Video Laryngoscopy vs Direct Laryngoscopy on Successful First-Pass Orotracheal Intubation Among ICU Patients: A Randomized Clinical Trial

Key Points

Question  Should video laryngoscopy be used for orotracheal intubation in the intensive care unit (ICU) despite conflicting evidence that it improves the first-pass success rate?

Findings  Video laryngoscopy for orotracheal intubation in the ICU did not improve the first-pass success rate compared with conventional direct laryngoscopy (67.7% vs 70.3%, respectively).

Meaning  Video laryngoscopy did not improve the frequency of successful first-pass intubation in the ICU.

Importance  In the intensive care unit (ICU), orotracheal intubation can be associated with increased risk of complications because the patient may be acutely unstable, requiring prompt intervention, often by a practitioner with nonexpert skills. Video laryngoscopy may decrease this risk by improving glottis visualization.

Objective  To determine whether video laryngoscopy increases the frequency of successful first-pass orotracheal intubation compared with direct laryngoscopy in ICU patients.

Design, Setting, and Participants  Randomized clinical trial of 371 adults requiring intubation while being treated at 7 ICUs in France between May 2015 and January 2016; there was 28 days of follow-up.

Interventions  Intubation using a video laryngoscope (n = 186) or direct laryngoscopy (n = 185). All patients received general anesthesia.

Main Outcomes and Measures  The primary outcome was the proportion of patients with successful first-pass intubation. The secondary outcomes included time to successful intubation and mild to moderate and severe life-threatening complications.

Results  Among 371 randomized patients (mean [SD] age, 62.8 [15.8] years; 136 [36.7%] women), 371 completed the trial. The proportion of patients with successful first-pass intubation did not differ significantly between the video laryngoscopy and direct laryngoscopy groups (67.7% vs 70.3%; absolute difference, −2.5% [95% CI, −11.9% to 6.9%]; P = .60). The proportion of first-attempt intubations performed by nonexperts (primarily residents, n = 290) did not differ between the groups (84.4% with video laryngoscopy vs 83.2% with direct laryngoscopy; absolute difference 1.2% [95% CI, −6.3% to 8.6%]; P = .76). The median time to successful intubation was 3 minutes (range, 2 to 4 minutes) for both video laryngoscopy and direct laryngoscopy (absolute difference, 0 [95% CI, 0 to 0]; P = .95). Video laryngoscopy was not associated with life-threatening complications (24/180 [13.3%] vs 17/179 [9.5%] for direct laryngoscopy; absolute difference, 3.8% [95% CI, −2.7% to 10.4%]; P = .25). In post hoc analysis, video laryngoscopy was associated with severe life-threatening complications (17/179 [9.5%] vs 5/179 [2.8%] for direct laryngoscopy; absolute difference, 6.7% [95% CI, 1.8% to 11.6%]; P = .01) but not with mild to moderate life-threatening complications (10/181 [5.4%] vs 14/181 [7.7%]; absolute difference, −2.3% [95% CI, −7.4% to 2.8%]; P = .37).

Conclusions and Relevance  Among patients in the ICU requiring intubation, video laryngoscopy compared with direct laryngoscopy did not improve first-pass orotracheal intubation rates and was associated with higher rates of severe life-threatening complications. Further studies are needed to assess the comparative effectiveness of these 2 strategies in different clinical settings and among operators with diverse skill levels.

Trial Registration  clinicaltrials.gov Identifier: NCT02413723

Quiz Ref IDIntubation of patients in the intensive care unit (ICU) carries a risk of potentially severe complications, including cardiac arrest.¹ Hypoxemia is common in patients in the ICU requiring intubation, which must be performed rapidly to avoid aspiration because the patient is usually not in a fasted state.² Studies have assessed interventions such as routine neuromuscular blockade that are designed to improve intubation success rates.³ Care bundles⁴ combined with training on simulators have improved the safety of intubation. Nevertheless, intubation in the ICU still carries higher morbidity and mortality rates compared with intubation in the operating room.⁵

Quiz Ref IDFor the past half century, orotracheal intubation has been performed using the Macintosh laryngoscope for direct laryngoscopy. The video laryngoscope is a recently developed device that provides indirect visualization of the glottis via a camera. Video laryngoscopes have been extensively studied for intubation in the operating room and may facilitate orotracheal intubation compared with direct laryngoscopy.⁶ Video laryngoscopes have either a curved blade similar to the Macintosh laryngoscope or a tube channel.

In the ICU, observational studies and small randomized studies support the use of video laryngoscopy for orotracheal intubation,⁷ regardless of the predicted difficulty of intubation. Some of these studies also recorded adverse effects such as longer duration of the orotracheal intubation procedure⁸ and higher mortality.⁹ Therefore, whether use of video laryngoscopes in ICUs¹⁰ is of greater benefit to patients deserves investigation.

The objective of this study was to test the hypothesis that routine use of the video laryngoscope for orotracheal intubation of patients in the ICU increased the frequency of successful first-pass intubation¹¹ compared with use of the Macintosh direct laryngoscope.

The McGrath Mac Videolaryngoscope Versus Macintosh Laryngoscope for Orotracheal Intubation in the Critical Care Unit (MACMAN) trial was an institutionally sponsored, nonblinded, multicenter, open-label, 2 parallel-group randomized clinical trial (RCT) conducted at 7 ICUs in France. The protocol¹² (appears in Supplement 1) was approved by the appropriate ethics committee (Comité de Protection des Personnes Ouest 2, #2014-A00674-43). According to French law, because the strategies used in both groups were considered components of standard care, consent was not required; however, it was mandatory that certain information be provided to the patient or next of kin.

If no next of kin was available, patients without decision-making competence were included in compliance with French law. Patients were informed as soon as they regained competence and were asked whether they wanted to remain in the trial. Data from patients who requested full withdrawal were to be excluded from the analysis in accordance with French law.

In addition to electronic database monitoring, onsite monitoring was performed by a study nurse at each ICU to ensure the good quality and completeness of the study data. All investigators attended a meeting about the trial before inclusion of the first patient.

Patients were recruited between May and December 2015. Patient follow-up was 28 days. The follow-up period ended in January 2016.

Quiz Ref IDInclusion criteria were ICU admission and need for orotracheal intubation to allow mechanical ventilation. Exclusion criteria were (1) contraindications to orotracheal intubation (eg, unstable spinal lesion), (2) insufficient time to include and randomize the patient (eg, because of cardiac arrest), (3) age younger than 18 years, (4) currently pregnant or breastfeeding, (5) correctional facility inmate, (6) under guardianship, (7) without health insurance, (8) refusal by patient or next of kin, and (9) previous enrollment in an RCT with intubation as the primary end point (including previous inclusion in the present trial).

The randomization sequence was generated by a statistician at the clinical research unit (Centre Hospitalier Département de la Vendée) who had no role in patient recruitment. Randomization was performed in blocks of 4. The randomization scheme was balanced and stratified by center and expert or nonexpert status of the individual performing intubation.¹³ An expert was defined as a physician who had either worked at ICUs for at least 5 years or worked at ICUs for at least 1 year after receiving at least 2 years of anesthesiology training. Physicians who did not meet these criteria were classified as nonexperts.

The software used to collect the data from the electronic report form automatically allocated the patients, thereby ensuring concealment. Included patients were followed up until day 28 after randomization.

All physicians working at the participating ICUs received hands-on training in the use of the video laryngoscope and conventional (direct) laryngoscope. Specific equipment was provided to each participating center for the training sessions (eg, size 3 and 4 blades of each laryngoscope type and manikins for intubation training). Orotracheal intubation performed by a nonexpert was always supervised by an expert. Orotracheal intubation was performed in both groups according to the following protocol:

1. Preoxygenation was achieved using the device chosen by the bedside physician according to the standard ICU protocol. Options included a bag valve mask delivering oxygen at a flow of 15 L/min or greater for at least 3 minutes; a nonrebreathing (high concentration) mask delivering oxygen at a flow of 15 L/min or greater for at least 3 minutes; a ventilator in noninvasive mode providing 100% fraction of inspired oxygen (Fio₂) for at least 3 minutes¹⁴; or a high-flow nasal oxygen device (eg, Optiflow) delivering oxygen at a flow of 60 L/min or greater with 100% Fio₂ for at least 3 minutes.¹⁵

2. General anesthesia was then induced by injecting a hypnotic agent and a neuromuscular blocking agent. The choice of agent and dosage were chosen by the individual performing the intubation. In agreement with the guidelines,¹⁶ 2 principles were applied: (1) the preferred neuromuscular blocking agent in the absence of contraindications (eg, hyperkalemia, burn injury >24 hours earlier, spinal lesion, or allergy) was 1 mg/kg of succinylcholine and the alternative was 1 mg/kg of rocuronium provided the antidote sugammadex (16 mg/kg) was available; and (2) the preferred hypnotic agent was either 0.2 to 0.3 mg/kg of etomidate or 1 to 2 mg/kg of ketamine.

3. Laryngoscopy was performed using the device allocated at random (ie, either a video laryngoscope with a requirement to obtain indirect glottis visualization via the camera for the first pass, or the Macintosh direct laryngoscope). The McGrath MAC video laryngoscope (Medtronic) was chosen for the intervention group because the intubation technique with this device is similar to that with the Macintosh laryngoscope (in particular, the blade curve is not specifically designed for difficult intubation), a previous study suggests benefits for ICU intubation,¹⁷ the small size of the device enabled bedside use, and the cost was low compared with other video laryngoscopes. As recommended by French guidelines,¹⁸ no stylet was used for the first-pass intubation attempt.

4. Intratracheal tube position was confirmed by analyzing the capnography curve over 4 breaths or more. After tube insertion, the cuff was inflated and the tube was connected to the ventilator. Use of the Sellick maneuver was at the discretion of the individual performing intubation and was recorded on the electronic case report form.

5. If the first-pass intubation attempt failed, the individual performing intubation chose between repeat laryngoscopy and an alternative intubation technique in accordance with French guidelines.¹⁸ During repeat laryngoscopies, the video laryngoscope could be used with either indirect or direct glottis visualization. Each introduction of the laryngoscope into the oral cavity was considered a separate laryngoscopy attempt.

The primary outcome measure was the proportion of patients with successful first-pass orotracheal intubation, which was defined based on a normal-appearing waveform of the partial pressure of end-tidal exhaled carbon dioxide curve over 4 or more breathing cycles.

The secondary outcomes included (1) the proportion of patients with successful orotracheal intubation at any attempt, (2) total time to successful orotracheal intubation (time from anesthesia induction initiation to confirmation of good tube position based on partial pressure of end-tidal exhaled carbon dioxide), (3) Cormack-Lehane grade of glottis visibility, (4) Percentage of Glottic Opening scale score,¹⁹ (5) proportion of patients with difficult intubation, (6) proportion of patients intubated using alternative techniques (gum elastic bougie, laryngeal mask airway [eg, Fastrach], video laryngoscope proven helpful in difficult orotracheal intubation [Airtraq or GlideScope], fiber optic endoscopy, or rescue percutaneous or surgical transtracheal oxygenation), (6) complications (death, cardiac arrest, severe cardiovascular collapse [systolic blood pressure <90 mm Hg], hypoxemia [oxygen saturation by pulse oximeter {SpO₂} <90%] or severe hypoxemia [SpO₂ <80%], esophageal intubation, aspiration, arrhythmia [ventricular tachycardia, ventricular fibrillation, salve of ventricular premature beats], and dental injury), (7) duration of mechanical ventilation, (8) ICU length of stay, (9) hospital length of stay, (10) ICU mortality, and (11) 28-day mortality. Previously described¹⁷ severe life-threatening complications included death, cardiac arrest, severe cardiovascular collapse, and severe hypoxemia and mild to moderate life-threatening complications included esophageal intubation, aspiration, arrhythmia, and dental injury.

Based on previous data,^17,20,21 the expected rate of successful first-pass orotracheal intubation was 65% for patients in the direct laryngoscopy group. Assuming that video laryngoscopy would increase this proportion to 80%,¹⁷ with type I error set at 5% and type II error set at 10%, 185 patients were needed in each group (ie, 370 patients total).

Baseline features were described as number (percentage) for categorical variables and mean (standard deviation) and quartiles for quantitative variables. Proportions of patients with successful first-pass orotracheal intubation were compared between groups using a mixed-effects logistic model to account for stratification factors. The model included center as a random effect and group and operator experience as fixed effects. The intention-to-treat principle was followed. A per-protocol analysis also was performed and excluded the patients who (1) did not meet inclusion or exclusion criteria, (2) did not receive invasive mechanical ventilation, or (3) had medical reasons for study withdrawal.

Patients without data for the primary outcome were classified as experiencing intubation failure. A sensitivity analysis based on the MACOCHA score (which is made up of a Mallampati score of 3 or 4, apnea syndrome [obstructive], cervical spine limitation, opening mouth <3 cm, coma, hypoxemia, and operator not being an anesthesiologist) for predicting difficult intubation was performed; when at least 1 component of the score was missing (161 patients), multiple imputation (100 imputations) based on randomization group, operator experience, and center was used.

Comparisons of the secondary outcomes were performed using the χ² or Fisher exact test for qualitative data and the t test or the Wilcoxon rank sum test for quantitative data as appropriate. Intubation procedure duration was assessed using Kaplan-Meier curves and the log-rank test. Post hoc subgroup analyses were conducted using repeated-measures mixed models in patients with (1) a ratio of Pao₂ to Fio₂ of less than 200 mm Hg or (2) of less than 150 mm Hg at enrollment²² to assess whether the severity of hypoxemia was related to low saturation during intubation.

All tests were 2-tailed. P values of less than .05 were considered significant. Multiple imputations were performed for missing data. Stata statistical software version 13 (StataCorp) was used. No adjustments were made for the multiple comparisons; therefore, the results for the secondary outcomes should be interpreted as exploratory.

Of 489 patients assessed for eligibility, 371 were randomized and included in the intention-to-treat analysis (mean [SD] age, 62.8 [15.8] years; 136 [36.7%] women) and 365 were included in the per-protocol analysis (Figure 1 and eTable 1 in Supplement 2). Baseline features were evenly balanced between groups (Table 1). The first orotracheal intubation attempt was performed by nonexperts in 83.8% of patients and by experts in 16.2% of patients.

Data on the primary outcome were unavailable for 5 patients, who were classified as experiencing first-pass orotracheal intubation failure in the intention-to-treat analysis. The 366 remaining patients were successfully intubated. The proportion of patients experiencing successful first-pass orotracheal intubation was not significantly different between the video laryngoscopy group (126 of 186 patients [67.7%]) and the direct laryngoscopy group (130 of 185 patients [70.3%]) (absolute difference, −2.5% [95% CI, −11.9% to 6.9%]; P = .60).

The frequency of first-attempt orotracheal intubation failure was not significantly different with video laryngoscopy (odds ratio [OR], 1.12 [95% CI, 0.71-1.78]; P = .63) both after adjustment for operator expertise (randomization stratification factor) and after adjustment for the MACOCHA score (OR, 1.10 [95% CI, 0.69-1.75]; P = .69). The main reason for patients to experience first-pass intubation failure was because the glottis was not visualized during direct laryngoscopy. For patients in the video laryngoscopy group, first-pass intubation failure was due to failure of tracheal catheterization (Table 2). Second-attempt laryngoscopy and total number of attempts to achieve intubation success did not differ between groups (Figure 2; eTable 2 and eTable 3 in Supplement 2).

The sensitivity analysis performed in the per-protocol population showed no significant between-group difference for the primary outcome in the subgroups with MACOCHA scores of less than 4 or scores of 4 or greater (eTable 4 and eTable 5 in Supplement 2).

There were 368 patients successfully intubated; therefore, no patients required alternative intubation or oxygenation methods. In the video laryngoscopy group, Cormack-Lehane grades of 1 or 2 (better glottis visualization) were more common, the percentage of glottic opening score was higher, and a gum elastic bougie was used more often during first-pass orotracheal intubation. Most first intubation attempts were made by nonexperts (primarily residents, n = 290) and most subsequent attempts were made by experts, yielding no significant between-group differences (Table 3). First intubation attempts were successful more often when performed by experts (55 of 60 patients [91.7%]) compared with when performed by nonexperts (201 of 311 patients [64.6%]) (absolute difference, 27.1% [95% CI, 18.2%-35.8%]; P = .001).

Bag valve ventilation was the most common preoxygenation method used in both groups. The median duration of the intubation procedure of 3 minutes (range, 2-4 minutes) did not differ between the 2 groups (absolute difference, 0 [95% CI, 0-0]; P = .95). In patients with successful first-pass orotracheal intubation, the median duration of the intubation procedure did not significantly differ between the video laryngoscopy group (2 minutes) and the direct laryngoscopy group (2.5 minutes) (absolute difference, 0 [95% CI, 0-0]; P = .61).

The proportion of patients with severe life-threatening complications was higher in the video laryngoscopy group (9.5% vs 2.8% in the direct laryngoscopy group; absolute difference, 6.7% [95% CI, 1.8% to 11.6%]; P = .01), whereas no significant between-group difference was found for mild to moderate life-threatening complications. Evolution of SpO₂ during intubation did not differ between the 2 groups across admission subgroups for ratio of Pao₂ to Fio₂ (eFigure 1, eFigure 2, and eFigure 3 in Supplement 2).

Duration of mechanical ventilation, ICU length of stay, sepsis-related organ failure assessment score on day 1, sepsis-related organ failure assessment score on day 2, ICU mortality, and 28-day mortality did not differ between the 2 groups (eTable 6 in Supplement 2).

Quiz Ref IDIn the MACMAN trial, video laryngoscopy did not improve the frequency of successful first-pass orotracheal intubation compared with direct laryngoscopy. Furthermore, the video laryngoscopy group had a higher frequency of severe life-threatening complications (but not mild to moderate life-threatening complications) and need for use of a gum elastic bougie during the first intubation attempt.

In observational studies,^23-25 a propensity-adjusted study,²⁶ a single-center RCT,⁷ and in 2 meta-analyses of the data,^27,28 video laryngoscopy improved the first-pass orotracheal intubation success rate compared with direct laryngoscopy. However, these studies had major methodological weaknesses such as (1) a retrospective design, before and after design, or single-center recruitment, (2) absence of routine neuromuscular blockade, and (3) exclusion of the patients with the most severe cases of hypoxemia (SpO₂ <92% after bag valve mask ventilation) from the RCT.⁷ Other studies^8,9,17,29-31 failed to show improvements with use of video laryngoscopy compared with use of direct laryngoscopy. Similarly, in 2 recent single-center RCTs,^32,33 the first-pass orotracheal intubation success rate was not higher with use of video laryngoscopy compared with use of direct laryngoscopy.

The present report adds to these results by providing data from a multicenter RCT with an objective primary outcome measure (ie, capnography), ensuring a low risk of bias and high external validity. Several factors may explain the discrepancy in results of early studies vs recent RCTs. One is a high success rate in the direct laryngoscopy group, related in particular to adherence to a standardized protocol,² including routine neuromuscular blockade.³ Thus, in the MACMAN trial, even the nonexperts had a first-pass intubation success rate of 70% with direct laryngoscopy, and the experts had a success rate of 93.2%. The direct laryngoscopy success rate confirms that the sample size was correctly estimated.

Quiz Ref IDImproved glottis visualization with video laryngoscopy did not translate into a higher success rate for first-pass intubation because tracheal catheterization under indirect vision was more difficult, in keeping with earlier data.^32,33 Conceivably, a video laryngoscope with an intubation channel might improve the success rate, although preliminary data obtained in the operating room are inconclusive.³⁴

The frequency of severe life-threatening complications was higher with video laryngoscopy than with Macintosh laryngoscopy. Previous RCTs in trauma patients found higher mortality rates in the subgroups with traumatic brain injury⁹ or longer duration of the orotracheal intubation procedure.^8,9,35 Consistent with the results reported herein, an RCT in ICU patients showed a lower median arterial oxygen saturation with video laryngoscopy (86% [interquartile range, 75%-93%]) than with direct laryngoscopy (95% [interquartile range, 85%-99%]; P = .04), possibly due to the longer median orotracheal intubation procedure duration with video laryngoscopy (221 seconds [interquartile range, 103-291 seconds] vs 156 seconds [interquartile range, 67-220 seconds] with direct laryngoscopy; P = .15).³²

The better visualization of the glottis with video laryngoscopy might lead to a false impression of safety when orotracheal intubation is performed by nonexperts. The subgroup analyses did not identify factors associated with life-threatening complications with video laryngoscopy. In addition, poorer alignment of the pharyngeal axis, laryngeal axis, and mouth opening despite good glottis visualization by video laryngoscopy can lead to mechanical upper airway obstruction and faster progression to hypoxemia.³⁶

Use of a gum elastic bougie during the first intubation attempt was more common with video laryngoscopy. Due to the indirect visualization of the glottis with video laryngoscopy, some manufacturers recommend using an intubation stylet. The manufacturer of the video laryngoscope used in this study does not recommend using a stylet because the blade curvature is similar to that of the Macintosh laryngoscope and direct glottis visualization is possible.³⁷ The 2 devices are also similar in regard to the grip handle and passage into the mouth and larynx. With the Macintosh laryngoscope, use of a gum elastic bougie (compared with a stylet³⁸) was associated with a higher success rate for orotracheal intubation in the event of poor glottis visibility; therefore, stylet use is considered inadvisable for difficult orotracheal intubation according to French guidelines.¹⁸

With video laryngoscopy, use of a gum elastic bougie has been reported to be as efficient as a stylet for improving success rates of first-pass orotracheal intubation.³⁹ A stylet was not used routinely for patients in the video laryngoscopy group. The use of a gum elastic bougie is more common in Europe than in the United States.⁶ Furthermore, in a trial involving routine use of a stylet,³³ success rates for first-pass orotracheal intubation were not significantly different between the video laryngoscopy and direct laryngoscopy groups.

This study has several limitations. It assessed a single type of video laryngoscope, which has a curved blade similar to the direct laryngoscope. Other video laryngoscopes with a hyperangulated blade or specific intubation channel might have produced different results. Most of the first attempts of intubation were made by nonexpert physicians for both the video laryngoscopy and direct laryngoscopy groups; however, the trial was intended to reflect actual clinical conditions in which orotracheal intubation is often performed by nonexperts.¹³ Physician intubation expertise requires theoretical skills, manikin practice, and supervised hands-on training. Adequate intubation training is defined as having performed at least 50 orotracheal intubation procedures under supervision.⁴⁰

Successful first-pass intubation was chosen as the primary outcome because several studies showed a strong correlation between the frequency of complications such as hypoxemia, cardiac arrest, and death and the number of laryngoscopy attempts.¹³ Blinding was not feasible so successful first-pass intubation defined by capnography was chosen because it is an objective outcome measure. The success rate of first-pass orotracheal intubation was consistent with previously published data.^17,25 The duration of the orotracheal intubation procedure was not significantly different between the 2 groups.

Among patients in the ICU requiring intubation, video laryngoscopy compared with direct laryngoscopy did not improve first-pass orotracheal intubation rates and was associated with higher rates of severe life-threatening complications. Further studies are needed to assess the comparative effectiveness of these 2 strategies in different clinical settings and among operators with diverse skill levels.

Corresponding Author: Jean Baptiste Lascarrou, MD, Service de Reanimation, Centre Hospitalier Départemental de la Vendée, 85000 La Roche-sur-Yon, France (jean-baptiste.lascarrou@chd-vendee.fr).

Group Information: The Clinical Research in Intensive Care and Sepsis (CRICS) Group is listed at the end of this article.

Published Online: January 24, 2017. doi:10.1001/jama.2016.20603

Author Contributions: Dr Lascarrou had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Boisrame-Helms and Bailly contributed equally to the article.

Concept and design: Lascarrou, Bailly, Reignier.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lascarrou, Bailly, Colin, Reignier.

Critical revision of the manuscript for important intellectual content: Lascarrou, Boisrame-Helms, Le Thuaut, Kamel, Mercier, Ricard, Lemiale, Mira, Meziani, Messika, Dequin, Boulain, Azoulay, Champigneulle, Reignier.

Statistical analysis: Lascarrou, Le Thuaut.

Obtained funding: Lascarrou, Reignier.

Administrative, technical, or material support: Lascarrou, Kamel, Colin, Messika, Dequin, Azoulay, Champigneulle, Reignier.

Supervision: Lascarrou, Kamel, Azoulay, Champigneulle, Reignier.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ricard reported receiving travel reimbursement from Fisher & Paykel. Dr Mira reported receiving personal fees from LFB and Merck Sharp & Dohme for serving on advisory boards; and nonfinancial support from Astellas. Dr Messika reported receiving consulting fees from Basilea Pharmaceutica. Dr Azoulay reported receiving personal fees from Gilead, Astellas, and Alexion; and grants from Cubist and Alexion. No other disclosures were reported.

Funding/Support: The nonprofit health care institution Centre Hospitalier Département de la Vendée was the study funder and sponsor.

Role of the Funder/Sponsor: Centre Hospitalier Département de la Vendée had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Contributors: Y. Alcourt, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); H. Allam, CRA (Medical Intensive Care Unit, University Hospital, Strasbourg, France); M. Arnaout, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); A. Aubrey, RN (Medical Intensive Care Unit, University Hospital, Tours, France); K. Bachoumas, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); F. Barbier, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); D. Benzekri-Lefevre, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); N. Bercault, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); L. Bodet Contentin, MD (Medical Intensive Care Unit, University Hospital, Tours, France); W. Bougouin, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); L. Boureau, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); A. Bretagnol, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); E. Canet, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); A. Cariou, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); J. Charpentier, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); L. Cheikh, CRA (Medical Intensive Care Unit, University Hospital, Colombes, France); S. Chenaf, CRA (Medical Intensive Care Unit, University Hospital, Strasbourg, France); A. Chermak, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); R. Clere-Jehl, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); G. Colin, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); K. Colonval, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); A. Contejean, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); X. Delabranche, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); A. Deschamps, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); E. Dubief, CRA (Medical Intensive Care Unit, University Hospital, Colombes, France; S. Ehrmann, MD (Medical Intensive Care Unit, University Hospital, Tours, France); M. Fiancette, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); V. Franja, RN (Medical Intensive Care Unit, University Hospital, Strasbourg, France); B. Gaboriau, RES (Medical Intensive Care Unit, University Hospital, Colombes, France); D. Garot, MD (Medical Intensive Care Unit, University Hospital, Tours, France); S. Gaudry, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); G. Geri, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); A. Guillon, MD (Medical Intensive Care Unit, University Hospital, Tours, France); M. Henry-Lagarrigue, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Joret, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); Y. Jouan, MD (Medical Intensive Care Unit, University Hospital, Tours, France); T. Khouri, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); C. Kummerlen, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); B. La Combe, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); J.-C. Lacherade, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); C. Lebert, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Legras, MD (Medical Intensive Care Unit, University Hospital, Tours, France); C. Loiseau, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); C. Mabilat, RN (Medical Intensive Care Unit, University Hospital, Tours, France); J. Mankikian, MD (Medical Intensive Care Unit, University Hospital, Tours, France); N. Maquigneau, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); N. Marin, PhD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); E. Mariotte, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); S. Martin, PharmD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); L. Martin-Lefevre, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Mathonnet, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); F. Meniolle-D’Hauthuille, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); I. Mezhari, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); E. Morawiec, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); G. Muller, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); O. Passouant, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); F. Pene, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); C. Pichereau, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); Y. Rabouel, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); H. Rahmani, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); J. Reignier, MD (Medical Intensive Care Unit, University Hospital, Nantes, France); A. Robert, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); J. Rouche, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); C. Rousseau, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); E. Rouve, MD (Medical Intensive Care Unit, University Hospital, Tours, France); D. Roux, MD (Medical Intensive Care Unit, University Hospital, Colombes, France); I. Runge, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); C. Salmon Gandonnière, MD (Medical Intensive Care Unit, University Hospital, Tours, France); S. Spagnolo, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); S. Valade, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); M. Venot, MD (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France); I. Vinatier, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Yehia, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); L. Zafrani, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); V. Zinzoni, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); J.-D. Chiche, MD (Medical Intensive Care Unit, University Hospital Cochin, Paris, France); V. Simon, RN (Medical Intensive Care Unit, University Hospital, Tours, France); V. Souppard, RN (Medical Intensive Care Unit, University Hospital Saint Louis, Paris, France).

Clinical Research in Intensive Care and Sepsis (CRICS) Group: Y. Alcourt, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); H. Allam, CRA (Medical Intensive Care Unit, University Hospital, Strasbourg, France); A. Aubrey, RN (Medical Intensive Care Unit, University Hospital, Tours, France); K. Bachoumas, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); F. Barbier, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); D. Benzekri-Lefevre, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); N. Bercault, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); L. Bodet Contentin, MD (Medical Intensive Care Unit, University Hospital, Tours, France); L. Boureau, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); A. Bretagnol, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); S. Chenaf, CRA (Medical Intensive Care Unit, University Hospital, Strasbourg, France); R. Clere-Jehl, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); G. Colin, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); K. Colonval, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); X. Delabranche, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); A. Deschamps, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); S. Ehrmann, MD (Medical Intensive Care Unit, University Hospital, Tours, France); M. Fiancette, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); V. Franja, RN (Medical Intensive Care Unit, University Hospital, Strasbourg, France); D. Garot, MD (Medical Intensive Care Unit, University Hospital, Tours, France); A. Guillon, MD (Medical Intensive Care Unit, University Hospital, Tours, France); M. Henry-Lagarrigue, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Joret, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); Y. Jouan, MD (Medical Intensive Care Unit, University Hospital, Tours, France); T. Khouri, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); C. Kummerlen, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); J.-C. Lacherade, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); C. Lebert, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Legras, MD (Medical Intensive Care Unit, University Hospital, Tours, France); C. Loiseau, RN (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); C. Mabilat, RN (Medical Intensive Care Unit, University Hospital, Tours, France); J. Mankikian, MD (Medical Intensive Care Unit, University Hospital, Tours, France); N. Maquigneau, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); S. Martin, PharmD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); L. Martin-Lefevre, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Mathonnet, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); G. Muller, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); Y. Rabouel, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); H. Rahmani, MD (Medical Intensive Care Unit, University Hospital, Strasbourg, France); J. Reignier, MD (Medical Intensive Care Unit, University Hospital, Nantes, France); A. Robert, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); C. Rousseau, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); E. Rouve, MD (Medical Intensive Care Unit, University Hospital, Tours, France); I. Runge, MD (Medical Intensive Care Unit, Regional Hospital Center, Orléans, France); C. Salmon Gandonnière, MD (Medical Intensive Care Unit, University Hospital, Tours, France); I. Vinatier, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); A. Yehia, MD (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); V. Zinzoni, RN (Medical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon, France); V. Simon, RN (Medical Intensive Care Unit, University Hospital, Tours, France).

Additional Contributions: We thank the health care staff and research nurses at the trial sites. We also thank A. Wolfe, MD, for assistance in preparing and reviewing the manuscript; S. Martin, PharmD (Clinical Reseach Unit, District Hospital Centre, La Roche Sur Yon, France), for reviewing the manuscript; E. Le Blanc (Delegation a la Recherche Clinique et a l'Innovation, CHU Nantes, Nantes, France) for managing the database; and J. Dimet, PharmD (Clinical Reseach Unit, District Hospital Centre, La Roche Sur Yon, France), for assistance with the administrative process. None of these persons were compensated for their contributions.