BJA Education, xxx(xxx): xxx (xxxx)

doi: 10.1016/j.bjae.2023.12.004
Advance Access Publication Date: XXX

Matrix codes: 1A02,

2C05, 2A10, 3C00

ESSENTIAL NOTES

Sedation with volatile anaesthetics in intensive care

M. Jabaudon1,2,* and J.-M. Constantin3
1
CHU Clermont-Ferrand, Clermont-Ferrand, France, 2iGReD, Universite
Clermont Auvergne, Clermont-
3

^ 
Ferrand, France and Pitie-Salpetriere Hospital, Sorbonne University, Paris, France
*Corresponding author: mjabaudon@chu-clermontferrand.fr

Keywords: anaesthetics; inhalation; intensive care unit; sedation

The application of volatile anaesthetics, including isoflurane
and sevoflurane, is expanding from the operating theatre into
the intensive care unit (ICU). Although commonly used for
general anaesthesia, their potential in critical care is attract-
ing increasing interest. This article discusses the theoretical
and practical considerations of using volatile anaesthetics for
sedation in ICU patients, evaluates the indications and
contraindications, weighs the benefits and drawbacks and
examines the surveillance measures and potential risks
involved. It further addresses implementation hurdles and
explores outstanding questions and future challenges. We
offer insights into the adoption of volatile anaesthetic seda-
tion into ICU practice, a strategy that may influence outcomes
while posing unique challenges that need consideration.
Pharmacokinetics and pharmacodynamics
The mechanism of action of volatile anaesthetic agents is
complicated and not fully understood. They suppress
presynaptic excitation and neurotransmitter release, inhibit
Matthieu Jabaudon MD PhD is professor of anesthesiology, critical
care and perioperative medicine at CHU Clermont-Ferrand and
iGReD, Universit
e Clermont Auvergne, CNRS, INSERM, Clermont-
Ferrand, France. He cares for critically ill patients in Clermont-
Ferrand University Hospital where he is passionate about
providing outstanding patient care and training the next generation
of anesthesiology and critical care physicians. He has a particular
interest in ARDS, mechanical ventilation and analgesia-sedation.
Jean-Michel Constantin MD PhD is professor of anesthesiology,
critical care and perioperative medicine at the Department of Anes-
thesiology and Critical care at Sorbonne University and Piti
e-Sal-
p^etriere Hospital, Assistance Publique-H^ opitaux de Paris, Paris,
France.
postsynaptic neurotransmitter activity and exert
anti-N-methyl-D-aspartic acid (anti-NMDA) and anticonvul-
sant effects. At higher doses, they can induce isoelectric
electroencephalograms with burst suppression.1 Further-
more, these agents have bronchodilatory effects, via direct
action on bronchial smooth muscle and inhibition of post-
ganglionic vagal impulses.
Volatile anaesthetics are fast-acting (onset in 1e2 min) and
fast-recovery (offset in 4e7 min) drugs that induce a dose-
dependent depth of sedation (Fig. 1). This fast offset results
from their pulmonary elimination and low degree of hepatic
metabolism (2e5% for sevoflurane, 0.2% for isoflurane and 0.02%
for desflurane), resulting in no active metabolites (fluorine ions)
or any significant change in hepatic or renal laboratory tests in
selected ICU patients who were enrolled in published trials.2,3
Although some studies have linked isoflurane or sevoflurane
use with a decrease in requirements for opioid and sedative
drugs, the mechanisms underlying their analgesic effects
remain unclear.2,4 End-tidal anaesthetic concentrations are
good surrogates of corresponding brain concentrations and,
despite the need to adjust sedation by using validated clinical
scores, end-tidal monitoring could serve as a useful method of
adjusting sedation according to the patient’s needs.5
Delivery devices
Dedicated reflectors have been developed and are now
available for use in critically ill patients in the ICU, with two
major systems currently available in many countries: the
Anaesthetic Conserving Device (Sedaconda ACD-S, Sedana
Medical, Danderyd, Sweden) and the Mirus system (TIM
GmbH, Koblenz, Germany).
Inhaled sedation devices are inline miniature vaporisers that
incorporate humidification and an antiviral filter. These devices
are connected between the patient and an ICU ventilator,
maintaining up to 90% of the volatile anaesthetic inside the

Accepted: 15 December 2023

© 2023 The Authors. Published by Elsevier Ltd on behalf of British Journal of Anaesthesia. This is an open access article under the CC BY license (http://
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Sedation with volatile anaesthetics

Potential clinical use

Expired fraction associated with RASS Indications
(light-to-deep targets)
Historically, volatile anaesthetic agents were first used for
patients with severe asthma or bronchospasm and refractory
Dedicated system status epilepticus, vaporised through conventional anaes-
for ICU sedation
with inhaled anaesthetics
thesia machines in the ICU. They became used increasingly in
the ICU in patients with high requirements for sedation such
Gas Rapid onset as those with a history of drug addiction or dependency.
monitor and offset of action Based on two recent surveys in French ICUs, the current
through the lungs
preferred indications of sedation with isoflurane or sevo-
Sevoflurane
flurane are severe asthma or bronchospasm, acute respiratory
lsoflurane distress syndrome (ARDS), and failure of intravenous (i.v.)
sedation.6,7 Currently, the Sedaconda ACD-S device is offi-
cially approved for delivery of isoflurane for ‘sedation of me-
chanically ventilated adult patients during intensive care’ in
16 European countries.8 This suggests that inhaled anaes-
VENT thetics (at least isoflurane at the moment) could be considered
more widely for this indication. This is in line with Germany’s
Scavenging national guidelines, in which using volatile anaesthetics in
filter the ICU can be considered a first-line option in patients un-
dergoing mechanical ventilation and in whom short wake-up
times are targeted.9

Contraindications and safety considerations

Minimal metabolism by the liver
2–5% for sevoflurane, 0.2% for isoflurane
Renal elimination of metabolites
Fig 1 Schematic representation of the use of volatile anaesthetics for
sedation in intensive care. RASS, Richmond Agitation Sedation Scale; VENT,
ventilator.
patient. These devices provide excellent humidification and
should be used without the addition of a heated humidifier.
Although the Sedaconda ACD-S allows for manual titration of
sedation through expired fractions of isoflurane or sevoflurane,
the Mirus automatically adjusts infusion rates to deliver volatile
anaesthetics according to concentration targets and allows use
of desflurane in addition to isoflurane or sevoflurane.
Patients with a history of malignant hyperthermia or known
sensitivity to volatile agents should not receive inhaled
sedation.
In patients at risk of increased intracranial pressure,
inhalational anaesthetics may be avoided because of their
theoretical effects on cerebral blood flow. However, when
assessed, the effects of inhaled anaesthetics on intracranial
pressure may be less than expected.10
Limited data suggest that low-dose isoflurane or sevo-
flurane has no considerable teratogenic effects in clinical
settings of anaesthesia or critical care, in contrast to the
incidence of birth defects observed in rats exposed to high,
clinically irrelevant doses of isoflurane combined with nitrous
oxide. Other potential adverse effects, such as haemodynamic
instability or respiratory depression, are dose-dependent and
similar to those of i.v. sedatives. Cases of polyuria from
nephrogenic diabetes insipidus have been reported with

Table 1 Advantages and disadvantages of volatile anaesthetic sedation compared with intravenous sedation in intensive care.

Aspect Volatile anaesthetic sedation Intravenous sedation

Onset and offset of Very rapid: onset 1e2 min, offset 4e7 min Variable
action
Metabolism and Minimal metabolism through the liver Important liver metabolism and renal elimination of
elimination of Renal elimination of inactive metabolites metabolites with risks of accumulation
metabolites
Sedation targets Light-to-deep sedation Variable: light-to-deep sedation for propofol, light
sedation only for dexmedetomidine
Titratability Precise adjustment of sedation depth, Limited titration capabilities because of longer context-
1
expired agent fraction can be monitored sensitive half-lives, except propofol (but doses >4 mg kg
h 1 associated with propofol infusion syndrome)
Specialised Requires dedicated vaporisers and Equipment may be readily available
equipment scavenging systems
Environmental Minimal risk of workplace contamination Minimal contribution to greenhouse gas emissions but
pollution and exposure unmetabolised drugs can seep into the environment with
Contribution to greenhouse gas emissions potentially chronic ecotoxic effects

2 BJA Education - Volume xxx, Number xxx, xxxx


sevoflurane, often after prolonged use at high doses (expired
fraction >1.5% for multiple days), for which precise causal
mechanisms warrant further investigation.11
Potential advantages
The titratability and pharmacology of volatile anaesthetics
enable precise adjustments of the level of sedation, allowing
for personalised treatment. Ideally, titration should follow
the same clinical analgesia-first sedation scores such as
those widely used in ICU patients under i.v. sedation.
However, using inhaled sedation also enables monitoring of
expired anaesthetic fractions, which could be of particular
interest in patients with deeper sedation targets or under
neuromuscular block.5 Using inhaled sedation for patients
in ICU has been associated with wake-up and extubation
times approximately half those of i.v. midazolam or pro-
pofol in clinical trials.4 Of note, specific potential ‘organ-
protective’ effects, anti-inflammatory effects, or both of
isoflurane or sevoflurane in ICU patients such as in those
with ARDS (whether or not related to COVID-19 pneumo-
nitis), sepsis, brain injury, delirium or after resuscitated
cardiac arrest have gained recent interest and are currently
under evaluation.
Potential disadvantages
Specialised equipment, including dedicated vaporisers and
scavenging systems, is required for the safe delivery of
inhaled sedation, which could increase the logistical
complexity and cost of inhaled ICU sedation. Environmental
pollution is another concern, shared by both volatile and i.v.
anaesthetics.12 The release of volatile agents may contribute
to both global warming and exposure of healthcare providers
if not used according to the manufacturers’ instructions,
which include frequent device replacement and the use of a
scavenging system to prevent pollution. Importantly, in order
to use volatile anaesthetics effectively and safely in the ICU, it
is crucial for healthcare professionals to receive thorough
training and education, including on how to recognise and
treat malignant hyperthermia. The ICU teams should have a
solid understanding of how to handle volatile agents, and
grasp the fundamentals of inhaled sedation and use suitable
monitoring techniques. It is also essential for standardised
protocols to be established locally so that volatile anaesthetics
can be used safely and efficiently. However, these protocols
should not deviate significantly from those used for i.v.
sedation and promote analgesia first; minimise sedation and
wakefulness; prevent delirium; and allow early rehabilitation
to facilitate weaning from ventilation and ICU discharge.
Unanswered questions
Despite the growing interest in using volatile anaesthetics in
the ICU, several unanswered questions remain. The value of
expired fraction monitoring in the management of
analgesia-sedation, currently based on clinical scores,
requires further investigation. Long-term effects and out-
comes associated with volatile-based sedation in ICU
patients are also still not fully understood or known. In
addition, the potential impact of volatile anaesthetics on
cognitive function and delirium in critically ill patients re-
quires further exploration.
Sedation with volatile anaesthetics
Future challenges
The future of volatile anaesthetic sedation in the ICU faces
various challenges. Large-scale studies are needed to further
establish the efficacy and safety of volatile anaesthetic use in
different patient populations and clinical scenarios in
comparison to i.v. sedative agents (Table 1). Research on
optimal dosing and duration strategies will further inform
ICU-relevant pharmacokinetic models for inhaled anaes-
thetics. In addition, addressing the environmental impact of
volatile agent release and implementing more and more effi-
cient capture, extraction and purification methods in the ICU
will be essential to reduce pollution risks, in parallel with
recent efforts in the operating theatre.13 Education and
training programs, and ongoing and future research, will also
be crucial in better personalising and delivering inhaled
sedation to ICU patients.
Conclusions
The use of volatile anaesthetics in the ICU offers advantages
such as rapid onset and offset of action enabling precise
titration, along with some potential organ-protective effects.
However, specific contraindications, specialised equipment
requirements and environmental pollution risks should be
carefully considered. Vigilant surveillance by educated and
trained teams is necessary to mitigate risks and further
research is needed to address unanswered questions and
potential organ-protective effects of inhaled anaesthetics.
Declaration of interests
MJ is a principal investigator of the SESAR trial (ClinicalTrials.
gov Identifier: NCT04235608), a trial funded by the French
Ministry of Health, the European Society of Anaesthesiology,
and Sedana Medical. JMC and MJ received fees from Sedana
Medical for participation in scientific advisory panels or
seminars; MJ received consulting fees from AbbVie. There was
no influence from any entities in writing this article.
References
1. Stetefeld HR, Schaal A, Scheibe F et al. Isoflurane in (Su-
per-) Refractory Status Epilepticus: A Multicenter Evalu-
ation. Neurocrit Care 2021; 35: 631e9
2. Meiser A, Volk T, Wallenborn J et al. Inhaled isoflurane via
the anaesthetic conserving device versus propofol for
sedation of invasively ventilated patients in intensive
care units in Germany and Slovenia: an open-label, phase
3, randomised controlled, non-inferiority trial. Lancet
Respir Med 2021; 9: 1231e40
3. Taylor B, Scott TE, Shaw J, Chockalingam N. Renal safety of
critical care sedation with sevoflurane: a systematic review
and meta-analysis. J Anesth 2023; 37: 794e805
4. Mesnil M, Capdevila X, Bringuier S et al. Long-term seda-
tion in intensive care unit: a randomized comparison
between inhaled sevoflurane and intravenous propofol or
midazolam. Intensive Care Med 2011; 37: 933e41
5. Blanchard F, Perbet S, James A et al. Minimal alveolar
concentration for deep sedation (MAC-DS) in intensive
care unit patients sedated with sevoflurane: a physio-
logical study. Anaesth Crit Care Pain Med 2020; 39: 429e34
BJA Education - Volume xxx, Number xxx, xxxx 3
Sedation with volatile anaesthetics
6. Blondonnet R, Quinson A, Lambert C et al. Use of volatile
agents for sedation in the intensive care unit: a national
survey in France. PLoS One 2021; 16, e0249889
7. Blondonnet R, Balde A, Zhai R et al. Use of volatile anes-
thetics for sedation in the ICU during the COVID-19
pandemic: a national survey in France (VOL’ICU 2
study). PLoS One 2022; 17, e0278090
8. Sedaconda (isoflurane). Sedana Medical. Available from
https://sedanamedical.com/products/sedaconda-
isoflurane/sedaconda-isoflurane/ (accessed 28 July 2023).
9. DAS-Taskforce 2015, Baron R, Binder A et al. Evidence and
consensus based guideline for the management of
delirium, analgesia, and sedation in intensive care med-
icine. Revision 2015 (DAS-Guideline 2015) - short version.
Ger Med Sci 2015; 13. Doc19
4 BJA Education - Volume xxx, Number xxx, xxxx
10. Ditz C, Baars H, Schacht H et al. Volatile sedation with
isoflurane in neurocritical care patients after poor-grade
aneurysmal subarachnoid hemorrhage. World Neurosurg
2023; 173: e194e206
11. L’Heude
M, Poignant S, Elaroussi D, Espitalier F, Ferrandie
re
M, Laffon M. Nephrogenic diabetes insipidus
associated with prolonged sedation with sevoflurane in the
intensive care unit. Br J Anaesth 2019; 122: e73e5
12. Lane SF. The environmental sustainability of propofol use
in daily practice. Br J Anaesth 2020; 124: e221e2. https://
doi.org/10.1016/j.bja.2020.03.009
13. Pauchard J-C, Hafiani E-M, Bonnet L et al. Guidelines for
reducing the environmental impact of general anaes-
thesia. Anaesth Crit Care Pain Med 2023; 42: 101291. https://
doi.org/10.1016/j.accpm.2023.101291