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. 2022 Dec 29;17(12):e0278090. doi: 10.1371/journal.pone.0278090

Use of volatile anesthetics for sedation in the ICU during the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)

Raiko Blondonnet 1,2,*, Aissatou Balde 1, Ruoyang Zhai 2, Bruno Pereira 3, Emmanuel Futier 1,2, Jean-Etienne Bazin 1, Thomas Godet 1, Jean-Michel Constantin 4, Céline Lambert 3, Matthieu Jabaudon 1,2,5
Editor: Silvia Fiorelli6
PMCID: PMC9799316  PMID: 36580451

Abstract

Background

The COVID-19 pandemic has increased the number of patients in ICUs leading to a worldwide shortage of the intravenous sedative agents obligating physicians to find alternatives including inhaled sedation. Inhaled sedation in French ICU has been previously explored in 2019 (VOL’ICU study). This survey was designed to explore the use of inhaled sedation two years after our first survey and to evaluate how the COVID-19 pandemic has impacted the use of inhaled sedation.

Methods

We designed a national survey, contacting medical directors of French ICUs between June and October 2021. Over a 50-item questionnaire, the survey covered the characteristics of the ICU, data on inhaled sedation, and practical aspects of inhaled ICU sedation for both COVID-19 and non-COVID-19 patients. Answers were compared with the previous survey, VOL’ICU.

Results

Among the 405 ICUs contacted, 25% of the questionnaires were recorded. Most ICU directors (87%) knew about the use of inhaled ICU sedation and 63% of them have an inhaled sedation’s device in their unit. The COVID-19 pandemic increased the use of inhaled sedation in French ICUs. The main reasons said by the respondent were “need for additional sedative” (62%), “shortage of intravenous sedatives” (38%) and “involved in a clinical trial” (30%). The main reasons for not using inhaled ICU sedation were “device not available” (76%), “lack of familiarity” (60%) and “no training for the teams” (58%). More than 70% of respondents were overall satisfied with the use of inhaled sedation. Almost 80% of respondents stated that inhaled sedation was a seducing alternative to intravenous sedation for management of COVID-19 patients.

Conclusion

The use of inhaled sedation in ICU has increased fastly in the last 2 years, and is frequently associated with a good satisfaction among the users. Even if the COVID-19 pandemic could have impacted the widespread use of inhaled sedation, it represents an alternative to intravenous sedation for more and more physicians.

Introduction

Sedation is used daily in intensive care units (ICUs) to manage patients. It improves comfort and tolerance during mechanical ventilation, therapeutic interventions, or nursing care [1]. Sedation is usually performed with intravenous drugs such as propofol, midazolam or dexmedetomidine [2]. However, these products can cause serious side effects including delirium, propofol infusion syndrome and hemodynamic failure and increase the time to liberation from mechanical ventilation and the duration of stay in the ICU. All these effects are associated with increase in hospital morbidity and mortality. Therefore, clinical practice guidelines for analgesia and sedation in the ICU (e.g., the Pain, Agitation/sedation, Delirium, Immobility and Sleep disruption (PADIS) guidelines [1]) have consistently focused on early rehabilitation and rapid ventilator liberation and have suggested the use of non-benzodiazepines drugs even if adaptation of ventilator settings should be systematically considered before administering additional medications [2]. The ideal sedative drug should be effective with few adverse effects, low accumulation, and a quick awakening at the end of administration.

Since the beginning of 2020, an unprecedented pandemic changed the daily management of ICUs worldwide: coronavirus disease 2019 (COVID-19) [3]. This pulmonary infection is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) -2, and has suddenly increased the number of patients hospitalized in ICUs due to respiratory failure. In France, almost 100.000 individuals were admitted to ICUs [4] and most of them needed intubation to support respiratory function. The pandemic posed a major challenge to health-care systems because of the need for intensive care therapy and mechanical ventilation including sedation. Because of this unusual situation, intensivists had to use more sedative products leading to a worldwide shortage in critical supplies such as main intravenous sedative agents [5–9]. Consequently, physicians had to find alternatives to intravenous sedation including inhaled sedation [10]. Inhaled sedation is performed with volatile agents such as sevoflurane, desflurane or isoflurane. Inhaled volatile agents are an abundant resource and an easily implementable solution for providing ICU sedation [11]. The recent development of anesthetic reflectors, such as the Anaesthetic Conserving Device (Sedaconda-ACD, Sedana Medical, Danderyd, Sweden) and the Mirus (Carelide GmbH, Mouvaux, France), has allowed delivering inhaled sedation in the ICU [12–14]. These two devices are inline miniature vaporisers with humidification and antiviral filter properties. For the Anaesthetic Conserving Device, the titration of the desired sedation level is performed manually whereas the Mirus system adjusts infusion rates to deliver volatile anesthetics through the automatic control of anesthetic concentration targets [15]. Indeed, in some national guidelines including Germany’s, the use of volatile agents in the ICU is an option [16]. Furthermore, using volatile anesthetics could now be considered for specific acute respiratory distress syndrome (ARDS) patients to reduce emergent delirium and cumulative propofol doses [2]. Recently, isoflurane received national approval from the French Agency for the Safety of Health Products (ANSM, for Agence nationale de sécurité du médicament et des produits de santé), among other European agencies, for inhaled sedation in the ICU.

A previous study from our group explored inhaled sedation practices in French ICUs in 2019 and demonstrated that, even if most physicians were familiar with inhaled sedation, it was underused because of a lack of available devices, physicians knowledge, and supporting literature [17]. Since March 2020, few studies have cared about the potential benefits of inhaled sedation in COVID-19 patients. Nevertheless, extant data suggest that inhaled sedation could be used safely in these patients [10, 11, 18]. Indeed, volatile agents may also provide important pulmonary benefits for COVID-19 patients with ARDS that could improve gas exchange, and reduce the time spent on a ventilator [11]. Currently, recent studies have shown that inhaled sedation in COVID-19 patients reduces the need for both intravenous sedation and opïods [18–20]. Furthermore, several clinical trials are ongoing to study the use of inhaled sedation in ICU patients with ARDS secondary or not to COVID-19 [21].

Therefore, this survey was designed to explore and describe the use of inhaled sedation two years after our first survey about inhaled sedation in France [17], and to evaluate how the COVID-19 pandemic has impacted the use of inhaled sedation by French physicians working in ICUs.

Methods

Survey development

This investigator-initiated survey was approved by an independent Ethics Committee (CERAR IRB 00010254–2021–128). A 50-item questionnaire was developed with questions designed by the authors (RB, AB, MJ) (S1 File); The survey covered four categories: general characteristics of the ICU, general data of COVID-19 patients in ICU, general data on inhaled sedation, and the practical aspects of inhaled ICU sedation for both COVID-19 and non-COVID-19 patients. Some answers were compared with the previous survey, VOL’ICU [17].

Survey sample

All French ICUs were identified and contacted. Pediatric ICUs were excluded from the survey. All the same ICUs were contacted in this study as were contacted in the VOL’ICU study in order to compare the answers between the two studies [17]. The current survey was conducted between June and October 2021. After short information about the survey design and objectives, the medical director of each ICU was questioned exclusively. Completion of the survey took approximately ten minutes. The first contact with the ICU directors to complete the survey was by email. In the case of non-response, a second attempt at contact was made by email or phone with the ICU director in order to recorded the survey and followed by a last call when necessary.

Statistical analysis

Statistical analysis was performed in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [22]. Statistical analysis was performed using Stata software (version 15; StataCorp, College Station, Texas, USA). All tests were two-sided, with a Type I error set at 0.05. Categorical data were expressed as frequencies and associated percentages, and quantitative data as mean ± standard deviation or median [1st quartile; 3rd quartile], according to statistical distribution. The results of the two surveys were compared using the chi-squared test or Fisher’s exact test (qualitative variables only). The paired qualitative data were compared by the Stuart-Maxwell test.

Results

General characteristics

Among the 405 French ICUs [23], 31 pediatric ICUs were excluded and 374 adult ICU directors were questioned. A total of 25% (102/405) of the questionnaires were recorded, 95% (97/102) electronically and 5% (5/102) orally. The general characteristics of ICU respondents and geographical distribution of respondents are reported in S2 and S3 Files. Of the answers, 52% (53/102) came from general hospitals, 38% (39/102) from teaching hospitals, 9% (9/102) from private medical centers and 1% (1/102) from military hospitals. Among the participating ICUs, 89% (91/102) were mixed (medical and surgical) ICUs, 10% (10/102) were only medical ICUs and 1% (1/102) was a burn center. The majority of the ICU respondents managed COVID-19 patients (95%, 97/102).

Practical aspects of inhaled ICU sedation

Among the respondents, 87% (89/102) stated that they knew about the use of inhaled sedation in the ICU. Among the 89 respondents, 9% (8/89) discovered inhaled sedation during the COVID-19 pandemic. Of these, 91% (81/89) knew about the SedaConda-ACD device and 10% (9/89) knew the Mirus device. Sixty-three percent (56/89) of respondents who knew about the use of inhaled sedation in the ICU reported disposing of a specific device in their unit. Among these respondents, 84% (47/56) declared they performed inhaled sedation with Sedaconda-ACD, and 14% (8/56) used Mirus. Five percent of respondents (3/56) declared to own both. Thirty-four percent (19/56) of respondents answered that they had acquired a device since the pandemic. If neither the Sedaconda-ACD nor the Mirus were available in their hospital, 11% (6/56) of respondents declared that they borrowed anesthesia ventilators from the operating room to deliver volatile anesthetics in the ICU.

According to all respondents, 35% (36/102) reported performing inhaled sedation in the ICU before the beginning of the COVID-19 pandemic and 47% (48/102) of respondents reported using inhaled sedation in the ICU since the COVID-19 pandemic began. Twenty-five percent of the respondents (25/102) declared that they had modified their use of inhaled sedation during COVID-19. The two main reasons for changing the use of inhaled sedation were: a more frequent use independent of COVID-19 and a more frequent use with ARDS patients. Among the respondents who did not use inhaled sedation, 34% (20/58) said they were favorable to developing inhaled sedation in their unit within the next two years.

During the COVID-19 pandemic, the reasons declared by the respondents to use inhaled sedation were in descending order: the need for additional sedative (62%, (28/45)), a shortage of intravenous sedatives (38%, (17/45)),the unit was involved in a clinical trial about inhaled sedation (30% (17/45)) and interest in the system (27%, (12/45)).

Indications and contraindications for inhaled ICU sedation

Twenty-seven percent of respondents (15/56) declared that inhaled sedation was performed by all physicians working in their units. The majority of the respondents answered they used inhaled sedation in the ICU in less than 20 patients per year before and after the beginning of COVID-19 (Fig 1).

Fig 1. Number of patients per year sedated with volatile sedation in ICU declared by the respondents (n = 102).

Fig 1

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Data are represented in numbers of ICU respondents.

Main reasons for not using inhaled ICU sedation were as follows: “device not available” (76%, (47/62)) and “lack of familiarity about the technique” (60%, (37/62)) and “lack of formation for both the physicians and the nurses” (58%, (36/62) each) and “halogenated-induced atmospheric pollution” (27%, (17/62)) (Fig 2).

Fig 2. Reasons declared by the respondents for not using inhaled sedation in ICU (n = 62).

Fig 2

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Data are represented in %.

About indications, the main reported by respondents were: “failure of intravenous sedation” (74%, (39/53)), “severe asthma” (64%, (34/53)), and ARDS (49%, (26/53)). The other indications mentioned are summarized in Fig 3. The main advantages for using volatile sedation answered by respondents were: bronchodilation (83%, (44/53)) and usability (64%, (34/53)).

Fig 3. Indications declared by the respondents for using inhaled sedation in ICU (n = 53).

Fig 3

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Data are represented in %.

Absolute contraindications for inhaled sedation were reported by 94% (68/72) of the respondents (Fig 4). Thirty-nine percent (22/57) of the respondents declared that they had already at least one adverse effect attributable to volatile anesthetics, mainly reporting diabetes insipidus, malignant hyperthermia, and hypercapnic acidosis.

Fig 4. Contraindications declared by the respondents for using inhaled sedation in ICU (n = 68).

Fig 4

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Data are represented in %.

Inhaled sedation in practice

Eighty-two percent of respondents (83/101) declared that they had a written protocol for sedation in their institution whereas 64% (34/53) of units had a specific protocol for inhaled sedation.

Among units using inhaled sedation, 41% (19/46) of the respondents said they received specific training on inhaled sedation, either from the companies developing the devices in 84% (16/19) of the respondents or through scientific conferences in 21% (4/19) of the respondents.

Sevoflurane and isoflurane were the main drugs used, as reported by the respondents (94%, (30/32) and 22%, (7/32) respectively) and 3 respondents (10% (3/32)) answered they used both. Four respondents (13%, (4/32)) said they used desflurane. To manage sedation, respondents reported achieving a target exhaled gas fraction with sevoflurane of 1.0 [0.8–1.2] (35/56) and 0.5 [0.4–0.7] (27/56) for deep sedation and light sedation, respectively. All respondents said that they used inhaled sedation with controlled ventilation mode. Forty-six percent of them (25/54) stated that they also used inhaled sedation during pressure support ventilation in intubated patients. Two respondents (4% (2/54)) declared that they had already used inhaled sedation during non-invasive ventilation.

All the respondents reported that they usually combined opioid-based analgesia with inhaled sedation, 65% (35/54) with sufentanil, 37% (20/54) with remifentanil and 6% (3/54) with fentanyl or morphine. One-third of them (18/54) answered that they combined gas with continuous intravenous sedative hypnotic, such as propofol (94%, (17/18)), midazolam (61%, (11/18)), ketamine (33%, (6/18)) or dexmedetomidine (17%, (3/18)).

When asked how they measured sedation objectives, most of the respondents (93%, (77/83)) answered using validated sedation scales or scores (such as The Richmond Agitation Sedation Scale (RASS)) rather than end-tidal gas concentration monitoring (42%, (35/83)). Forty-eight percent of the respondents (40/83) used the bispectral index (BIS-ASPECT-A-2000; Aspect Medical Systems, Norwood, USA). Only one ICU director reported that he measured plasma concentrations of volatile anesthetics or their metabolites when monitoring inhaled sedation.

According to the ICU directors’ answers, 65% (35/54) interrupted inhaled sedation when patients began the process of weaning from ventilation and 37% (20/54) did not specifically set any maximal duration for inhaled sedation in their ICU patients.

Overall satisfaction with the use of inhaled sedation among users is represented in Fig 5. Seventy-nine percent (69/87) of the respondents declared that inhaled sedation could be an interesting alternative to intravenous sedation and especially for COVID-19 patients for 76% (62/82) of the respondents.

Fig 5. Overall satisfaction of respondents regarding the use of inhaled sedation before (n = 43) and since the COVID-19 (n = 53).

Fig 5

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Data are represented in %.

Evolution of inhaled sedation use compared to VOL’ICU study

The comparison between the data from VOL’ICU and VOL’ICU2 is summarized in Table 1. Since the beginning of COVID-19, the respondents declared that they know more about inhaled sedation in the ICU and dispose more frequently of use at least one of the devices for delivering inhaled sedation. The indications for the use of inhaled sedation declared by the respondents were unchanged between VOL’ICU and VOL’ICU2 except for an increased use for medical indications since the COVID-19 pandemic. The two main volatile anesthetics used remained sevoflurane and isoflurane, but 13% of respondents declared to use desflurane in VOL’ICU2 compared to zero respondents in VOL’ICU. No significant modification of the rate of adverse effects was shown between the two studies.

Table 1. Comparisons between the answers provided by the respondents in the VOL’ICU (n = 187) and VOL’ICU2 (n = 102) studies.

Results are presented as numbers (with associated percentages). Percentages were rounded to the nearest whole number depending on whether the value after the decimal was greater than or less than 5.

VARIABLE VOL’ICU VOL’ICU 2 p value
Knowledge of inhaled sedation, n (%)
Yes 137 (73) 89 (87) 0.006
No 50 (27) 13 (22)
Availability of the device in the unit, n (%)
Yes 40 (21) 56 (55) < 0.001
No 147 (79) 45 (55)
Indications, n (%)
Medical 13 36 0.01
Post-operative 13 13 0.92
ARDS 65 49 0.13
Trauma 3 6 0.63
Failed sedation 75 74 0.88
Asthma 75 64 0.26
Status epilepticus 10 13 0.64
Cardioprotection 13 2 0.08
No specific indication 3 6 0.63
Reasons declared for not using inhaled sedation, n (%)
No device available 39 76 < 0.001
Lack of medical training 22 58 < 0.001
Lack of paramedic training 16 58 < 0.001
Complexity 12 19 0.14
Ecological concern 7 27 < 0.001
Adverse effects 1 13 < 0.001
Lack of familiarity 35 60 < 0.001
Cost 21 18 0.58
Sedation protocol, n (%)
Intravenous sedation
Yes 157 (84) 83 (82) 0.7
No 30 (16) 18 (18)
Inhaled sedation
Yes 17 (45) 34 (34) 0.23
No 21 (55) 67 (66)
Volatile anesthetics, n (%)
Sevoflurane 88 94 0.45
Isoflurane 20 22 0.85
Desflurane 0 13 0.04
Adverse effects, n (%)
Yes 11 (28) 22 (39) 0.26
No 29 (73) 35 (61)
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Discussion

This survey is the first to re-evaluate the use of inhaled sedation after the COVID-19 pandemic in French ICUs. This survey shows that, in 2021, both knowledge of and interest in inhaled sedation are growing significantly among French intensivists. Nonetheless, the lack of devices with which to perform inhaled sedation in units and the insufficient training of both medical and paramedical teams remain barriers to widespread use of inhaled sedation.

The COVID-19 pandemic has led to a worldwide shortage of intravenous sedative drugs, prompting intensivists to search for alternatives to sedate ICU patients [5–9]. Interestingly, French intensivists mainly justified the use of inhaled sedation in their units during COVID-19 with the need for additional sedatives [10]. Thus, COVID-19 patients, especially when they develop ARDS, need higher doses of sedatives to reach the sedation objective compared to non-COVID-19 patients [24]. This element may also explain the increase of use of inhaled sedation with or without another hypnotic in our survey. The use of inhaled sedation due to shortages was declared by only one-third of the respondents as well as the involvement of the unit in clinical trials on inhaled sedation. This point suggests that the popularity of inhaled sedation may be increased because of its intrinsic sedative characteristics. The respondents also reported potential interest in the bronchodilator effect and the manageability of inhaled sedation which could explain why volatile anesthetics may be a more popular option in the management of COVID-19 patients. Indeed, the efficacy of volatile anesthetic is also demonstrated in patients with refractory life-threatening status asthmaticus [25]. Furthermore, some studies also suggest that volatile anesthetics has a good manageability, avoids tachyphylaxis and perhaps anti-inflammatory effects [26, 27]. For all these reasons, volatile sedation may become, theoretically, an ideal option for intensivists in order to manage sedation. Furthermore, a large number of clinical trials studying the effects of inhaled sedation with either sevoflurane or isoflurane on major clinical outcomes in both non-COVID-19 and COVID-19 patients are actually enrolling patients (ClinicalTrials.gov: NCT04235608, ClinicalTrials.gov: NCT04415060, ClinicalTrials.gov: NCT04341350). In addition to providing important results about inhaled sedation in ICU, these trials may contribute to help participating centers to be more familiar with this technique.

However, we noted that scarcity was not the main reason for the increased use of volatile sedation in ICUs since the pandemic started: indeed, respondents reported that they used volatile anesthetics to achieve better sedation and to manage patients with ARDS. Volatile anesthetics contraindications in ICU seem known by almost all participants even if answers varied. Malignant hyperthermia was the contraindication mainly responded by the physicians and clearly documented by studies in the literature [28]. The other contraindications remained unclear for ICU’s practitioners and it could be explained by a very scarce literature about at-risk patient categories. Inhaled sedation should be avoided when there is a risk of increased intracranial pressure. However, inhaled sedation could be used, in some circumstances, both in neurosurgical and neurocritical patients [29]. Indeed, volatile anesthetics are known for their antiepileptic properties and may have therapeutic benefits in patients with refractory status epilepticus [15, 30–32]. Furthermore, volatile anesthetics have also been studied in patients with stroke and subarachnoid hemorrhage, but with less promising results [31]. During pregnancy, the use of sevoflurane seems safe, but the “precautionary principle” should be applied to limit exposure as much as possible [33]. Interestingly, the number of adverse effects reported by the users of inhaled sedation did not statistically change between VOL’ICU and VOL’ICU2. Some respondents reported suspected or confirmed cases of diabetes insipidus, but also malignant hyperthermia and hypercapnia with acidosis. Unfortunately, the literature about adverse events related to inhaled sedation use is limited and the most often, the causality remains under debate. Nevertheless, the prolonged use of inhaled sedation (e.g., for >48 h) has shown good safety with equivalent effects on hemodynamic stability, no hepatorenal toxicity, and possibly less agitation compared to intravenous agents [34–37]. Even if large-scale studies are urgently needed to confirm safety of inhaled ICU sedation, the multicenter randomized controlled SEDACONDA study found that ICU sedation with isoflurane for up to 54 h is safe and efficacious as a sole sedative and non-inferior to propofol in maintaining targeted sedation levels [38].

Managing inhaled sedation could be frightening for ICU teams when starting, notably with regards to the sedation levels targeted. Interestingly, most of the respondents mainly managed inhaled sedation in ICU patients using validated sedation scales or scores (e.g., RASS) rather than end-tidal gas concentration monitoring. Anyway, monitoring sedation level with a validated tool, titrating all sedative agents and reassessing the target sedation level several times a day are needed to manage sedation in ICU whatever the sedatives [2]. Meanwhile, modern approaches of “analgesia-first’’ or “analgesic-based sedation” are growing favoring the use of an analgesic before a sedative for pain management in ICU [2]. As intravenous sedation has to be titrated by ICU teams, inhaled sedation should be managed by an “inhaled titration” of volatile anesthetics agents using scales such as the RASS. All the more, the end-tidal gas concentration monitoring and RASS are correlated in ICU patients [39]. No data are available to date on the safety and efficacy to manage inhaled sedation only using clinical sedation scores. In some specific patients, such as ARDS patients with neuromuscular blockade (NMBA), management of inhaled sedation should probably integrate end-tidal gas concentration monitoring and/or instruments. Indeed, among patients receiving NMBAs, neither the gold standard for pain assessment (i.e., the patient’s self-report) or recommended behavioral measures can be used. Alternative approaches for pain and sedation assessment in paralyzed patients are being explored, such as the analgesia nociception index or the pupillary pain index [2]. Unfortunately, we did not investigate in our survey if the scales or scores were evaluated by nurses or by doctors. Indeed, the use of nurse-directed analgesia/sedation protocols, which enable bedside nurses to adjust opioids and sedatives can reduce drug exposure and shorten weaning from mechanical ventilation and ICU discharge.

The major restraining factors for a more widespread use of inhaled sedation remains the availability of the device and the training of both medical and paramedical teams. Nevertheless, devices to perform inhaled sedation are available in 36% of additional ICU and 10% of additional ICU just started using inhaled sedation, compared to the results of our first survey. The same restraining factors were answered by the respondents in 2019 in the VOL’ICU study. These points strengthen the importance of education programs of the caregivers who work in ICUs to decrease the fear of using a “new” sedation technique whatever their specialty track. Indeed, some other european and non-european intensivists with different specialty track trains compared to France use inhaled sedation in ICU [37, 38]. These elements should encourage the practitioners to reinforce the training and pedagogical requirements about inhaled sedation in their units and to integrate inhaled sedation into multifaceted bundles of sedation in the ICU [2]. The education of both practitioners and nurses is crucial to developing the use of inhaled in the ICU. Hopefully, the use of volatile anesthetics can now be considered for specific ARDS patients to reduce emergent delirium and cumulative propofol doses [2]. Furthermore, isoflurane received approvals from 15 European medicines agencies for inhaled sedation in ICU which will result in an increased use of inhaled sedation. This increase in the use of inhaled sedation should be supported by the writing of a specific protocol for inhaled sedation which is insufficiently present in the units to date. Indeed, oversedation remains common in many ICUs such that an sedation protocol is frequently beneficial for patients. Another point is that even if industries provided many devices all around France during the COVID-19 pandemic, some ICUs could have experienced shortages in some devices or consumables, thus restraining inhaled sedation use and explaining that 47/62 respondents did not use the device due to lack of availability. Furthermore, due to the difference in price between the Sedaconda-ACD and MIRUS devices, the MIRUS may not be suitable for short-term acquisition and could be an explanation for the clear dominance of the Sedaconda-ACD use in our study.

Extracorporeal membrane oxygenation (ECMO) is used for patients with severe respiratory failure and received particular attention during the COVID-19 pandemic [40]. Usually, patients are sedated using intravenous sedative drugs to reduce oxygen consumption. However, patients undergoing ECMO require more intravenous sedative drugs because of the loss of these drugs via the ECMO circuit [41, 42]. During the shortage in intravenous sedatives, the sedation of ECMO patients could be challenging. Use of inhaled sedation in ARDS patients treated with ECMO is relatively novel and raises several feasibility and safety questions. Nevertheless, volatile anesthetics administration was effective finor ARDS patients undergoing ECMO [43–45]. Volatile anesthetics could be delivered through the mechanical ventilation [43] or the ECMO [44] circuits. Inhaled sedation could be used for patients undergoing cardiac surgery with administration of volatile anesthetics through the Sedaconda-ACD connected directly to the extra corporeal circulation [46]. However, more data on the use of this method and further clinical studies are needed before such a method can be generalized.

The risk of room and environmental pollution remains a limiting factor among the respondents for the use of inhaled sedation in ICU. It is true that average threshold limit concentrations for volatile anesthetics differ significantly between countries or are not even defined at all, leading to raising concerns among teams who work in ICU [47]. Actually multiple studies reported room pollution far below the recommended exposure limits even in countries with lowest recommendations [33, 48, 49]. Concerns are often historically founded, when personnel were exposed to high concentrations of evidently toxic substances, which were used in rooms without air-conditionings and gas scavenging systems. However, based on currently available data, there is no significant pollution when the anesthetic reflectors are correctly set up and used in accordance with recommendations from their manufacturers. Besides, in order to decrease room pollution, the Swedish and American authorities recommend that ICU rooms are equipped with air conditioning that has at least 6 air changes per hour. Indeed effective air conditioning is an effective system to maintain low values of waste volatile anesthetics below the recommendations [33, 49]. Additionally, devices such as the Sedaconda-ACD reflects moisture back to the patient, but also reflects up to 90% of the volatile anesthetics by adsorbing and releasing the volatile using a proprietary carbon filament reflecting medium. This reflection reduces the total amount of volatile anesthetics needed, reducing that which is exhausted or scavenged [50]. Furthermore, activated carbon systems connected to the expiratory branch of the ventilator or active scavengers connected to the vacuum system exist worldwide to capture the volatile anesthetics no longer absorbed by the devices; ideally, these residuals could be recycled in the future [47, 51–53].

Our survey has several limitations. First, with 102 survey responses, the participation rate in this second survey was lower than in our previous survey (n = 187, 50% response rate). With the second survey, we were only able to reach about 27% of potentially eligible adult ICUs in France [16]. Since the beginning of the COVID-19 crisis, the French healthcare system has been challenged with reorganizations of critical care all around the country including major physician and nurse turnovers [54]. Furthermore, a lower interest in this survey could be explained by the amount of work for some ICU directors due to a number of COVID-19 cases that remain high in some regions. Nevertheless, the characteristics of the answering ICUs were comparable to those of our previous survey. Furthermore, we used the same information channels to distribute the survey link and the time-period (summer) was identical to our first survey. Second, declarative surveys can only provide limited information due to intrinsic bias which could be avoided with an observational study. Nevertheless, the validity of our findings is highlighted by the design of the study in which only ICU directors were questioned to limit both the non-response rate and the response bias. 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, our study shows that the use of inhaled sedation in ICU has increased since 2019, and is frequently associated with a good satisfaction among the users. Especially since the COVID-19 pandemic, the use of inhaled sedation could represent an alternative to intravenous sedation for more and more French physicians. Nonetheless, both lack of devices available in the units and insufficient training of ICU teams remain the two major restraining factors for the use of inhaled ICU sedation.

Supporting information

S1 Data

(XLSX)

Click here for additional data file. (332KB, xlsx)
S1 File. Survey questionnaire.

(DOCX)

Click here for additional data file. (235.5KB, docx)
S2 File. Characteristics of the centers where respondents worked and characteristics of the non-COVID-19 and COVID-19 patients estimated by the respondents.

(DOCX)

Click here for additional data file. (23.9KB, docx)
S3 File. Geographical distribution and epidemiological data on respondents.

(XLSX)

Click here for additional data file. (332.1KB, xlsx)

Acknowledgments

The authors would like to thank all the respondents of the survey.

Abbreviations

ARDS

Acute respiratory distress syndrome

COVID-19

2019 Coronavirus disease

ECMO

Extracorporeal membrane oxygenation

ICU

Intensive care unit

NMBA

Neuromuscular blocking agent

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

There was no funding for this work. This work was supported by internal funding of the Department of Perioperative medicine, CHU Clermont-Ferrand, France. Sedana Medical and Abbvie provided support in the form of fees for authors [MJ; JMC], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

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Decision Letter 0

Silvia Fiorelli

15 Sep 2022

PONE-D-22-06434Use of volatile anesthetics for sedation in the ICU after the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)PLOS ONE

Dear Dr. Blondonnet,

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Reviewer #1: 1. Title should be changed - from "...in the ICU AFTER COVID 19..." in "...in the ICU DURING COVID 19...." because the survey questions were related to COVID19 period.

2. Figure no. 1 has to changed into a more clear one. Legend should be chnaged (grey shades used can lead to mistakes - "no answer" and "> 100 patients" having a similar colour). Also the legend is not intelligible and not totally compatible with the text description.

Reviewer #2: I would like to express my gratitude for the opportunity to review the submitted intriguing work on the use of volatile sedation in France. Unfortunately, the work in its current form still has a number of shortcomings.

I am sorry, but I have to criticise the inadequate referencing work. The study by your French colleague (reference 5 ) does not describe an actual shortage of sedatives! The colleagues describe aptly in their introduction to your study project: “Another major concern was to ensure access to mandatory anesthetics drugs medications, or neuromuscular blockade agents. In response to such shortages, we decided to diversify our sedative agents panel and thus to use volatile agents…”. However, authors should not be guided by the title of a paper without allowing its content to be presented in the referenced study! So far, the manuscript fails to provide appropriate references for the presentation of a real drug shortage. This applies equally to the corresponding section of the discussion.

How do the authors conclude that volatile substances are an "abundant" resource? Whereas, according to them, intravenous sedatives are a scarce resource?

I'm not sure, but if I'm not mistaken, the MIRUS is the MIRUS device from the company Technologie Institut Medizin, which is distributed in by carelide, Dahlhausen, Anandic or Pall?

In another passage, the authors cite a well-done Narrative Review by the esteemed colleague Jerath on Volatile Sedation in COVID-19 (reference 11), which raises the hypothesis outlined, but does not substantiate it with appropriate COVID-19-specific data. Such data should present masterful performance 3 months after the global COVID-19 outbreak as well. A corresponding referencing with current data would be exciting.

Regarding the acquisition of medical devices, it seems that 34% new acquisitions during the pandemic is a quite high rate of observation. However, it should be discussed that the purchase of a Sedaconda ACD membrane is around 16€ and a MIRUS device costs several thousand euros. Therefore, the MIRUS Device is not suitable for short-term acquisitions and would be an explanation for the clear dominance of the Anaesthetic conserving Device: AnaConDa/SeDaConDa.

How do the authors explain that 47/62 respondents did not use the device due to lack of availability, when the majority of them used Sedaconda as a patient-specific single-use material?

The authors disclose early on that numerous uses of volatile sedatives are under study conditions. Has it been evaluated on your part whether the center determining intravenous gas concentrations of volatiles is a study condition determination? I can't explain it any other way. And it does seem a bit confusing to someone not versed in the field.

“Thus, COVID-19 patients, especially when they develop ARDS, need higher doses of sedatives to reach the sedation objective compared to non-COVID19 patients [11].” As noted above, this source does not reflect the aggravated sedation per se, here the evidence has already been provided elsewhere: https://doi.org/10.1371/journal.pone.0253778/ https://doi.org/10.1371/journal.pone.0253778.

„The respondents also reported potential interest in the bronchodilator effect and…” also the bronchodilator properties could already be demonstrated several times and is accordingly not only an assumption of individual responders. Accordingly, the use in asthma is also found explicitly in your survey as one of the most frequently selected fields of application. https://doi.org/10.1111/pan.12577

„However, inhaled sedation should be avoided when there is a risk of increased intracranial pressure.” Considering that volatiles are used for the treatment of status epilepticus as well as in the neurosurgical ICU, I would be interesting to know the underlying recommendation. In your data, volatiles were used for the therapy of status epilepticus in 22% of the respondents. Please provide references.

I think it is problematic to primarily use the RAAS to monitor the level of sedation. This score may be helpful to measure shallow sedation or agitation, but deep sedation in severe ARDS in particular is not adequately captured by the assessment on which the score is based. Please specify your recommendations.

It might be worth mentioning that the titration of the desired sedation state using the minimum alveolar concentration with the closed loop system of the MIRUS system works without intervention depending on age, gender and weight, whereas this has to be done manually with the Anaconda device.

„always with a good satisfaction among the users” I think that it is not possible to speak of "always" with just under 74% of the users being very satisfied!

A problem not discussed appears to be the high number of ECMO treatments among COVID-19 patients and the impossible use of volatile sedatives in this patient population.

It should perhaps be mentioned that in the meantime activated charcoal systems exist on international markets to capture the volatile sedative no longer absorbed by the ACD, which even allows recycling. This would provide an approach to the ecological concerns expressed by 27 respondents.

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Reviewer #2: No

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PLoS One. 2022 Dec 29;17(12):e0278090. doi: 10.1371/journal.pone.0278090.r002

Author response to Decision Letter 0

24 Oct 2022

RESPONSE TO EDITOR AND REVIEWER COMMENTS

Reference: MS#: PONE-D-22-06434

Title: Use of volatile anesthetics for sedation in the ICU during the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)

Raiko Blondonnet, Aissatou Balde, Ruoyang Zhai, Bruno Pereira, Emmanuel Futier, Jean-Etienne Bazin, Thomas Godet, Jean-Michel Constantin, Céline Lambert, Matthieu Jabaudon

We thank the Editors and the Reviewers for their careful reading 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.

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R1. We have carefully proofread the manuscript in order to be in accordance with the PLOS ONE’s style requirements.

C2. Thank you for stating the following in the Competing Interests section:

“The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: 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; MJ received consulting fees from Abbvie. Other authors have no competing interest. There are no patents, products in development or marketed products to declare”

We note that one or more of the authors are employed by a commercial company: SESAR, Sedana Medical

a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. >>>

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C2a. As requested, we have changed the Funding Statement and the Competing Interests Statement according to the journal requirements. Nevertheless, neither Matthieu Jabaudon (MJ) nor Jean-Michel Constantin (JMC) are employed by Sedana Medical or Abbvie. JMC and MJ received fees from Sedana Medical for participation in a scientific advisory panel; MJ received consulting fees from Abbvie.

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.

C2b. As requested, we have changed the Funding Statement and the Competing Interests Statement according to the journal requirements. Neither Sedana Medical or Abbvie has no influence in the study and collection, analysis, and interpretation of data and in writing of the current study.

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R3. As requested, we included the recommended statement.

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C4. As requested, we included both an updated Funding Statement and Competing Interests Statement in your cover letter.

EDITORIAL COMMENTS

REVIEWER COMMENTS

REVIEWER #1

C1. Title should be changed - from "...in the ICU AFTER COVID 19..." in "...in the ICU DURING COVID 19...." because the survey questions were related to COVID19 period.

R1. As suggested, we changed the title of the manuscript.

C2. Figure no. 1 has to changed into a more clear one. Legend should be chnaged (grey shades used can lead to mistakes - "no answer" and "> 100 patients" having a similar colour). Also the legend is not intelligible and not totally compatible with the text description

R2. We thank Reviewer #1 for this comment. As suggested, we updated both the Figure 1and the legend in order to improve the understanding.

REVIEWER #2

Reviewer #2: I would like to express my gratitude for the opportunity to review the submitted intriguing work on the use of volatile sedation in France. Unfortunately, the work in its current form still has a number of shortcomings.

C3. I am sorry, but I have to criticise the inadequate referencing work. The study by your French colleague (reference 5 ) does not describe an actual shortage of sedatives! The colleagues describe aptly in their introduction to your study project: “Another major concern was to ensure access to mandatory anesthetics drugs medications, or neuromuscular blockade agents. In response to such shortages, we decided to diversify our sedative agents panel and thus to use volatile agents…”. However, authors should not be guided by the title of a paper without allowing its content to be presented in the referenced study! So far, the manuscript fails to provide appropriate references for the presentation of a real drug shortage. This applies equally to the corresponding section of the discussion.

R3. We apologize for the inadequate referencing work. We truly agree with Reviewer #2 about not to be guided only by the title of the paper and we applied the “reference 5 - doi: 10.1016/j.jcrc.2020.09.009” to the corresponding sentence. The “reference 5 - doi: 10.1016/j.jcrc.2020.09.009” argued that inhaled sedation could be an effective therapy in settings of medication shortages. As suggested, we added new references to report drug shortage worldwide in both the introduction and the discussion.

C4. How do the authors conclude that volatile substances are an "abundant" resource? Whereas, according to them, intravenous sedatives are a scarce resource?

R4. We thank Reviewer #1 for this comment. Around 300 million surgical operations are performed globally worldwide each year and this number is increasing (https://doi.org/10.1016/j.ijsu.2020.07.017). Volatile anesthetics are used daily to provide general anesthesia in the operating room. Consequently, volatile anesthetics appear as an important actor in the hospital, which made us conclude that volatile anesthetics are an abundant resource, as suggested by Jerath et al. in their recent review (https://doi.org/10.1007/s00134-020-06154-8). As answered to the previous comment, the intravenous sedatives were a scarce resource during the shortage due to the COVID-19 pandemic. In order to avoid any confusion and to increase readability, we have rephrased the corresponding sentence.

C5. I'm not sure, but if I'm not mistaken, the MIRUS is the MIRUS device from the company Technologie Institut Medizin, which is distributed in by carelide, Dahlhausen, Anandic or Pall?

R5. We thank Reviewer #2 for this comment. Indeed, the MIRUS is the MIRUS device from the company Technologie Institut Medizin, which is currently distributed by Carelide (Mouvaux, France). Previously, the MIRUS device was distributed by Pall medical.

C6. In another passage, the authors cite a well-done Narrative Review by the esteemed colleague Jerath on Volatile Sedation in COVID-19 (reference 11), which raises the hypothesis outlined, but does not substantiate it with appropriate COVID-19-specific data. Such data should present masterful performance 3 months after the global COVID-19 outbreak as well. A corresponding referencing with current data would be exciting.

R6. We thank Reviewer #2 for this comment. We added in the introduction some recent studies that have shown a potential beneficial effect of the inhaled sedation on the need for both intravenous sedatives and opioïds. Furthermore, we added a recent systematic review about inhaled sedation for invasively ventilated COVID-19 patients that lists the ongoing clinical trials on the effects of the inhaled sedation in ICU (https://doi.org/10.3390/jcm11092500).

C7. Regarding the acquisition of medical devices, it seems that 34% new acquisitions during the pandemic is a quite high rate of observation. However, it should be discussed that the purchase of a Sedaconda ACD membrane is around 16€ and a MIRUS device costs several thousand euros. Therefore, the MIRUS Device is not suitable for short-term acquisitions and would be an explanation for the clear dominance of the Anaesthetic conserving Device: AnaConDa/SeDaConDa.

R7. We thank Reviewer #2 for this interesting comment. As suggested, we added these elements to the Discussion.

C8. How do the authors explain that 47/62 respondents did not use the device due to lack of availability, when the majority of them used Sedaconda as a patient-specific single-use material?

R8. We agree with Reviewer #2 that this point is intriguing. It could explain that even if the industries have provided many devices all around France during the COVID-19 pandemic, some ICUs could experience shortages of some devices or consumables, thus restraining the use of inhaled sedation. We have rephrased the corresponding sentence in the Discussion.

C9. The authors disclose early on that numerous uses of volatile sedatives are under study conditions. Has it been evaluated on your part whether the center determining intravenous gas concentrations of volatiles is a study condition determination? I can't explain it any other way. And it does seem a bit confusing to someone not versed in the field.

R9. We agree with Reviewer #2 that is a difficult question and it could be confusing for “non-experts” in inhaled sedation, especially when implementing for the first time the use of inhaled sedation in the ICU. In this study, we did not assess the intravenous gas concentrations used via the expired fractions of sevoflurane declared used by the respondents under study condition. But, for example, in the SESAR study (https://doi.org/10.3390/jcm11102796), a large RCT conducted by our group, the level of sedation in the both groups (i.e., intravenous sedation or inhaled sedation) is protocolized using the Richmond Assessment Sedation Scale with the BIS value (if the patients are also the neuromuscular blockade). We rephrased the discussion in order to add this point.

C10. “Thus, COVID-19 patients, especially when they develop ARDS, need higher doses of sedatives to reach the sedation objective compared to non-COVID19 patients [11].” As noted above, this source does not reflect the aggravated sedation per se, here the evidence has already been provided elsewhere: https://doi.org/10.1371/journal.pone.0253778/

R10. We thank Reviewer #2 for this comment and for the help. As suggested, we added this reference.

C11. „The respondents also reported potential interest in the bronchodilator effect and…” also the bronchodilator properties could already be demonstrated several times and is accordingly not only an assumption of individual responders. Accordingly, the use in asthma is also found explicitly in your survey as one of the most frequently selected fields of application. https://doi.org/10.1111/pan.12577

R11. As suggested, we discussed the efficacy of inhaled sedation in patients with refractory life-threatening status asthmaticus and we added the reference. Thank you.

C12. However, inhaled sedation should be avoided when there is a risk of increased intracranial pressure.” Considering that volatiles are used for the treatment of status epilepticus as well as in the neurosurgical ICU, I would be interesting to know the underlying recommendation. In your data, volatiles were used for the therapy of status epilepticus in 22% of the respondents. Please provide references.

R12. We thank Reviewer #2 for this comment. As suggested, we added references about the use of volatile anesthetics for the treatment of refractory status epilepticus and for neurosurgical patients to the Discussion.

C13. I think it is problematic to primarily use the RAAS to monitor the level of sedation. This score may be helpful to measure shallow sedation or agitation, but deep sedation in severe ARDS in particular is not adequately captured by the assessment on which the score is based. Please specify your recommendations.

R13. We thank the Reviewer #2 for this valuable comment and we agree that evaluation of the sedation is challenging in patients with ARDS.

Before and after administering an NMBA, patients should receive an intravenous analgesic medication sufficient to provide acceptable pain relief, as well as a sedative to target a deep level of sedation. Sedation management in patients receiving NMBAs should ideally rely on validated scales or tools. However, the assessment of anxiety and pain when patients cannot communicate or express behavioral reactions is challenging. Among patients receiving NMBAs, neither the gold standard for pain assessment (i.e., the patient’s self-report) or recommended behavioral measures, such as the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT) can be used. Approaches for pain and sedation assessment in paralyzed patients are being explored such as the analgesia nociception index, or the pupillary pain index or the BIS-value.

We rephrased this point in the discussion to improve the understanding.

C14. It might be worth mentioning that the titration of the desired sedation state using the minimum alveolar concentration with the closed loop system of the MIRUS system works without intervention depending on age, gender and weight, whereas this has to be done manually with the Anaconda device.

R14. We thank the Reviewer #2 for this comment and as suggested we added this point in the introduction to improve the readability.

C15. „always with a good satisfaction among the users” I think that it is not possible to speak of "always" with just under 74% of the users being very satisfied!

R15. We thank Reviewer #2 for this comment and as suggested we changed the word “always” by “frequently associated” in both the conclusion and the abstract.

C16. A problem not discussed appears to be the high number of ECMO treatments among COVID-19 patients and the impossible use of volatile sedatives in this patient population.

R16. We thank Reviewer #2 for this interesting comment. Even if inhaled sedation in ARDS patients undergoing ECMO is relatively novel and raises several feasibility and safety questions, the use of volatile anesthetics in such a situation is possible and has ever been published in both COVID-19 and non COVID-19 patients. We added this important point in the discussion.

C17. It should perhaps be mentioned that in the meantime activated charcoal systems exist on international markets to capture the volatile sedative no longer absorbed by the ACD, which even allows recycling. This would provide an approach to the ecological concerns expressed by 27 respondents.

R17. We thank Reviewer #2 for this important comment and we agree that environmental and occupational considerations of anesthesia and critical care medicine are very important. As suggested, we added in the discussion the need for a scavenging system, such as an activated carbon system.

Attachment

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Decision Letter 1

Silvia Fiorelli

10 Nov 2022

Use of volatile anesthetics for sedation in the ICU during the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)

PONE-D-22-06434R1

Dear Dr. Blondonnet,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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congratulations to the authors and thanks to the reviewers for the suggestions provided which really helped improve the quality of the manuscript

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Reviewer #2: All comments have been addressed

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Reviewer #2: I once again would like to thank you for the opportunity to review this work.

Furthermore, I would like to thank the authors for their very conscientious revision.

It appears to be a matter of taste, but did the authors consider using colour instead of patterned greys for Figure1?

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Acceptance letter

Silvia Fiorelli

18 Nov 2022

PONE-D-22-06434R1

Use of volatile anesthetics for sedation in the ICU during the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)

Dear Dr. Blondonnet:

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Data

    (XLSX)

    Click here for additional data file. (332KB, xlsx)
    S1 File. Survey questionnaire.

    (DOCX)

    Click here for additional data file. (235.5KB, docx)
    S2 File. Characteristics of the centers where respondents worked and characteristics of the non-COVID-19 and COVID-19 patients estimated by the respondents.

    (DOCX)

    Click here for additional data file. (23.9KB, docx)
    S3 File. Geographical distribution and epidemiological data on respondents.

    (XLSX)

    Click here for additional data file. (332.1KB, xlsx)
    Attachment

    Submitted filename: R1_RESPONSE TO EDITOR AND REVIEWER COMMENTS_VOLICU2 (1).docx

    Click here for additional data file. (20.8KB, docx)

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