Jean-Yves Lefrant

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.)

Positive End-Expiratory Pressure Setting in Adults With Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

CONTEXT The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated. OBJECTIVE To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. DESIGN, SETTING, AND PATIENTS A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005. INTERVENTION Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385). MAIN OUTCOME MEASURES The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. RESULTS The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements. CONCLUSIONS A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00188058.

Clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit : A prospective, multiple-center study

Objectives:To describe the current practice of physicians, to report complications associated with endotracheal intubation (ETI) performed in THE intensive care unit (ICU), and to isolate predictive factors of immediate life-threatening complications. Design:Multiple-center observational study. Setting:Seven intensive care units of two university hospitals. Patients:We evaluated 253 occurrences of ETI in 220 patients. Interventions:From January 1 to June 30, 2003, data related to all ETI performed in ICU were collected. Information regarding patient descriptors, procedures, and immediate complications were analyzed. Measurements and Main Results:The main indications to intubate the trachea were acute respiratory failure, shock, and coma. Some 148 ETIs (59%) were performed by residents. At least one severe complication occurred in 71 ETIs (28%): severe hypoxemia (26%), hemodynamic collapse (25%), and cardiac arrest (2%). The other complications were difficult intubation (12%), cardiac arrhythmia (10%), esophageal intubation (5%), and aspiration (2%). Presence of acute respiratory failure and the presence of shock as an indication for ETI were identified as independent risk factors for occurrence of complications, and ETI performed by a junior physician supervised by a senior (i.e., two operators) was identified as a protective factor for the occurrence of complications. Conclusions:ETI in ICU patients is associated with a high rate of immediate and severe life-threatening complications. Independent risk factors of complication occurrence were presence of acute respiratory failure and presence of shock as an indication for ETI. Further studies should aim to better define protocols for intubation in critically ill patients to make this procedure safer.

Impact of systematic evaluation of pain and agitation in an intensive care unit.

Objective:To measure the impact of implementation of the systematic evaluation of pain and agitation by nurses using the Behavioral Pain Scale (BPS), the Numerical Rating Scale (NRS) for pain, and the Richmond Agitation Sedation Scale (RASS) associated with medical staff education in analgesia and sedation management in intensive care unit (ICU) patients. Design:Two-phase, prospective, controlled study. Setting:Twelve-bed medical-surgical ICU in a university hospital. Patients:Consecutive patients staying >24 hrs in ICU. Interventions:BPS, NRS, and RASS were measured twice daily, at rest, by independent observers during 21 wks (control group) and after 4 wks of training, by nurses during 29 wks (intervention group). In the intervention group, the treating physician was alerted in case of pain defined by BPS >5 or NRS >3 or in case of agitation defined by RASS >1. Measurements and Main Results:A total of 230 patients were included (control group, n = 100; intervention group, n = 130). Baseline characteristics were not significantly different. The incidence of pain and agitation decreased significantly in the intervention group: 63% vs. 42% (p = .002) and 29% vs. 12% (p = .002), respectively. Rate of severe pain and agitation events defined by NRS >6 and RASS >2, respectively, also decreased significantly. There were significantly more therapeutic changes in the intervention group in the way of an escalation but also in the way of a de-escalation for analgesic and psychoactive drugs. Compared with the control group, there was a marked decrease in the duration of mechanical ventilation (120 [interquartile range 48–312] vs. 65 (24–192) hrs, p = .01) and nosocomial infections rate (17% vs. 8%, p < .05) in the intervention group. There was no significant difference in median length of stay (9 [4, 15] vs. 7 [4, 13] days) and mortality in ICU (12 vs. 15%). Conclusions:Systematic evaluation of pain and agitation, and analgesics and sedatives need was associated with a decrease in incidence of pain and agitation, duration of mechanical ventilation and nosocomial infections.

Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

BACKGROUND Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. METHODS In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0.3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. FINDINGS 234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0-1.4], p=0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0-3] in both groups; p=0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug. INTERPRETATION Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis. FUNDING French Ministry of Health.

The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales

&NA; Unlike wards, where chronic and acute pain are regularly managed, comparisons of the most commonly used self‐report pain tools have not been reported for the intensive care unit (ICU) setting. The objective of this study was to compare the feasibility, validity and performance of the Visual Analog Scale (horizontal (VAS‐H) and vertical (VAS‐V) line orientation), the Verbal Descriptor Scale (VDS), the 0–10 oral Numeric Rating Scale (NRS‐O) and the 0–10 visually enlarged laminated NRS (NRS‐V) for pain assessment in critically ill patients. One hundred and eleven consecutive patients admitted into a medical‐surgical ICU were included as soon as they became alert and were able to follow simple commands. Pain was measured using the 5 scales in a randomized order upon enrollment‐(T1) and after‐(T2) administration of an analgesic or, in absence of pain upon enrollment, after a nociceptive procedure. The rate of any response obtained both at T1 and T2 (success rate) was significantly higher for NRS‐V (91%) compared with NRS‐O (83%), VDS (78%), VAS‐H (68%) and VAS‐V (66%). Pain intensity changed significantly between T1 and T2, showing a good validity and responsiveness for the 5 scales, which correlated well between each other. The negative predictive value calculated from true and false negatives defined by real and false absence of pain was highest for NRS‐V (90%). In conclusion, the NRS‐V should be the tool of choice for the ICU setting, because it is the most feasible and discriminative self‐report scale for measuring critically ill patients’ pain intensity.

An Increase in Aortic Blood Flow after an Infusion of 100 ml Colloid over 1 Minute Can Predict Fluid Responsiveness The Mini-fluid Challenge Study

Background: Predicting fluid responsiveness remains a difficult question in hemodynamically unstable patients. The authors objective was to test whether noninvasive assessment by transthoracic echocardiography of subaortic velocity time index (VTI) variation after a low volume of fluid infusion (100 ml hydroxyethyl starch) can predict fluid responsiveness. Methods: Thirty-nine critically ill ventilated and sedated patients with acute circulatory failure were prospectively studied. Subaortic VTI was measured by transthoracic echocardiography before fluid infusion (baseline), after 100 ml hydroxyethyl starch infusion over 1 min, and after an additional infusion of 400 ml hydroxyethyl starch over 14 min. The authors measured the variation of VTI after 100 ml fluid (&Dgr;VTI100) for each patient. Receiver operating characteristic curves were generated for (&Dgr;VTI100). When available, receiver operating characteristic curves also were generated for pulse pressure variation and central venous pressure. Results: After 500 ml volume expansion, VTI increased ≥ 15% in 21 patients (54%) defined as responders. &Dgr;VTI100 ≥ 10% predicted fluid responsiveness with a sensitivity and specificity of 95% and 78%, respectively. The area under the receiver operating characteristic curves of &Dgr;VTI100 was 0.92 (95% CI: 0.78–0.98). In 29 patients, pulse pressure variation and central venous pressure also were available. In this subgroup of patients, the area under the receiver operating characteristic curves for &Dgr;VTI100, pulse pressure variation, and central venous pressure were 0.90 (95% CI: 0.74–0.98, P < 0.05), 0.55 (95% CI: 0.35–0.73, NS), and 0.61 (95% CI: 0.41–0.79, NS), respectively. Conclusion: In patients with low volume mechanical ventilation and acute circulatory failure, &Dgr;VTI100 accurately predicts fluid responsiveness.

Early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the MACOCHA score in a multicenter cohort study.

RATIONALE Difficult intubation in the intensive care unit (ICU) is a challenging issue. OBJECTIVES To develop and validate a simplified score for identifying patients with difficult intubation in the ICU and to report related complications. METHODS Data collected in a prospective multicenter study from 1,000 consecutive intubations from 42 ICUs were used to develop a simplified score of difficult intubation, which was then validated externally in 400 consecutive intubation procedures from 18 other ICUs and internally by bootstrap on 1,000 iterations. MEASUREMENTS AND MAIN RESULTS In multivariate analysis, the main predictors of difficult intubation (incidence = 11.3%) were related to patient (Mallampati score III or IV, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening); pathology (severe hypoxia, coma); and operator (nonanesthesiologist). From the β parameter, a seven-item simplified score (MACOCHA score) was built, with an area under the curve (AUC) of 0.89 (95% confidence interval [CI], 0.85-0.94). In the validation cohort (prevalence of difficult intubation = 8%), the AUC was 0.86 (95% CI, 0.76-0.96), with a sensitivity of 73%, a specificity of 89%, a negative predictive value of 98%, and a positive predictive value of 36%. After internal validation by bootstrap, the AUC was 0.89 (95% CI, 0.86-0.93). Severe life-threatening events (severe hypoxia, collapse, cardiac arrest, or death) occurred in 38% of the 1,000 cases. Patients with difficult intubation (n = 113) had significantly higher severe life-threatening complications than those who had a nondifficult intubation (51% vs. 36%; P < 0.0001). CONCLUSIONS Difficult intubation in the ICU is strongly associated with severe life-threatening complications. A simple score including seven clinical items discriminates difficult and nondifficult intubation in the ICU. Clinical trial registered with www.clinicaltrials.gov (NCT 01532063).

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

IMPORTANCE Observational 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. OBJECTIVE To determine whether statin therapy can decrease day-28 mortality in patients with VAP. DESIGN, SETTING, AND PARTICIPANTS Randomized, 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. INTERVENTIONS Participants 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. MAIN OUTCOMES AND MEASURES Primary 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. RESULTS The 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%]; P = .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 (P = .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. CONCLUSIONS AND RELEVANCE In 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01057758.

pulsed Doppler Ultrasonography Guidance for Catheterization of the Subclavian Vein : a Randomized Study

Background Catheterization of the subclavian vein may lead to severe complications. The current randomized study compared a technique of pulsed Doppler ultrasonography guidance and the standard method for subclavian vein catheterization. Methods Standard and Doppler ultrasonography guidance methods were performed by the same physician in 286 patients, 143 in each group. Primary end points were immediate complications (arterial puncture, pneumothorax, wrong position of catheter tip), failures, the number of subclavian vein catheterizations with immediate complication or failure, the number of skin punctures per catheterization, and the time to placement of the guide wire. The secondary end points were the determination of predicting factors of successful cannulation in each group. Results Both groups were similar according to morphologic parameters of the patients. A greater number of subclavian vein catheterizations were performed on the right side using Doppler guidance (105 vs. 73, P < 0.01). Doppler guidance decreased complications (5.6% vs. 16.8%, P < 0.01), largely because of a smaller number of catheters for which the tip was defined to be in incorrect position (0.7% vs. 7.7%, P < 0.01). The time to catheterization was longer with Doppler guidance (300 vs. 27 s, P < 0.001). Failures, catheterizations of the subclavian vein with immediate complications or failure, and the total number of skin punctures per catheterization were similar in both groups. Using Doppler guidance, the presence of a good Doppler signal (124 of 143) was predictive of successful catheterization (123 successful cannulations, P < 0.001). Conclusions Doppler guidance reduces the incidence of inappropriately positioned subclavian catheters.