Thierry Boulain

Prone Positioning in Severe Acute Respiratory Distress Syndrome

BACKGROUND Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial

BACKGROUND Whether continuous renal replacement therapy is better than intermittent haemodialysis for the treatment of acute renal failure in critically ill patients is controversial. In this study, we compare the effect of intermittent haemodialysis and continuous venovenous haemodiafiltration on survival rates in critically ill patients with acute renal failure as part of multiple-organ dysfunction syndrome. METHODS Our prospective, randomised, multicentre study took place between Oct 1, 1999, and March 3, 2003, in 21 medical or multidisciplinary intensive-care units from university or community hospitals in France. Guidelines were provided to achieve optimum haemodynamic tolerance and effectiveness of solute removal in both groups. The two groups were treated with the same polymer membrane and bicarbonate-based buffer. 360 patients were randomised, and the primary endpoint was 60-day survival based on an intention-to-treat analysis. FINDINGS Rate of survival at 60-days did not differ between the groups (32% in the intermittent haemodialysis group versus 33% in the continuous renal replacement therapy group [95 % CI -8.8 to 11.1,]), or at any other time. INTERPRETATION These data suggest that, provided strict guidelines to improve tolerance and metabolic control are used, almost all patients with acute renal failure as part of multiple-organ dysfunction syndrome can be treated with intermittent haemodialysis.

High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure

BACKGROUND Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. METHODS We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. RESULTS A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006). CONCLUSIONS In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).

Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study

Introduction Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. Methods In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. Results 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Conclusion Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups. ClinicalTrials.gov NCT00464204

Mortality rate attributable to ventilator-associated nosocomial pneumonia in an adult intensive care unit: a prospective case-control study.

Objective To evaluate the mortality rate attributable to nosocomial ventilator-associated pneumonia in an intensive care unit. Design Prospective, matched, risk-adjusted cohort study. Setting A 18-bed adult medical-surgical intensive care unit in a 1,100-bed regional and teaching hospital in France. Patients From January 1, 1996, to April 30, 1999, 135 patients who developed nosocomial pneumonia were matched with 135 control patients without nosocomial pneumonia. Interventions None. Measurements and Main Results Nosocomial pneumonia was identified on the basis of results of distal bronchial samples. The matching process was conducted according to the following primary criteria: cause of admission, indication for ventilatory support, immunologic status, cardiac status, probability of death (±5%), Glasgow Coma Scale score (±2 points), age (±7 yrs), and duration of exposure to risk. When possible, case and control patients were matched according to five secondary criteria: respiratory and alcoholism status before admission, diagnosis categories, surgical procedure or not, and gender. The mortality rates were compared between case and control patients by using the Kaplan-Meier estimate and the log-rank test. The influence of nosocomial pneumonia on mortality rate then was tested by adjusting for the secondary criteria and other possible confounding factors by using the Cox proportional-hazards model. The matching process was successful for 1,080 of 1,080 primary criteria. The crude intensive care unit mortality rate was higher in patients with nosocomial pneumonia than in control patients (41 vs. 14%;p < .0001). In actuarial survival analysis, the probability of intensive care unit death was higher in the case patients (odds ratio = 2.7, 95% confidence interval = 1.8–3.1, p = .028). After adjustment, the occurrence of nosocomial pneumonia remained an independent risk factor of death (odds ratio = 2.1, 95% confidence interval = 1.2–3.6, p = .008). Nosocomial pneumonia attributable to multiresistant microorganisms was significantly associated with death (odds ratio = 2.6, 95% confidence interval = 1.1–5.8, p = .02). The length of intensive care unit stay was higher in case than in control patients (31 ± 19 vs. 26 ± 17 days, p < .0001). Conclusions Nosocomial pneumonia is independently associated with death in the intensive care unit. In addition, it increases the length of intensive care unit stay.

Obesity-related excess mortality rate in an adult intensive care unit: A risk-adjusted matched cohort study.

ObjectiveTo evaluate the obesity-related mortality rate in an intensive care unit. DesignAn exposed/unexposed matched cohort study. SettingAn 18-bed adult medical-surgical intensive care unit in a 1,100-bed regional and teaching hospital in France. PatientsFrom January 1, 1999, to December 31, 2001, 170 mechanically ventilated exposed patients (obese patients with body mass index of >30 kg/m2) were matched with 170 mechanically ventilated unexposed patients (with ideal body mass index of 18.5–24.9 kg/m2). InterventionsNone. Measurements and Main ResultsThe matching process was conducted according to eight criteria: cause of admission, indication for ventilatory support, immunologic status, cardiac status, probability of death (±5%), age (±7 yrs), gender, and acquisition of severe events appearing within 24 hrs before admission (defined as resuscitated cardiac arrest, acute respiratory distress syndrome, or septic shock). The mortality rate between exposed and unexposed patients was compared by univariate analysis and then was adjusted for other possible confounding factors by multivariate analysis, using conditional logistic regression. The matching process was successful for 1,360 of 1,360 criteria. Obesity was significantly associated with intensive care unit mortality (odds ratio, 2.1; 95% confidence interval, 1.2–3.6). Obesity-related excess mortality was verified mainly for the youngest patients (odds ratio, 2.5; 95% confidence interval, 1.6–6.1) and for the patients with a probability of intensive care unit death of 11–50% (odds ratio, 2.6; 95% confidence interval, 1.2–5.5). This excess mortality rate could be explained by the higher risk of intensive care unit acquired complications among obese patients than among the unexposed ones (odds ratio, 4; 95% confidence interval, 1.4–11.8). ConclusionsObesity is an independent risk factor for intensive care unit death and should be regarded as a severe comorbidity in such units.

EffectofNotMonitoringResidualGastricVolume on Risk of Ventilator-Associated Pneumonia in Adults Receiving Mechanical Ventilation and Early Enteral Feeding A Randomized Controlled Trial

IMPORTANCE Monitoring of residual gastric volume is recommended to prevent ventilator-associated pneumonia (VAP) in patients receiving early enteral nutrition. However, studies have challenged the reliability and effectiveness of this measure. OBJECTIVE To test the hypothesis that the risk of VAP is not increased when residual gastric volume is not monitored compared with routine residual gastric volume monitoring in patients receiving invasive mechanical ventilation and early enteral nutrition. DESIGN, SETTING, AND PATIENTS Randomized, noninferiority, open-label, multicenter trial conducted from May 2010 through March 2011 in adults requiring invasive mechanical ventilation for more than 2 days and given enteral nutrition within 36 hours after intubation at 9 French intensive care units (ICUs); 452 patients were randomized and 449 included in the intention-to-treat analysis (3 withdrew initial consent). INTERVENTION Absence of residual gastric volume monitoring. Intolerance to enteral nutrition was based only on regurgitation and vomiting in the intervention group and based on residual gastric volume greater than 250 mL at any of the 6 hourly measurements and regurgitation or vomiting in the control group. MAIN OUTCOME MEASURES Proportion of patients with at least 1 VAP episode within 90 days after randomization, as assessed by an adjudication committee blinded to patient group. The prestated noninferiority margin was 10%. RESULTS In the intention-to-treat population, VAP occurred in 38 of 227 patients (16.7%) in the intervention group and in 35 of 222 patients (15.8%) in the control group (difference, 0.9%; 90% CI, -4.8% to 6.7%). There were no significant between-group differences in other ICU-acquired infections, mechanical ventilation duration, ICU stay length, or mortality rates. The proportion of patients receiving 100% of their calorie goal was higher in the intervention group (odds ratio, 1.77; 90% CI, 1.25-2.51; P = .008). Similar results were obtained in the per-protocol population. CONCLUSION AND RELEVANCE Among adults requiring mechanical ventilation and receiving early enteral nutrition, the absence of gastric volume monitoring was not inferior to routine residual gastric volume monitoring in terms of development of VAP. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01137487.

12-h pretreatment with methylprednisolone versus placebo for prevention of postextubation laryngeal oedema: a randomised double-blind trial

BACKGROUND The efficacy of corticosteroids in reducing the incidence of postextubation laryngeal oedema is controversial. We aimed to test our hypothesis that methylprednisolone started 12 h before a planned extubation could prevent postextubation laryngeal oedema. METHODS We did a placebo-controlled, double-blind multicentre trial in 761 adults in intensive-care units. Patients who were ventilated for more than 36 h and underwent a planned extubation received intravenous 20 mg methylprednisolone (n=380) or placebo (381) 12 h before extubation and every 4 h until tube removal. The primary endpoint was occurrence of laryngeal oedema within 24 h of extubation. Laryngeal oedema was clinically diagnosed and deemed serious if tracheal reintubation was needed. Analyses were done on a per protocol and intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00199576. FINDINGS 63 patients could not be assessed, mainly because of self-extubation (n=16) or cancelled extubation (44) between randomisation and planned extubation. 698 patients were analysed (343 in placebo group, 355 in methylprednisolone group). Methylprednisolone significantly reduced the incidence of postextubation laryngeal oedema (11 of 355, 3%vs 76 of 343, 22%, p<0.0001), the global incidence of reintubations (13 of 355, 4%vs 26 of 343, 8%, p=0.02), and the proportion of reintubations secondary to laryngeal oedema (one of 13, 8 %vs 14 of 26, 54%, p=0.005). One patient in each group died after extubation, and atelectasia occurred in one patient given methylprednisolone. INTERPRETATION Methylprednisolone started 12 h before a planned extubation substantially reduced the incidence of postextubation laryngeal oedema and reintubation. Such pretreatment should be considered in adult patients before a planned extubation that follows a tracheal intubation of more than 36 h.

Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial

IMPORTANCE Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00774631.

Intrahospital transport of critically ill ventilated patients: A risk factor for ventilator-associated pneumonia : A matched cohort study

LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Identify the risk factors for ventilator-associated pneumonia (VAP). Describe the risk of VAP after intrahospital transport. Use this information in a clinical setting. All of the authors have disclosed that they have no financial relationships with or interest in any commercial companies pertaining to this educational activity. Wolters Kluwer Health has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit. Objective:To evaluate the impact of intrahospital transport of critically ill ventilated patients on the acquisition of ventilator-associated pneumonia. Design:An exposed/unexposed matched cohort study. Setting:An 18-bed adult medical-surgical intensive care unit in a 1,100-bed regional and teaching hospital in France. Patients:From January 1, 2001, to December 31, 2002, 118 of 228 ventilated patients transported out of the intensive care unit (exposed patients) were matched with 118 unexposed patients selected among 295 ventilated patients who did not undergo intrahospital transport. Interventions:None. Measurements and Main Results:The matching process was conducted according to six criteria: duration of mechanical ventilation, duration of antibiotherapy, indication for ventilatory support, age, probability of death, and surgical procedures or not during intensive care unit stay. The rates of ventilator-associated pneumonia (as defined by usual clinical and biological criteria plus positive culture of bronchoscopy directed catheter) acquisition between exposed and unexposed patients were compared by univariate analysis and then by multivariate analysis (conditional logistic regression and Coxs proportional-hazards model) to account for potential confounding factors. The ventilator-associated pneumonia rate was 26% in exposed patients compared with 10% in the matched unexposed patients. Using conditional logistic regression, two factors were independently associated with ventilator-associated pneumonia: intrahospital transport (odds ratio, 3.1; 95% confidence interval, 1.4–6.7) and the need for reintubation. Using Coxs model, three independent risk factors were identified: the need for reintubation, enteral nutrition, and intrahospital transport (odds ratio, 2.9; 95% confidence interval, 1.4–5.7). The intensive care unit mortality rate was similar (p > .1) in exposed (35%) and unexposed patients (26%) Conclusions:Intrahospital transport appears to be a significant risk factor for ventilator-associated pneumonia. However, the respective roles of intrahospital transport and of the cause that leads clinicians to transport patients (mainly for radiographic examinations) are difficult to dissociate even after multiple statistical adjustments. When intrahospital transport is needed, very cautious measures must be taken before and during intrahospital transport to prevent ventilator-associated pneumonia. In addition, in the few days after intrahospital transport, intensive search for ventilator-associated pneumonia is justified.