented by a standardized multimodal approach and the use of selective digestive decontamination in units where multidrug-resistant bacteria prevalence was below 20%. Diagnosis relies on clinical assessment and microbiological findings. Monotherapy, in the absence of risk factors for multidrug-resistant bacteria, non-fermenting Gram negative bacilli and/or increased mortality (septic shock, organ failure), is strongly recommended. After microbiological documentation, it is recommended to reduce the spectrum and to prefer monotherapy for the antibiotic therapy of HAP, including for non-fermenting Gram-negative bacilli.

Risk factors for mortality in postoperative peritonitis in critically ill patients

AIM To identify the risk factors for mortality in intensive care patients with postoperative peritonitis (POP). METHODS This was a retrospective analysis using a prospective database that includes all patients hospitalized in a surgical intensive care unit for POP from September 2006 to August 2011. The data collected included demographics, comorbidities, postoperative severity parameters, bacteriological findings, adequacy of antimicrobial therapy and surgical treatments. Adequate source control was defined based on a midline laparotomy, infection source control and intraoperative peritoneal lavage. The number of reoperations needed was also recorded. RESULTS A total of 201 patients were included. The overall mortality rate was 31%. Three independent risk factors for mortality were identified: The Simplified Acute Physiological II Score (OR = 1.03; 95%CI: 1.02-1.05, P < 0.001), postoperative medical complications (OR = 6.02; 95%CI: 1.95-18.55, P < 0.001) and the number of reoperations (OR = 2.45; 95%CI: 1.16-5.17, P = 0.015). Surgery was considered as optimal in 69% of the cases, but without any significant effect on mortality. CONCLUSION The results from the large cohort in this study emphasize the role of the initial postoperative severity parameters in the prognosis of POP. No predefined criteria for optimal surgery were significantly associated with increased mortality, although the number of reoperations appeared as an independent risk factor of mortality.

High-Dose Continuous Oxacillin Infusion Results in Achievement of Pharmacokinetics Targets in Critically Ill Patients with Deep Sternal Wound Infections following Cardiac Surgery

ABSTRACT Knowledge regarding antimicrobial therapy strategies in deep sternal wound infections (DSWI) following cardiac surgery is limited. Therefore, we aimed to determine the steady-state plasma and mediastinal concentrations of oxacillin administered by continuous infusion in critically ill patients with DSWI and to compare these concentrations with the susceptibility of staphylococci recovered. A continuous infusion of oxacillin (150 to 200 mg/kg of body weight/24 h) was administered after a loading dose (50 mg/kg). Plasma and mediastinal concentrations of total and unbound oxacillin were determined 4 h after the loading dose (H4) and then at day 1 (H24) and day 2 (H48). Twelve patients were included. Nine patients exhibited bacteremia, 5 were in septic shock, 8 were positive for Staphylococcus aureus, and 4 were positive for coagulase-negative staphylococci. The median MIC (first to third interquartile range) was 0.25 (0.24 to 0.41) mg/liter. Median plasma concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 64.4 (41.4 to 78.5) and 20.4 (12.4 to 30.4) mg/liter, 56.9 (31.4 to 80.6) and 21.7 (6.5 to 27.3) mg/liter, and 57.5 (32.2 to 85.1) and 20 (14.3 to 35.7) mg/liter. The median mediastinal concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 2.3 (0.7 to 25.9) and 0.9 (<0.5 to 15) mg/liter, 29.1 (19.7 to 38.2) and 12.6 (5.9 to 19.8) mg/liter, and 31.6 (14.9 to 42.9) and 17.1 (6.7 to 26.7) mg/liter. High-dose oxacillin delivered by continuous infusion is a valuable strategy to achieve our pharmacokinetic target (4× MIC) at the site of action at H24. But concerns remain in cases of higher MICs, emphasizing the need for clinicians to obtain the MICs for the bacteria and to monitor oxacillin concentrations, especially the unbound forms, at the target site.

Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment

Objectives The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Results Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Effect of continuous versus intermittent subglottic suctioning on tracheal mucosa by the mallinckrodt taperguard evac oral tracheal tube in intensive care unit ventilated patients: A prospective randomized study

Background and Aims: A risk of tracheal mucosa injury induced by subglottic suctioning has been raised. Therefore, this prospective randomized study aims to compare the effect of continuous suctioning of subglottic secretions versus intermittent suctioning of subglottic secretions (CSSS vs. ISSS) secretions on tracheal mucosa in front of the suctioning port of the endotracheal tube. Patients and Methods: Patients requiring intubation or reintubation in Intensive Care Unit with an expected ventilation duration > 24 h were eligible. Participants received CSSS at −20 mmHg or ISSS at −100 mmHg during 15 s and no suction during 8 s. The effect on tracheal mucosa in front of the suction port was assessed after intubation (T0) and before extubation (T1) using bronchoscopy. Tracheal mucosa damages were graded into five categories (no injury, erythema, edema, ulceration, or necrosis). The occurrence (no injury observed at T0 but present at T1) or the worsening (injury observed at T0 exacerbating at T1) was studied. Results: Seventy-three patients were included and 53 patients (CSSS, n = 26 and ISSS, n = 27) were evaluable on the primary endpoint. The occurrence or worsening of tracheal mucosal damages did not differ between the two groups (CSSS, n = 7 [27%] vs. ISSS, n = 5 [17%], P = 0.465). Daily average volume of suctioned secretion was higher with ISSS (74 ± 100 ml vs. 20 ± 25 ml, P < 0.001). Impossibility to aspirate was higher with CSSS (0.14 ± 0.16 per day vs. 0.03 ± 0.07 per day, P < 0.001). Conclusions: Our results suggest that tracheal mucosal damages did not differ between CSSS and ISSS. The aspirated volume was higher and impossibility to aspirate was lower with ISSS. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01555229.

Impact of Low-Dose Hydrocortisone on the Incidence of Atrial Fibrillation in Patients With Septic Shock: A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study

Purpose: Atrial fibrillation (AF) is common in the intensive care unit (ICU), notably in patients with septic shock for whom inflammation is an already identified risk factor. The aim of this study was to evaluate the effect of low-dose hydrocortisone on AF occurrence in patients with septic shock. Methods: We performed a prospective nonrandomized observational study in 5 academic ICUs in France. From November 2012 to June 2014, all patients ≥16 years having septic shock were included, except those who had a history of AF, had a pacemaker, and/or experienced AF during hospitalization before the onset of shock or in whom the onset of shock occurred prior to admission to the ICU. Hydrocortisone was administered at the discretion of the attending physician. The incidence of AF was compared among patients who received hydrocortisone, and the effect of low-dose hydrocortisone on AF was estimated using the inverse probability treatment weighting method based on propensity scores. Results: A total of 261 patients were included (no-hydrocortisone group, n = 138; hydrocortisone group, n = 123). Atrial fibrillation occurred in 57 (22%) patients. Atrial fibrillation rates were 33 (24%) and 24 (19%) in no-hydrocortisone patients and hydrocortisone patients, respectively. In the weighted sample, the proportion of patients who developed AF was 28.8% in the no-hydrocortisone group and 16.8% in the hydrocortisone group (difference: −11.9%; 95% confidence interval: −23.4% to −0.5%; P = .040). Conclusion: In patients with septic shock, low-dose hydrocortisone was associated with a lower risk of developing AF during the acute phase.