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. 2021 Apr 15;16(4):e0249889. doi: 10.1371/journal.pone.0249889

Use of volatile agents for sedation in the intensive care unit: A national survey in France

Raiko Blondonnet 1,2,*, Audrey Quinson 1, Céline Lambert 3, Jules Audard 1,2, Thomas Godet 1, Ruoyang Zhai 2, Bruno Pereira 3, Emmanuel Futier 1,2, Jean-Etienne Bazin 1, Jean-Michel Constantin 4, Matthieu Jabaudon 1,2,5
Editor: Corstiaan den Uil6
PMCID: PMC8049230  PMID: 33857185

Abstract

Background

Current intensive care unit (ICU) sedation guidelines recommend strategies using non-benzodiazepine sedatives. This survey was undertaken to explore inhaled ICU sedation practice in France.

Methods

In this national survey, medical directors of French adult ICUs were contacted by phone or email between July and August 2019. ICU medical directors were questioned about the characteristics of their department, their knowledge on inhaled sedation, and practical aspects of inhaled sedation use in their department.

Results

Among the 374 ICUs contacted, 187 provided responses (50%). Most ICU directors (73%) knew about the use of inhaled ICU sedation and 21% used inhaled sedation in their unit, mostly with the Anaesthetic Conserving Device (AnaConDa, Sedana Medical). Most respondents had used volatile agents for sedation for <5 years (63%) and in <20 patients per year (75%), with their main indications being: failure of intravenous sedation, severe asthma or bronchial obstruction, and acute respiratory distress syndrome. Sevoflurane and isoflurane were mainly used (88% and 20%, respectively). The main reasons for not using inhaled ICU sedation were: “device not available” (40%), “lack of medical interest” (37%), “lack of familiarity or knowledge about the technique” (35%) and “elevated cost” (21%). Most respondents (80%) were overall satisfied with the use of inhaled sedation. Almost 75% stated that inhaled sedation was a seducing alternative to intravenous sedation.

Conclusion

This survey highlights the widespread knowledge about inhaled ICU sedation in France but shows its limited use to date. Differences in education and knowledge, as well as the recent and relatively scarce literature on the use of volatile agents in the ICU, might explain the diverse practices that were observed. The low rate of mild adverse effects, as perceived by respondents, and the users’ satisfaction, are promising for this potentially important tool for ICU sedation.

Background

In the intensive care unit (ICU), sedation is used to improve comfort and tolerance during mechanical ventilation, invasive diagnostic and therapeutic interventions or nursing care [1]. Recent surveys of sedation practices report that midazolam and propofol remain mostly used for ICU sedation [2]. However, the literature highlights numerous adverse effects of such intravenous sedatives, including prolonged mechanical ventilation and ICU duration of stay, increased delirium, and risk of hemodynamic failure or severe syndromes such as propofol infusion syndrome [3–7]. The ideal sedative agent should act rapidly, provide effective sedation without side effects, not accumulate and allow fast awakening when interrupted. Current international guidelines recommend that sedation strategies using non-benzodiazepine drugs should be preferred over sedation with benzodiazepines to improve clinical outcomes in mechanically ventilated adult patients [8]. In some national guidelines, such as in Germany, the use of volatile anesthetics is also considered a feasible option [9]. Since the development of anesthetic reflectors, such as the Anaesthetic Conserving Device (AnaConDa, Sedana Medical, Danderyd, Sweden) and the Mirus (Carelide GmbH, Mouvaux, France), inhaled sedation has become more popular in the ICU [10–12]. These devices are suitable with modern critical care ventilators without extraordinary expense or technical difficulty, while ensuring the safety of both patients and ICU care providers and the protection of the workplace environment [13–16]. Volatile anesthetics have a bronchodilatory effect [17, 18] and may be protective for some organs, such as the heart [19, 20] and the kidney [21–23]. Moreover, animal and human studies support the protective effects of a pretreatment with volatile anesthetics before prolonged ischemia of the liver [24], the brain [25] or the heart [19]. Preclinical studies have also shown that inhaled sevoflurane could improve gas exchange [26, 27], reduce alveolar oedema [26, 27], and attenuate pulmonary and systemic inflammation [28] in experimental models of acute respiratory distress syndrome (ARDS). In a pilot randomised controlled trial, early use of inhaled sevoflurane was associated with improved oxygenation and a reduction of some proinflammatory markers and of a marker of lung epithelial injury in patients with ARDS, compared to intravenous midazolam [29].

Although volatile anesthetics could be part of the modern management of sedation of critically ill patients, data on their use in the ICU setting are scarce. This survey was undertaken to explore the use of volatile agents for ICU sedation in France, to assess the indications and modalities of their use by ICU care providers, and to understand the potential reasons against their use, if any.

Methods

Survey development

This investigator-initiated survey did not require approval by an Ethics Committee, as per French law. A 26-item questionnaire was developed with questions designed by the authors (RB, AQ, JEB, JMC, MJ) (Supplemental Content 1 of S1 File); it covered three categories: general characteristics of the ICU; general data on inhaled sedation use, and practical aspects of inhaled ICU sedation.

Survey sample

All French ICUs were identified and contacted unless they were pediatric ICUs. The survey was conducted between July and August 2019. Almost all responses were recorded orally. After short information about the survey design and objectives, the medical director of each ICU was exclusively questioned. Completion of the survey took approximately five minutes. After a first phone contact, and upon request of the ICU director, some questionnaires were emailed individually. In the absence of a reply after one month, a second contact with the ICU director was performed by telephone and followed by a third call when necessary.

Statistical analysis

Statistical analysis was performed in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [30]. Results were requested both in a descriptive manner and, for all closed questions, in absolute numbers or percentages. Responses to each questionnaire were recorded into a Microsoft Excel database and analysed using Stata software version 15 (StataCorp, College Station, Texas, USA). Categorical parameters were expressed as frequencies and associated percentages, and continuous data as mean ± standard deviation or median [interquartile range], according to statistical distribution. The Gaussian distribution was verified by the Shapiro-Wilk test.

Results

Out of the 405 ICUs located in France [31], 31 pediatric ICUs were excluded and 374 adult ICU directors were directly questioned. A total of 50% (187/405) of the questionnaires were recorded; 81% (152/187) orally and 19% (35/187) electronically. There were 24% (45/187) of answers from teaching hospitals, 60% (111/187) from general hospitals, 14% (27/187) from private medical centers, and 2% (4/187) from military hospitals. Among participating ICUs, 91% (170/187) were mixed (medical and surgical) ICUs, 8% (15/187) were medical ICUs and 1% (2/187) were burn centers. General characteristics of ICU respondents are reported in Supplemental Contents 2 and 3 of S1 File.

Among the respondents, 73% (137/187) declared they knew about the use of inhaled sedation in the ICU. Of these, 98% (134/137) knew the AnaConDa device and 15% (20/137) knew the Mirus device. Twenty-one percent (40/187) of respondents declared they routinely performed inhaled sedation in their unit, 90% (36/40) with the AnaConDa and 10% (4/40) with the Mirus. However, no respondent had both devices available. Sixty-three percent declared they had used volatile agents for sedation for less than five years. In 45% (18/40) of respondents, inhaled sedation was performed only by a few practitioners from the medical team. Seventy-five percent (30/40) of the respondents declared they used inhaled ICU sedation in less than 20 patients per year (Fig 1).

Fig 1. Number of patients in whom inhaled sedation was used each year in responding intensive care units in which a dedicated device was available.

Fig 1

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Data are represented in %.

In case neither the AnaConDa nor the Mirus were available in their hospital, 23% (34/147) of respondents declared they had already borrowed an anesthesia machine from the operating room to deliver inhaled sedation with volatile anesthetics in an ICU patient. The three main reasons for not using inhaled ICU sedation were: “device not available” (40% (58/147)), “no clear clinical benefit” (37% (55/147)), and “lack of familiarity or knowledge about the technique” (35% (51/147)). Seven percent of respondents (10/147) mentioned the potential risk of halogenated-induced atmospheric pollution, and only one respondent answered that he did not use volatile agents because of their potential adverse effects. Other indications evoked by respondents for not using inhaled ICU sedation are summarised in Fig 2.

Fig 2. Reasons reported for not using inhaled sedation in surveyed intensive care units.

Fig 2

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(n = 147) Data are represented in %.

The three main indications reported by the respondents were: failure of intravenous sedation (75% (30/40)), severe asthma (75% (30/40)), and ARDS (65% (26/40)). Other indications evoked by respondents for using inhaled ICU sedation are summarised in Fig 3. Sixty-nine percent (129/187) of respondents said they were aware of potential benefits of inhaled ICU sedation as reported in Fig 4. The main benefit being reported was bronchodilation (88% (114/129)), both by respondents who had a device suitable for inhaled ICU sedation available in their unit (90%, 35/39) and those who did not (88%, 79/90).

Fig 3. Indications of volatile anesthetics for intensive care sedation, as reported by users.

Fig 3

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(n = 40) Data are represented in %. ARDS: Acute Respiratory Distress Syndrome; IV: Intravenous.

Fig 4. Properties of volatile anesthetics for inhaled intensive care unit sedation, as reported by respondents.

Fig 4

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(n = 129) Data are represented in %.

Eighty-four percent (157/187) of respondents declared they had a written protocol for sedation in their institution, whereas only 43% (17/40) of units in which volatile agents were used had a specific protocol for inhaled sedation. One-fifth (39/187) of respondents declared they had received specific training on inhaled sedation; 69% (27/39) and 64% (25/39) of this training originated from the companies developing the AnaConda or the Mirus devices and through scientific conferences, respectively.

Sevoflurane or isoflurane were mainly used by the respondents (88% (35/40) or 20% (8/40), respectively), and three respondents answered they used both. Desflurane was not used by any respondent. In 93% (37/40) of ICUs, respondents reported they usually combined opioid-based analgesia with inhaled sedation (73%, (29/40) with sufentanil, 40% (16/40) with remifentanil, and 3% (1/40) with fentanyl). Almost half (48% (19/40)) of respondents answered that they would combine inhaled sedation with continuous intravenous administration of at least one other hypnotic agent (38% (15/40) propofol, 20% (8/40) midazolam, 8% (3/40) dexmedetomidine, and 3% (1/40) ketamine).

Inhaled sedation was used along with controlled ventilation modes in all ICUs and 53% (21/40) of respondents using inhaled sedation reported they would also use inhaled sedation during pressure support ventilation in intubated patients. One respondent declared it has already used inhaled sedation during noninvasive ventilation. Most respondents (79%, (31/40)) answered they would use validated scales or scores, rather than end-tidal gas concentration monitoring, to titrate their sedation goals. The Richmond Agitation Sedation Scale (RASS) was used in 90% (36/40) of ICUs; 35% (14/40) of respondents declared they also monitored the bispectral index (BIS-ASPECT-A-2000; Aspect Medical Systems, Norwood, USA), and 25% (10/40) of ICUs monitored end-tidal gas concentration to titrate sedation. No ICU director reported they measured plasma concentrations of volatile anesthetics or their metabolites when monitoring inhaled sedation.

Sixty-three percent (25/40) of respondents answered they did not specifically set any maximal duration for inhaled sedation in their ICU patients. Thirty-three percent (13/40) of respondents declared they would interrupt inhaled sedation when patients are entering the process of weaning from ventilation. Five percent (2/40) of respondents declared they would systematically stop inhaled sedation within a maximum of five days.

Absolute contraindications for inhaled sedation could be reported by 53% (99/187) of respondents (Fig 5). At least one adverse effect attributable to volatile anesthetics already occurred in 28% (11/40) surveyed ICUs. Malignant hyperthermia, hypercapnic acidosis, diabetes insipidus, renal failure, cholestasis, arrhythmia, hemodynamic failure, and dysnatremia were reported as potential adverse effects. Five percent (2/40) of respondents mentioned that some nurses may have developed headaches after they had used volatile agents in their units.

Fig 5. Contraindication of volatile anesthetics for intensive care sedation, as reported by users.

(n = 99) Data are represented in %.

Overall satisfaction with the use of inhaled sedation among the users is represented in Fig 6.

Fig 5

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Fig 6.

Fig 6

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(A) Overall satisfaction of respondents who had a device suitable for inhaled sedation available in their intensive care unit regarding the use of inhaled sedation. (n = 40) (B) Answers to the question « Do you think that inhaled sedation is an interesting alternative to intravenous sedation in the intensive care unit? » by users and non-users of the technique. (n = 187) Data are represented in %.

Discussion

This survey is the first to investigate the use of inhaled sedation and to assess the spread of knowledge about the technique in French ICUs. The high response rate (50%) to the survey suggests this was a relatively representative sample, especially because the distribution of hospital types within respondents was broadly comparable to the distribution of hospitals in France [32].

Differences in practices between medical and polyvalent ICUs, as well as disparities in knowledge on inhaled sedation between responders, could be explained by the various proportions of anesthesiologists-intensivists working in these units. In France, a combined anesthesiology, critical care and perioperative medicine specialty track trains “anesthesiologists-intensivists” who can subsequently work in the ICU, in the operative room, or in both. A distinct specialty track trains French “medical intensivists” who can work in ICUs but are not anesthesiologists. Anesthesiologists-intensivists are more likely to be trained to use volatile anesthetics during their residency program that involves more time working in the operating room. Unfortunately, the proportion of staff anesthesiologists-intensivists in each participating unit was not assessed in this survey. Differences in education and knowledge might also explain why many respondents reported poor medical interest (37%) for inhaled sedation use and lack of familiarity (35%) with the technique as main reasons for not using inhaled sedation in their units. Even if the recent and relatively scarce literature on volatile agents used in the ICU could explain these answers, this survey highlights a real interest in, and potentially a new application for, inhaled sedation in multiple French ICUs. However, the interest developed by the physicians may be impacted by their working environment. Indeed, respondents from general hospitals declared they were less interested by inhaled sedation than their colleagues from university hospitals. This could be explained, at least in part, because university hospitals, including major academic medical centers, may offer more advanced clinical capabilities and opportunities for medical research, education, and innovation [33].

One fifth of intensivists answered that they did not use inhaled sedation because of its related cost. Even if inhaled ICU sedation might sometimes be perceived as more costly [34, 35], reductions in indirect costs through shortened times to liberation from mechanical ventilation, patient recovery, and ICU discharge, as well as reduced needs for sedative and opioid agents, are plausible but often difficult to demonstrate [13, 34–37]. Regarding direct costs, in some patients in whom sedation is deemed more difficult, inhaled sedation may significantly decrease costs of sedation, with daily costs being similar when using midazolam or isoflurane, and the cost difference could favor inhaled sedation in the subgroup of patients who required high doses of midazolam [34].

Main indications and advantages reported through this survey are in accordance with previously published evidence [15]. Most users are interested by the rapid onset of volatile anesthetics, their low metabolism and blood solubility, while avoiding tolerance or addiction phenomena and allowing fast awakening, as compared to current intravenous sedation practices. Indeed, in a recent meta-analysis by Jerath et al., time to extubation was reduced with volatile-based sedation, compared to intravenous sedation with either midazolam or propofol [38].

Half of physicians declared they used volatile agents in spontaneously breathing patients under pressure support ventilation. Nevertheless, adding the AnaConDa itself to the respiratory circuit may increase work-of-breathing, due to a dead space effect that is only partially explained by its larger internal volume. However, simultaneous sevoflurane inhalation decreases this increase in work-of-breathing, suggesting specific effects of sevoflurane through decreased carbon dioxide reflection [39] rather than through sevoflurane induced-bronchodilation, as previously suggested [40]. There is indeed growing evidence supporting that light sedation with sevoflurane through the AnaConDa is feasible in severely ill ICU patients [38].

Most surveyed ICU directors reported they did not set any maximal duration for inhaled ICU sedation in their patients. Mesnil et al. demonstrated that sevoflurane delivered through a dedicated device was a safe and effective alternative to intravenous sedation in ICU patients receiving under sedation for a median time of 50 [39–71] hours [13]. In addition, in this study, inhaled sevoflurane was associated with decreased awakening and extubation times, postextubation morphine consumption, and increased awakening quality [13]. Similar results were found with isoflurane [36]. Recent research suggests that volatile anesthetics could even have some protective effects on the kidney by attenuating renal tubular necrosis and decreasing the nephrotoxic effects of proinflammatory cytokines [21, 23]. A recent work that studied longer exposures has reported cases of nephrogenic diabetes insipidus (NDI) in patients under inhaled sedation with sevoflurane, which could be related to high doses and long durations of use [41]. In this cohort, patients who developed NDI were exposed for longer durations and with higher end-tidal concentrations of sevoflurane than those who did not. However, it was shown that, even if serum inorganic fluoride (a metabolite of sevoflurane that may be involved in renal injury) concentrations exceeded 50 μmol/L during prolonged anesthesia with sevoflurane [42], no significant change in markers of renal function has been reported to date in both healthy volunteers and ICU patients [14, 29, 43, 44]. Nevertheless, clinicians should be cautious if volatile anesthetics are used for durations longer than 48 hours. Furthermore, data supporting potential beneficial pre- or post-conditioning effects of volatile anesthetics on the liver, the heart or the kidneys in the setting of anesthesia might not be transposable to ICU patients.

Most respondents evoked malignant hyperthermia as a specific contraindication to volatile anesthetics. Indeed, although its incidence is rare, malignant hyperthermia is an absolute contraindication and can be a serious and life-threatening condition. Almost half of physicians answered that they strictly avoid using volatile agents in pregnant patients. Few animal studies were published on the effects of volatile anesthetics during pregnancy and they reported conflicting on potential neurodevelopmental toxicity [45, 46]. Although their precise effects during human pregnancy are still largely unknown, an overall cautious strategy is currently recommended. Intracranial hypertension was a contraindication for 20% of respondents; although volatile anesthetics do result in cerebral vasodilatation and are therefore likely to increase intracranial pressure, their vasodilator effect is dose-dependent and it has been shown that cerebral autoregulation remains intact during sevoflurane anesthesia in humans [47].

Previous experience of adverse events were reported by 11 (28%) respondents; none was described as life-threatening, reinforcing previous data on the safety of inhaled ICU sedation [2, 13, 38]. Severe hypercapnic acidosis due to inhaled sedation was reported by one respondent, which could be explained by the increased instrumental deadspace volume of 100 mL generated by the AnaConDa or Mirus devices [39, 40, 48], although a miniaturised version of the AnaConDa has been developed with an instrumental deadspace volume of 50 mL, allowing the use of a minimum tidal volume of 200 mL [37, 49]. Two respondents reported histories of headaches in some nurses, which can be compatible with exposition to environmental pollution from volatile anesthetics. Indeed, volatile anesthetics induced- pollution is a major concern for environmental protection. However, atmospheric pollution is normally avoided by the use of charcoal filters with activated carbon connected to the expiratory branch of the ventilator or of active scavenging connected to the vacuum system. Possibly due to their use of such pollution-limiting systems, only 10 respondents had concerns about the risk of air pollution and mentioned it as a reason not to use inhaled ICU sedation. Thirty-four percent of respondents stated that inhaled sedation might represent a good alternative to intravenous sedation in ICU patients; however, this rate increased to 72% when considering only the answers from current users of the technique. However, and although inhaled sedation might represent a viable alternative to some situations of shortage in intravenous sedatives, such as during the Covid-19 pandemics [50], more studies are now needed to confirm its potential benefits in ICU patients.

Our study has several limitations. First, a survey has an intrinsic bias which could only decrease with a prospective study. Indeed, such declarative surveys can only provide limited information and an observational study over a given time or repeated over time would have given more scope to clinical observations and more relevance to the real-life use of volatile anesthetics in the ICU setting. Nevertheless, the validity of the results is strengthened by the high response rate and a good distribution of the different hospital types in France among respondents. Moreover, geographical distributions of respondents and non-respondents were similar (Supplemental Content 4 of S1 File). Furthermore, this survey was designed to question ICU directors only, which limits both the non-response rate and the response bias, and may increase the validity of our findings. Second, although the oral presentation of the survey may have favored the response rate and allowed precise answers to some descriptive questions, it is possible that, for the closed questions, reported numbers might have been overestimated. Finally, these findings, which reflect the use of inhaled sedation as reported by French intensivists, may not be extrapolated to other countries with distinct ICU organizations.

Conclusion

In conclusion, this survey highlights both good knowledge about inhaled ICU sedation and its limited use in France to date. Most respondents declared they used inhaled sedation in few patients per year and since a few years only. Differences in education and knowledge of intensivists, as well as the recent and relatively scarce literature on the use of volatile agents in the ICU, might explain the diverse practices as observed.

Supporting information

S1 File

(DOCX)

Click here for additional data file. (16.7KB, docx)
S2 File. STROBE statement—checklist of items that should be included in reports of observational studies.

(DOCX)

Click here for additional data file. (22.7KB, docx)

Abbreviations

ARDS

Acute respiratory distress syndrome

COVID-19

2019 Coronavirus Disease

ICU

Intensive care unit

STROBE

Strengthening the reporting of observational studies in epidemiology

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was supported by internal funding of the Department of Perioperative medicine, CHU Clermont-Ferrand, France.

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Decision Letter 0

Corstiaan den Uil

22 Jan 2021

PONE-D-20-38460

Use of volatile agents for sedation in the intensive care unit: A national survey in France

PLOS ONE

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"The authors declare that there is no conflict of interest regarding the publication of this survey. MJ is a principal investigator of the SEvoflurane for Sedation in ARds (SESAR) (ClinicalTrials.gov Identifier: NCT04235608) and the ISCA study (ClinicalTrials.gov Identifier: NCT04383730), which are co-funded and funded, respectively, by grants from Sedana Medical. JMC and MJ received fees from Sedana Medical for participation in a scientific advisory panel in 2019; MJ received consulting fees from Abbvie in 2020. Neither Sedana Medical or Abbvie has no influence in the study and collection, analysis, and interpretation of data and in writing."

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

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Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors performed a survey in French adult ICUs about the use and about the knowledge, perceived advantages, and disadvantages of inhaled sedation for invasively ventilated patients. The presented results are robust due to a large number of responding ICUs. The conclusions drawn are supported by the results and are of great importance and currentness in view of the ongoing Covid-19 pandemic with increased demand on artificial ventilation and sedation.

However, there are some major points that should be addressed before the paper is ready for publication:

1. Background, P4L14: As the Mirus is still quite unknown, as shown by the results of your paper, please quote at least two publications about the new device, e.g. the following

• Bomberg et al: A novel device for target-controlled administration and reflection of desflurane - the Mirus. Anaesthesia 2014, 69: 1241-50

• Bomberg et al.: AnaConDa and Mirus for intensive care sedation, SpringerPlus 2016: 5:420

• Romagnoli: The New Mirus System for Short-Term Sedation in Postsurgical ICU patients. Crit Care Med. 2017

2. Methods, 1st para: “was granted exemption from review…” - What does this mean? And how can the IRB waive the need for informed consent, if it did not know the survey?

3. Results, 1st para: How is it possible that 91% of responding ICUs are polyvalent (I would prefer the term “mixed”) and 8% were medical and none was surgical? I am not familiar with the situation of ICUs in France, but complete absence of predominantly surgical ICUs might impact the findings. Please comment on that issue.

4. Rest of results: Please write more clearly. Avoid synonyms like "participating ICUs", “surveyed ICUs” and "respondents", “users” and “units in which volatile agents were used”. Define strict terms, like “respondents” versus “non-respondents”, “users” versus “non-users”, may-be “frequent users” or “regular users” versus “occasional users.” Also, please report data always in the same way, e.g. number (percentage) or better percentage (17/45). Please check, whether more data can be displayed in figures and shorten the text.

I personally got quite confused and had to read the results section several times to understand. Please rewrite the results section.

5. Figures:

Figure 1: In the legend you write: “in surveyed ICUs in which a dedicated device was available” (do you mean: users? Or regular users?) In the figure it says: “percentage of ICU respondents” This is not the same. Also, please stick to one term: either “surveyed ICU” or “responding ICU”.

Figure 3: similar: In the legend you write “respondents who use the technique” (please use one term throughout, I suggest “users”) and in the figure “percentage of respondents.”

Figure 4: are these truly all respondents? (90% are convinced of a beneficial bronchodilatory effect but have never used inhaled sedation?)

Figure 5A: How can “respondents” be satisfied (or dissatisfied) with a technique, if they do not use it? And why are there only 40 “respondents”???

6. Discussion, P13 second half of first paragraph: it is true that there is evidence for protection by volatile anesthetics against ischemia-reperfusion injury also in the kidney. But the use of sevoflurane for (much) longer than 48 hours should be strongly discouraged, especially if fluoride levels are not monitored daily. Off label use with scientific evidence of benefit, as for isoflurane or sevoflurane up to 48 hours, is a very much different from off-label use with scientific evidence of harm.

7. Literature:

Please quote more literature from the ICU and less from anesthesia for short lasting invasive procedures, e.g. 17 (Uhlig), 31 (Tyagi), 32 (Golembiewski), 35 (Ibrahim),43 (Perbet), 38 (Ogurlu), also 37 (Pavcnik) which refers to pediatric ICU.

Inhaled sedation should not be used via face masks in critically ill patients with respiratory failure!!!

I suggest not to mention this aspect, or else to discourage this use more strongly than simply stating that it is not supported by evidence. Quoting literature from the OR, where this is done, is not helpful! The situation in the ICU is completely different (longer time, patients not fasting (!) and with respiratory failure, no close supervision by anesthesiologist).

Instead of Uhlig, Bellgardt et al., EJA 2016 33:6-13 could be used.

For cost, consumption of iso (Sackey 2004: 2.1 ml/h; Bomberg JCMC 2018, 32:639-46: 3.1 ml/h) or sevo (Röhm ICM 2008 34:1683-9: 3.2 mL/h including cost analysis!) may be quoted, as well as L’Her, which you cite.

P12 para3L5: please do not quote Chabanne as evidence for bronchodilation. We now know that the increase in work of breathing was caused by severe carbon dioxide reflection by the device in the absence of sevoflurane.

P14 para 2 line 5: “deadspace…by AnaConDa or Mirus”: please also quote:

• Bomberg et al. Volumetric and reflective device dead space of anesthetic reflectors… JCMC 2018 32:1073-80.

Only this paper evaluated AnaConDa and the Mirus and made the distinction by volumetric (internal size) and reflective (caused by CO reflection) dead space.

P14 para 2 line 5: “a miniaturised version of the AnaConDa” please quote the first descriptions of this new device:

• Bomberg et al.: Halving the volume of AnaConDa…in critically ill patients. JCMC 2018 32:639-46, and

• Bomberg et al.: Halving the volume of AnaConDa…in a test lung model Anesthesiology 2019 129:371-79.

Minor issues:

Language: please use specific terms throughout. My preference for the substances in question would be volatile anesthetics. Halogenated agents are also part of refrigerators.

Background:

p4L5: intravenous anaesthetics --> intravenous sedatives

P4L9: guidelines reported --> guidelines recommend

P4L17 protection of the workplace environment

Results:

P8, para2, L1-2: suggestion: “Among responding ICUs, 73% (137/1XX?) declared that they knew about the use of inhaled sedation in the ICU. Of these, 98% (135/137) knew the AnaConDa and 15% (xx/137) knew the Mirus device.”

P10Para2L6: Halogenated-related adverse events – poor style

P10 para 2 last line: “after using volatile anesthetics...", “since" may imply a causal relationship

P12 para3 L7: replace “severe” by “severely ill” or “critically ill”

Discussion:

P14para2 L10: by use of charcoal filters with activated carbon placed on the expiratory branch of the ventilator or by active scavenging connected to the vacuum system.

P14 para 2 last but one line: “inform” did you mean “confirm”?

Reviewer #2: Blondonnet and colleagues should be commended to analyze in a survey the use of inhaled ICU sedation practice in France. The topic is original. The authors reported the interest of such a method for the intensivists but only few management in the daily clinical practice . Some reasons for indications and limitation of use were reported. However some few concerns deserve comments

Main comments:

- The main drawback of this type of study is the unreliable character of the veracity/quality of the data related to the questionnaires. Physicians have a real tendency to reduce or increase the number of patients, the difficulties or ease of obtaining devices, etc. An observational study over a given time or repeated twice a year over a month, for instance, would have given more scope to clinical observations and more relevance to the indications. I think that authors should mention that point.

- It is difficult to compare the reported effects in anesthesia for the preconditioning found with halogenated and the effects sought in intensive care, in particular for ventilation, which are very far from the effects associated with anesthesia using large expiratory fraction and high MAC.It is very surprising for the reviewer to see in the table some preconditioning expected effects as reported in cardiac anesthesia for instance. The reviewer should comment about these points.

- What is the training or fellowship of the physicians responders, ICU anesthesiologists or strictly intensivists? Is there a difference in the answers between the doctors from these two different training courses?

- Did the teams that manage patients with inhaled sedation use pollution-limiting systems on the ventilator's expiratory branch?

- Did the teams that used sevoflurane and isoflurane notice a difference in the hemodynamic profile of he ICU patients or the quality of the sedation?

- Can the authors have an idea on the cost-effectiveness profile of this type of management compared to IV sedation.

Reviewer #3: The authors present results from a survey of ICUs in France on their use of inhaled sedation. They provide descriptive statistics about the use and beliefs regarding inhaled sedation from about 50% of the non-pediatric ICUs in the country. The manuscript will be strengthened if the authors consider the following points.

1. Only 50% of ICUs provided information for the survey. Do authors have any information about the non-respondents to be able to comment on the similarities and differences (besides saying the respondents are geographically distributed and so authors feel they are representative)? Do authors have reasons why certain ICUs did not participate? Was that solely due to being unable to contact the ICU director?

2. Authors provide largely descriptive results from this survey. Were there any underlying hypotheses of interest that might be tested given the information that was being asked in the survey? I ask partially because in the Discussion, the authors state "Differences in practices between medical and polyvalent ICUs...", which could be just a general statement about medical and polyvalent ICUs being different rather than specific differences identified in the survey.

3. In the presentation of results (including in the Abstract), authors present frequencies and corresponding percentages. Sometimes, these percentages are calculated out of the entire sample of respondents, sometimes out of those using inhaled sedation, sometimes out of those not using inhaled sedation. It is not always clear which subgroup is being referenced, especially when (it seems) results across different subgroups are presented in the same paragraph or section. Authors should read the results section carefully and think about the organization or clarification that can be added, to ensure that it is clear who specifically the results are about.

4. Authors should think about the importance of the various figures. In many cases, authors provide all (or most) of the information in the figure in the text as well.

Minor points:

1. 9th line under results: "whose 98% percent knew..." - since "%" is already there, authors can remove "percent". This sentence should also be rephrased as it is a bit unclear as currently written.

2. 13th line under results: "44% (17/40)", 17/40 does not equal 44%

**********

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Reviewer #1: Yes: Priv.-Doz. Dr. med. Andreas Meiser

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2021 Apr 15;16(4):e0249889. doi: 10.1371/journal.pone.0249889.r002

Author response to Decision Letter 0

24 Mar 2021

RESPONSE TO EDITOR AND REVIEWER COMMENTS

Reference: MS#: PONE-D-20-38460

Title: Use of volatile agents for sedation in the intensive care unit: A national survey in France

Raiko Blondonnet, Audrey Quinson, Céline Lambert, Jules Audard, Thomas Godet, Ruoyang Zhai, Bruno Pereira, Emmanuel Futier, Jean-Etienne Bazin, Jean-Michel Constantin, Matthieu Jabaudon

We thank the Editors and the Reviewers for their careful read and thoughtful comments on the previous manuscript version. We have carefully taken these comments into consideration in preparing our revision, and we hope the manuscript has been improved. Please find below a point-by-point response to the comments and questions.

EDITORIAL COMMENTS

Dear Dr. BLONDONNET,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process

REVIEWERS COMMENTS

REVIEWER #1: The authors performed a survey in French adult ICUs about the use and about the knowledge, perceived advantages, and disadvantages of inhaled sedation for invasively ventilated patients. The presented results are robust due to a large number of responding ICUs. The conclusions drawn are supported by the results and are of great importance and currentness in view of the ongoing Covid-19 pandemic with increased demand on artificial ventilation and sedation.

However, there are some major points that should be addressed before the paper is ready for publication

Major issues

C1. Background, P4L14: As the Mirus is still quite unknown, as shown by the results of your paper, please quote at least two publications about the new device, e.g. the following

Bomberg et al: A novel device for target-controlled administration and reflection of desflurane - the Mirus. Anaesthesia 2014, 69: 1241-50

Bomberg et al.: AnaConDa and Mirus for intensive care sedation, SpringerPlus 2016: 5:420

Romagnoli: The New Mirus System for Short-Term Sedation in Postsurgical ICU patients. Crit Care Med. 2017

R1. As suggested by Reviewer #1, we added these three references on the Mirus system in the revised version of the manuscript.

C2. Methods, 1st para: “was granted exemption from review…” - What does this mean? And how can the IRB waive the need for informed consent, if it did not know the survey?

R2. According to French law and by design, such a survey did not require examination by an Ethics Committee and consequently, no informed consent was needed.

We have rephrased the sentence to avoid any misunderstanding. Thank you.

C3. Results, 1st para: How is it possible that 91% of responding ICUs are polyvalent (I would prefer the term “mixed”) and 8% were medical and none was surgical? I am not familiar with the situation of ICUs in France, but complete absence of predominantly surgical ICUs might impact the findings. Please comment on that issue.

R3. We agree that the French organization of ICU staffing can be complicated to international readers.

In France, a combined anesthesiology, critical care and perioperative medicine specialty track qualifies a MD as an “anesthesiologist and intensivist” specialist, who can work in the operating room, in the ICU, or in both.

In addition, a distinct specialty track of medical critical care trains French “medical intensivists” who can work in ICUs but cannot practice anesthesiology. Currently, ICUs managed by anesthesiologists-intensivists represent 82% of the total number of ICUs in France, that are mainly surgical and/or medical (grouped under the term “polyvalent” or “mixed”, as suggested). In contrast, ICUs managed by “medical intensivists” are usually called “medical”. Unfortunately, the proportion of anesthesiologist-intensivist staff in each participating unit was not assessed in this survey.

As suggested by Reviewer #1, we have changed the term “polyvalent” for “mixed” and added, in the Discussion paragraph, some description of ICU organization and staffing in France, in order to help the reader better understand the findings.

C4. Rest of results: Please write more clearly. Avoid synonyms like "participating ICUs", “surveyed ICUs” and "respondents", “users” and “units in which volatile agents were used”. Define strict terms, like “respondents” versus “non-respondents”, “users” versus “non-users”, may-be “frequent users” or “regular users” versus “occasional users.” Also, please report data always in the same way, e.g. number (percentage) or better percentage (17/45). Please check, whether more data can be displayed in figures and shorten the text.

I personally got quite confused and had to read the results section several times to understand. Please rewrite the results section.

R4. We thank Reviewer #1 for the comment and we apologize if our manuscript could be confusing under its previous form.

As requested, we changed the Results section to avoid synonyms (eg, we chose the term “respondents” as suggested) and we rephrased all numbers using percentages (x/x) to improve readability.

We also significantly re-organized the Results section to avoid redundancy and illustrate more data with figures, while reducing the text.

C5. Figures:

Figure 1: In the legend you write: “in surveyed ICUs in which a dedicated device was available” (do you mean: users? Or regular users?) In the figure it says: “percentage of ICU respondents” This is not the same. Also, please stick to one term: either “surveyed ICU” or “responding ICU”.

Figure 3: similar: In the legend you write “respondents who use the technique” (please use one term throughout, I suggest “users”) and in the figure “percentage of respondents.”

Figure 4: are these truly all respondents? (90% are convinced of a beneficial bronchodilatory effect but have never used inhaled sedation?)

Figure 5A: How can “respondents” be satisfied (or dissatisfied) with a technique, if they do not use it? And why are there only 40 “respondents”???

C5. Figure 1: As previously answered, and to be in accordance with the body of the manuscript (where the word “respondents” was used), we changed the legend with the term “responding intensive care units”. Figure 1 showed the number of patients in whom inhaled sedation was used each year but only in responding ICU in which a dedicated device was available (i.e., either AnaConDa or Mirus). “n=40” reported the total number of responding ICU with such a device was available. We deleted “n=40” in the legend to avoid any confusion with the number of patients receiving inhaled sedation.

Figure 3: As suggested, we have added “percentage of respondents” to the figure and changed the legend to add information on “users”.

Figure 4: Figure 4 reported data from respondents who declared they were aware of potential benefits of inhaled ICU sedation (n=129). In this sample of respondents, 88% (114/129) reported bronchodilation as a potential benefit; this percentage was very close between respondents who had a device available in their unit (90%, 35/39) and those who did not (88%, 79/90) . We have rephrased the revised manuscript to better detail these results.

Figure 5: We thank Reviewer #1 for this suggestion. We added a figure (new Figure 5), and previous Figure 5 is now Figure 6 in the revised manuscript. Figure 6A only reported satisfaction of respondents who had an inhaled ICU sedation device available and, therefore, used inhaled sedation in practice, which explains “n=40”. We rephrased the legend of Figure 6 to improve the understanding by the readers.

C6. Discussion, P13 second half of first paragraph: it is true that there is evidence for protection by volatile anesthetics against ischemia-reperfusion injury also in the kidney. But the use of sevoflurane for (much) longer than 48 hours should be strongly discouraged, especially if fluoride levels are not monitored daily. Off-label use with scientific evidence of benefit, as for isoflurane or sevoflurane up to 48 hours, is very much different from off-label use with scientific evidence of harm.

R6. We thank Reviewer #1 for the comment. As suggested, we rephrased this paragraph to highlight that clinicians should be very cautious if they use sevoflurane or isoflurane for ICU sedation for more than 48 hours.

C7. Literature:

Please quote more literature from the ICU and less from anesthesia for short lasting invasive procedures, e.g. 17 (Uhlig), 31 (Tyagi), 32 (Golembiewski), 35 (Ibrahim),43 (Perbet), 38 (Ogurlu), also 37 (Pavcnik) which refers to pediatric ICU.

Inhaled sedation should not be used via face masks in critically ill patients with respiratory failure!!!

I suggest not to mention this aspect, or else to discourage this use more strongly than simply stating that it is not supported by evidence. Quoting literature from the OR, where this is done, is not helpful! The situation in the ICU is completely different (longer time, patients not fasting (!) and with respiratory failure, no close supervision by anesthesiologists).

Instead of Uhlig, Bellgardt et al., EJA 2016 33:6-13 could be used.

For cost, consumption of iso (Sackey 2004: 2.1 ml/h; Bomberg JCMC 2018, 32:639-46: 3.1 ml/h) or sevo (Röhm ICM 2008 34:1683-9: 3.2 mL/h including cost analysis!) may be quoted, as well as L’Her, which you cite.

R7. As suggested by Reviewer #1, we edited the references and removed articles from anesthesia to increase data from ICU using the reference of Bellgardt. We also used all references suggested by Reviewer #1 regarding the cost of inhaled ICU sedation. Thank you.

We fully agree with Reviewer #1 that inhaled sedation should not be used via face mask in critically ill patients with respiratory failure. As suggested, we removed this part to avoid any misunderstanding and to strongly discourage this use.

C9. P12 para3L5: please do not quote Chabanne as evidence for bronchodilation. We now know that the increase in work of breathing was caused by severe carbon dioxide reflection by the device in the absence of sevoflurane.

R9. As suggested by Reviewer #1, we rephrased the related paragraph highlighting that the increase in work of breathing was caused by severe CO2 reflection by the device in the absence of sevoflurane and not by bronchodilation. We also quoted the study of Sturesson et al. (Br J Anaesth 2014) to reinforce this point.

C10. P14 para 2 line 5: “deadspace…by AnaConDa or Mirus”: please also quote:

Bomberg et al. Volumetric and reflective device dead space of anesthetic reflectors… JCMC 2018 32:1073-80. Only this paper evaluated AnaConDa and the Mirus and made the distinction by volumetric (internal size) and reflective (caused by CO reflection) dead space.

R10. As suggested by Reviewer #1, we added this reference to the revised manuscript.

C11. P14 para 2 line 5: “a miniaturised version of the AnaConDa” please quote the first descriptions of this new device:

Bomberg et al.: Halving the volume of AnaConDa…in critically ill patients. JCMC 2018 32:639-46, and

Bomberg et al.: Halving the volume of AnaConDa…in a test lung model Anesthesiology 2019 129:371-79.

R11. As suggested by Reviewer #1, we added these references to the revised manuscript.

Minor issues:

C12. Language: please use specific terms throughout. My preference for the substances in question would be volatile anesthetics. Halogenated agents are also part of refrigerators.

R12. As suggested by Reviewer #1, we used the term “volatile anesthetics” rather than “halogenated agents” in our revision.

C13. Background:

p4L5: intravenous anaesthetics --> intravenous sedatives

P4L9: guidelines reported --> guidelines recommend

P4L17 protection of the workplace environment

R13. As suggested by Reviewer #1, we changed these sentences in the Background section.

C14. Results:

P8, para2, L1-2: suggestion: “Among responding ICUs, 73% (137/1XX?) declared that they knew about the use of inhaled sedation in the ICU. Of these, 98% (135/137) knew the AnaConDa and 15% (xx/137) knew the Mirus device.”

R14. As suggested by Reviewer #1, we have rephrased this paragraph in the Results section.

C15. P10Para2L6: Halogenated-related adverse events – poor style

P10 para 2 last line: “after using volatile anesthetics...", “since" may imply a causal relationship

P12 para3 L7: replace “severe” by “severely ill” or “critically ill”

R15. As suggested by Reviewer #1, these sentences have been changed.

C16. Discussion:

P14para2 L10: by use of charcoal filters with activated carbon placed on the expiratory branch of the ventilator or by active scavenging connected to the vacuum system.

P14 para 2 last but one line: “inform” did you mean “confirm”?

R16. As recommended by Reviewer #1, the sentences have been changed in the Discussion section. Thank you.

REVIEWER #2: Blondonnet and colleagues should be commended to analyze in a survey the use of inhaled ICU sedation practice in France. The topic is original. The authors reported the interest of such a method for the intensivists but only few management in the daily clinical practice . Some reasons for indications and limitation of use were reported. However some few concerns deserve comments

Main comments:

C17. The main drawback of this type of study is the unreliable character of the veracity/quality of the data related to the questionnaires. Physicians have a real tendency to reduce or increase the number of patients, the difficulties or ease of obtaining devices, etc. An observational study over a given time or repeated twice a year over a month, for instance, would have given more scope to clinical observations and more relevance to the indications. I think that authors should mention that point.

R17. We thank Reviewer #2 and fully agree with this comment. Actually, in order to better and more accurately describe the use of inhaled ICU sedation, our group is currently completing an international observational study (ClinicalTrials.gov Identifier: NCT04383730), but in the specific setting of COVID-19-related acute respiratory distress syndrome.

As suggested, we added this limitation of our survey to the Discussion section.

C18. It is difficult to compare the reported effects in anesthesia for the preconditioning found with halogenated and the effects sought in intensive care, in particular for ventilation, which are very far from the effects associated with anesthesia using large expiratory fraction and high MAC.It is very surprising for the reviewer to see in the table some preconditioning expected effects as reported in cardiac anesthesia for instance. The reviewer should comment about these points.

R18. We thank Reviewer #2 for the comment. We added a comment to these specific points in the Discussion (page 15 of the revised manuscript).

C19. What is the training or fellowship of the physicians responders, ICU anesthesiologists or strictly intensivists? Is there a difference in the answers between the doctors from these two different training courses?

R19. As previously answered to Reviewer #1 in C3, the French organization of ICU staffing can be complicated to international readers.

In France, a combined anesthesiology, critical care and perioperative medicine specialty track qualifies a MD as an “anesthesiologist and intensivist” specialist, who can work in the operating room, in the ICU, or in both.

In addition, a distinct specialty track of medical critical care trains French “medical intensivists” who can work in ICUs but cannot practice anesthesiology. Currently, ICUs managed by anesthesiologists-intensivists represent 82% of the total number of ICUs in France, that are mainly surgical and/or medical (grouped under the term “polyvalent” or “mixed”, as suggested). In contrast, ICUs managed by “medical intensivists” are usually called “medical”. Unfortunately, the proportion of anesthesiologist-intensivist staff in each participating unit was not assessed in this survey.

In order to better characterize the population of respondents and their levels of training, we reported in the Results section whether respondents had received specific training on inhaled sedation, either originated from the companies developing the AnaConda or the Mirus devices and/or through scientific conferences.

As suggested by Reviewer #2, we also discussed these points in the revised Discussion.

C20. Did the teams that manage patients with inhaled sedation use pollution-limiting systems on the ventilator's expiratory branch?

R20. We thank Reviewer #2 for this important comment and we agree that volatile anesthetics induced-pollution is a major concern for environmental protection. Unfortunately, we did not assess this specific point in our survey, as we postulated that the use of a pollution-limiting system (scavenger) connected to the ventilator’s expiratory branch was part of good clinical practice, as recommended by manufacturers of inhaled ICU devices.

Indeed, and possibly due to their use of such pollution-limiting systems, only 10/147 respondents on the survey had concerns about the risk of air pollution, which could be felt as a reason not to use inhaled ICU sedation.

We have discussed this important point in the revised Discussion (page 16).

C21. Did the teams that used sevoflurane and isoflurane notice a difference in the hemodynamic profile of the ICU patients or the quality of the sedation?

R21. We thank Reviewer #2 for this interesting comment; unfortunately, we did not ask specific questions on the hemodynamic profiles or sedation efficacy in our survey.

C22. Can the authors have an idea on the cost-effectiveness profile of this type of management compared to IV sedation.

R22. We thank Reviewer #2 for this comment.

One fifth of the respondents answered that they did not use inhaled sedation because of its related cost.

Even if inhaled ICU sedation might be perceived as “more costly” at present, reductions in indirect costs through shortened times to liberation from mechanical ventilation, patient recovery, and ICU discharge following the judicious use of volatile anesthetics, combined with a reduction in the need for other treatments (such as opioid use), are plausible but often difficult to demonstrate in studies.

Regarding direct costs, in some patients in whom sedation is deemed more difficult, inhaled sedation may significantly decrease costs of sedation, with daily costs being similar between midazolam or isoflurane, and the cost difference could favor inhaled sedation in the subgroup of patients who required high doses of midazolam (L’Her et al.). We further discussed this point in the Discussion section (page 13).

REVIEWER #3: The authors present results from a survey of ICUs in France on their use of inhaled sedation. They provide descriptive statistics about the use and beliefs regarding inhaled sedation from about 50% of the non-pediatric ICUs in the country. The manuscript will be strengthened if the authors consider the following points.

Major points

C23. Only 50% of ICUs provided information for the survey. Do authors have any information about the non-respondents to be able to comment on the similarities and differences (besides saying the respondents are geographically distributed and so authors feel they are representative)? Do authors have reasons why certain ICUs did not participate? Was that solely due to being unable to contact the ICU director?

R23. We thank Reviewer #3 for this valuable comment, and we regret we did not assess this detailed information for non-respondent centers.

Indeed, after a first contact by telephone, and upon request from the ICU Medical Chief office, some questionnaires were emailed individually. In the absence of a reply after one month, a second contact with the ICU Director was performed by telephone and followed by a third call when necessary.

Among the units that were contacted, some centers did not want to participate in the survey and/or did not have time to respond. Furthermore, when no answer was received after the third reminder by phone, the center was considered as “non-respondent”. Unfortunately, we did not distinguish centers which did not want to participate from those that did not respond to our three invitations. The only element that was collected was the geographical distribution of non-respondents, which has been added as a limitation and a supplemental content (Supplemental Content 4) to our revised manuscript.

C24. Authors provide largely descriptive results from this survey. Were there any underlying hypotheses of interest that might be tested given the information that was being asked in the survey? I ask partially because in the Discussion, the authors state "Differences in practices between medical and polyvalent ICUs...", which could be just a general statement about medical and polyvalent ICUs being different rather than specific differences identified in the survey.

R24. We agree with Reviewer #3 and, as previously answered to both Reviewer #1 and Reviewer #2, we agree the French organization of ICU staffing can be complicated to international readers; additional information has been added to the Discussion section to decrease the risk of any misunderstanding. The paragraph related to this statement about “medical” and “polyvalent” ICUs has, therefore, been rephrased.

C25. In the presentation of results (including in the Abstract), authors present frequencies and corresponding percentages. Sometimes, these percentages are calculated out of the entire sample of respondents, sometimes out of those using inhaled sedation, sometimes out of those not using inhaled sedation. It is not always clear which subgroup is being referenced, especially when (it seems) results across different subgroups are presented in the same paragraph or section. Authors should read the results section carefully and think about the organization or clarification that can be added, to ensure that it is clear who specifically the results are about.

R25. We thank Reviewer #3 and apologize if our previous presentations of results could be confusing. As also suggested by Reviewer #1 and Reviewer #2, we carefully reorganized and rephrased the Results section to improve readability.

C26. Authors should think about the importance of the various figures. In many cases, authors provide all (or most) of the information in the figure in the text as well.

R26. As suggested by Reviewer #3, we rephrased the Results section to avoid redundancies between the text and the figures.

Minor points:

C27. 9th line under results: "whose 98% percent knew..." - since "%" is already there, authors can remove "percent". This sentence should also be rephrased as it is a bit unclear as currently written.

R27. We apologize for this mistake and, as previously suggested by Reviewer #1, the sentence has been rephrased. Thank you.

C28. 13th line under results: "44% (17/40)", 17/40 does not equal 44%

R28. Thank you for pointing out this mistake. We apologize and have corrected the percentage that was wrong in our previous version.

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Decision Letter 1

Corstiaan den Uil

29 Mar 2021

Use of volatile agents for sedation in the intensive care unit: A national survey in France

PONE-D-20-38460R1

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Acceptance letter

Corstiaan den Uil

5 Apr 2021

PONE-D-20-38460R1

Use of volatile agents for sedation in the intensive care unit: A national survey in France

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