Jean-Marie Forel

Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

BACKGROUND In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS. METHODS In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. RESULTS The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups. CONCLUSIONS In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)

Femoral vs Jugular Venous Catheterization and Risk of Nosocomial Events in Adults Requiring Acute Renal Replacement Therapy : A Randomized Controlled Trial

CONTEXT Based on concerns about the risk of infection, the jugular site is often preferred over the femoral site for short-term dialysis vascular access. OBJECTIVE To determine whether jugular catheterization decreases the risk of nosocomial complications compared with femoral catheterization. DESIGN, SETTING, AND PATIENTS A concealed, randomized, multicenter, evaluator-blinded, parallel-group trial (the Cathedia Study) of 750 patients from a network of 9 tertiary care university medical centers and 3 general hospitals in France conducted between May 2004 and May 2007. The severely ill, bed-bound adults had a body mass index (BMI) of less than 45 and required a first catheter insertion for renal replacement therapy. INTERVENTION Patients were randomized to receive jugular or femoral vein catheterization by operators experienced in placement at both sites. MAIN OUTCOME MEASURES Rates of infectious complications, defined as catheter colonization on removal (primary end point), and catheter-related bloodstream infection. RESULTS Patient and catheter characteristics, including duration of catheterization, were similar in both groups. More hematomas occurred in the jugular group than in the femoral group (13/366 patients [3.6%] vs 4/370 patients [1.1%], respectively; P = .03). The risk of catheter colonization at removal did not differ significantly between the femoral and jugular groups (incidence of 40.8 vs 35.7 per 1000 catheter-days; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.62-1.16; P = .31). A prespecified subgroup analysis demonstrated significant qualitative heterogeneity by BMI (P for the interaction term < .001). Jugular catheterization significantly increased incidence of catheter colonization vs femoral catheterization (45.4 vs 23.7 per 1000 catheter-days; HR, 2.10; 95% CI, 1.13-3.91; P = .017) in the lowest tercile (BMI <24.2), whereas jugular catheterization significantly decreased this incidence (24.5 vs 50.9 per 1000 catheter-days; HR, 0.40; 95% CI, 0.23-0.69; P < .001) in the highest tercile (BMI >28.4). The rate of catheter-related bloodstream infection was similar in both groups (2.3 vs 1.5 per 1000 catheter-days, respectively; P = .42). CONCLUSION Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high BMI, and may have a higher risk of hematoma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00277888.

Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

BACKGROUND The timing of renal-replacement therapy in critically ill patients who have acute kidney injury but no potentially life-threatening complication directly related to renal failure is a subject of debate. METHODS In this multicenter randomized trial, we assigned patients with severe acute kidney injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 [stages range from 1 to 3, with higher stages indicating more severe kidney injury]) who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure to either an early or a delayed strategy of renal-replacement therapy. With the early strategy, renal-replacement therapy was started immediately after randomization. With the delayed strategy, renal-replacement therapy was initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg per deciliter, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60. RESULTS A total of 620 patients underwent randomization. The Kaplan-Meier estimates of mortality at day 60 did not differ significantly between the early and delayed strategies; 150 deaths occurred among 311 patients in the early-strategy group (48.5%; 95% confidence interval [CI], 42.6 to 53.8), and 153 deaths occurred among 308 patients in the delayed-strategy group (49.7%, 95% CI, 43.8 to 55.0; P=0.79). A total of 151 patients (49%) in the delayed-strategy group did not receive renal-replacement therapy. The rate of catheter-related bloodstream infections was higher in the early-strategy group than in the delayed-strategy group (10% vs. 5%, P=0.03). Diuresis, a marker of improved kidney function, occurred earlier in the delayed-strategy group (P<0.001). CONCLUSIONS In a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients. (Funded by the French Ministry of Health; ClinicalTrials.gov number, NCT01932190.).

Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome

Objective:To evaluate the effects of neuromuscular blocking agents (NMBAs) on pulmonary and systemic inflammation in patients with acute respiratory distress syndrome ventilated with a lung-protective strategy. Design:Multiple-center, prospective, controlled, and randomized trial. Setting:One medical and two medical–surgical intensive care units. Patients:A total of 36 patients with acute respiratory distress syndrome (Pao2/Fio2 ratio of ≤200 at a positive end-expiratory pressure of ≥5 cm H2O) were included within 48 hrs of acute respiratory distress syndrome onset. Interventions:Patients were randomized to receive conventional therapy plus placebo (n = 18) or conventional therapy plus NMBAs (n = 18) for 48 hrs. Both groups were ventilated with a lung-protective strategy (tidal volume between 4 and 8 mL/kg ideal body weight, plateau pressure of ≤30 cm H2O). Measurements and Main Results:Bronchoalveolar lavages and blood samples were performed, before randomization and at 48 hrs, to determine the concentrations of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-8. Pao2/Fio2 ratio was evaluated before randomization and at 24, 48, 72, 96, and 120 hrs. A decrease over time in IL-8 concentrations (p = .034) was observed in the pulmonary compartment of the NMBA group. At 48 hrs after randomization, pulmonary concentrations of IL-1β (p = .005), IL-6 (p = .038), and IL-8 (p = .017) were lower in the NMBA group as compared with the control group. A decrease over time in IL-6 (p = .05) and IL-8 (p = .003) serum concentrations was observed in the NMBA group. At 48 hrs after randomization, serum concentrations of IL-1β (p = .037) and IL-6 (p = .041) were lower in the NMBA group as compared with the control group. A sustained improvement in Pao2/Fio2 ratio was observed and was reinforced in the NMBA group (p < .001). Conclusion:Early use of NMBAs decrease the proinflammatory response associated with acute respiratory distress syndrome and mechanical ventilation.

Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome

ObjectiveTo evaluate the effects of a 48-hr neuromuscular blocking agents (NMBA) infusion on gas exchange over a 120-hr time period in patients with acute respiratory distress syndrome. DesignMultiple center, prospective, controlled, and randomized trial. SettingFour adult medical or mixed medical-surgical intensive care units. PatientsA total of 56 patients with acute respiratory distress syndrome with a Pao2/Fio2 ratio of <150 at a positive end-expiratory pressure of ≥5 cm H2O. InterventionsAfter randomization, patients received either conventional therapy without NMBA (control group) or conventional therapy plus NMBA for the next 48 hrs. The initial ventilator mode was volume-assist/control. The ventilator remained on assist-control mode throughout the initial 48-hr period in both groups. Tidal volume was 6–8 mL/kg ideal body weight. Measurements and Main ResultsWhen analyzed for the entire 120 hrs, there was a significant effect of the NMBA on the course of Pao2/Fio2 ratio (p = .021). Separate comparisons at each time point indicated that patients randomized to the NMBA group had a higher Pao2/Fio2 at 48, 96, and 120 hrs after randomization. Moreover, a decrease of positive end-expiratory pressure (p = .036) was only found in the NMBA group. Two-way repeated-measures analysis of variance exhibited a decrease in positive end-expiratory pressure over time (p = .036). Concerning short-term effects, there was no modification of Pao2/Fio2 ratio 1 hr after randomization in either group. Only one patient (from the control group) developed pneumothorax. ConclusionsUse of NMBA during a 48-hr period in patients with acute respiratory distress syndrome is associated with a sustained improvement in oxygenation.

Comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome*

Objective:Both prone position and high-frequency oscillatory ventilation (HFOV) have the potential to facilitate lung recruitment, and their combined use could thus be synergetic on gas exchange. Keeping the lung open could also potentially be lung protective. The aim of this study was to compare physiologic and proinflammatory effects of HFOV, prone positioning, or their combination in severe acute respiratory distress syndrome (ARDS). Design:Prospective, comparative randomized study. Setting:A medical intensive care unit. Patients:Thirty-nine ARDS patients with a Pao2/Fio2 ratio <150 mm Hg at positive end-expiratory pressure ≥5 cm H2O. Interventions:After 12 hrs on conventional lung-protective mechanical ventilation (tidal volume 6 mL/kg of ideal body weight, plateau pressure not exceeding the upper inflection point, and a maximum of 35 cm H2O; supine-CV), 39 patients were randomized to receive one of the following 12-hr periods: conventional lung-protective mechanical ventilation in prone position (prone-CV), HFOV in supine position (supine-HFOV), or HFOV in prone position (prone-HFOV). Measurements and Main Results:Prone-CV (from 138 ± 58 mm Hg to 217 ± 110 mm Hg, p < .0001) and prone-HFOV (from 126 ± 40 mm Hg to 227 ± 64 mm Hg, p < 0.0001) improved the Pao2/Fio2 ratio whereas supine-HFOV did not alter the Pao2/Fio2 ratio (from 134 ± 57 mm Hg to 138 ± 48 mm Hg). The oxygenation index ({mean airway pressure × Fio2 × 100}/Pao2) decreased in the prone-CV and prone-HFOV groups and was lower than in the supine-HFOV group. Interleukin-8 increased significantly in the bronchoalveolar lavage fluid (BALF) in supine-HFOV and prone-HFOV groups compared with prone-CV and supine-CV. Neutrophil counts were higher in the supine-HFOV group than in the prone-CV group. Conclusions:Although HFOV in the supine position does not improve oxygenation or lung inflammation, the prone position increases oxygenation and reduces lung inflammation in ARDS patients. Prone-HFOV produced similar improvement in oxygenation like prone-CV but was associated with higher BALF indexes of inflammation. In contrast, supine-HFOV did not improve gas exchange and was associated with enhanced lung inflammation.

Long-term outcome in medical patients aged 80 or over following admission to an intensive care unit

IntroductionThe aim of this study was to evaluate factors influencing short- and long-term survival in medical patients aged 80 and over following admission to an intensive care unit.MethodsAll patients aged 80 years or over and admitted between 2001 and 2006 were included in this study. Survival was evaluated between the time of admission and June 2009; factors associated with mortality were determined. Health-related quality of life was evaluated using Short Form (SF)-36 in long-term survivors.ResultsFor the 299 patients included (mean age, 84 ± 4 y), hospital mortality was 55%. Factors independently associated with hospital mortality were a higher SAPS II score at ICU admission; the existence of a fatal disease as reflected by the McCabe score and a cardiac diagnosis at admission. In the 133 hospital survivors, median survival time was 710 days (95% CI, 499-921). Two-year mortality rates were 79% of the initial cohort and 53% of hospital survivors. The standardized ratio of mortality at 2 years after hospital discharge was 2.56 (95% CI, 2.08-3.12) when compared with age- and gender-adjusted mortality of the general population. Factors independently associated with mortality at 2 years after hospital discharge were SAPS II score at ICU admission and the McCabe score. Conversely, functional status prior to admission as assessed by Knaus or Karnofsky scores was not associated with long-term mortality. In long-term survivors, SF-36 physical function scores were poor but scores for pain, emotional well-being and social function were not much affected.ConclusionsThe severity of acute disease at admission influences mortality at the hospital and following discharge in patients aged 80 or over. Although up to 50% of patients discharged from the hospital were still alive at 2 years, mortality was increased when compared with the general population. Physical function of long-term hospital survivors was greatly altered.

Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients.

Objective:To assess the incidence, risk factors, and outcome of active cytomegalovirus (CMV) infection in nonimmunosuppressed intensive care unit (ICU) patients. Design:Prospective epidemiologic study. Setting:A medical ICU in a university hospital. Patients:Two hundred forty-two nonimmunosuppressed ICU patients mechanically ventilated for ≥2 days. Interventions:Routine pp65 antigenemia and serology for CMV were performed at admission, and then weekly. Bronchoalveolar lavage viral cultures were done when pneumonia was suspected. Measurements and Main Results:Thirty-nine of the 242 ICU patients (16.1%, confidence interval 11.5% to 20.7%) developed an active CMV infection, as diagnosed by positive antigenemia (85%) and/or positive rapid viral culture in bronchoalveolar lavage (26%). Antiviral treatment was initiated in 21 (54%) patients. ICU mortality (54% vs. 37%, p = 0.082) and in-hospital mortality (59% vs. 41%, p = 0.058) were increased in patients with active CMV infection, as compared with those without active CMV infection. Active CMV infection and Simplified Acute Physiology Score II at admission were associated with ICU death on multivariate analysis. The patients with active CMV infection had longer mechanical ventilation and longer ICU stay and were significantly more prone to developing bacterial nosocomial infections (p < 0.001). Logistic regression analysis showed that prior admission to other wards (p = 0.043; odds ratio [OR], 2.49), blood transfusions (p = 0.04; OR, 3.31), enteral feeding (p = 0.005; OR, 3.00), recent corticosteroid use before ICU admission (p = 0.08; OR, 2.26), and age (p = 0.07; OR, 1.026) were associated with the occurrence of active CMV infection. Conclusions:Active CMV infection is common among previously healthy patients under mechanical ventilation in a medical ICU. Further studies are needed to evaluate the role of antiviral treatments to reduce both the incidence and the outcome impact of active CMV infection.

Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial.

Objective: The type III secretion system is an important Pseudomonas aeruginosa-virulence determinant in animal models of infection and in humans. Antibody-mediated inhibition of the PcrV protein, an essential component of this system, might abrogate the Pseudomonas aeruginosa ability to damage epithelial cells, neutrophils, and macrophages, thereby limiting its pathogenicity. The objective of the trial was to determine the safety, pharmacokinetics, and ability to prevent Pseudomonas aeruginosa ventilator–associated pneumonia of KB001, a recombinant, PEGylated, engineered, human Fab′ fragment that specifically binds to a Pseudomonas aeruginosa PcrV epitope and blocks its function. Design: Multicenter, randomized, placebo-controlled, double-blind, phase-2a trial. Setting: Ten intensive care units across France. Patients: Thirty-nine Pseudomonas aeruginosa-colonized, but not infected, mechanically ventilated patients. Interventions: Patients were randomized 1:1:1 to receive a single intravenous infusion of KB001, 3 mg/kg (n = 13) or 10 mg/kg (n = 14), or placebo (n = 12). Measurements and Main Results: The primary end points were KB001 safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Secondary end points included serum and lung KB001 pharmacokinetics, and Pseudomonas aeruginosa pneumonia rate within 28 days of its infusion. KB001 was well tolerated and not immunogenic. The 3- and 10-mg/kg groups had respective maximum serum concentrations of 52,811–88,660 and 121,857–285,454 ng/mL, with mean elimination half-lives of 8.1 and 9.3 days. KB001 was detected in endotracheal aspirates from all patients receiving it, as early as day 1 and up to 28 days. Respective mean endotracheal aspirate/serum concentration ratios were 0.092 and 0.085 for the 3- and 10-mg/kg groups, who developed Pseudomonas aeruginosa pneumonia less frequently (33% and 31%, respectively) than placebo recipients (60%). Conclusions: KB001 was safe and well tolerated in this study, with a favorable pharmacokinetic profile and promising potential for reducing Pseudomonas aeruginosa pneumonia incidence in intensive care unit mechanically ventilated patients colonized with this bacterium.

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14(+)CD16(+) proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1β and tumor necrosis factor α. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14(+)CD16(+) monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions.