Eur J Anaesthesiol 2016; 33:45

INVITED COMMENTARY

Isoflurane for ICU sedation dead or alive?

Peter Sackey

European Journal of Anaesthesiology 2016, 33:45

This Invited Commentary accompanies the following original article:

Bellgardt M, Bomberg H, Herzog-Niescery J, et al.
Survival after long-term isoflurane sedation as
opposed to intravenous sedation in critically ill surgical patients. Eur J Anaesthesiol 2016; 33:613.

In this issue of European Journal of Anaesthesiology,

Bellgardt et al. (pp. 613) present a study comparing
hospital mortality and 1-year mortality in postoperative
ICU patients, sedated with either isoflurane or a propofol/
midazolam combination.
The original 369 consecutive surgical patients were
restricted to a group of 200 in order to make groups
similar. This included only patients aged 4079 years
and those who required more than 96 hours of sedation,
and excluded those who received both types of sedation.
The authors found that those receiving isoflurane had a
lower risk of death in hospital [odds ratio (OR) 0.39, 95%
confidence interval (CI) 0.220.71, P 0.002] and within
the first 365 days (OR 0.45, 95% CI 0.250.82, P 0.009)
than those who received propofol/midazolam. After
adjusting for potential confounders, patients given
isoflurane still had a lower risk of death in hospital
(OR 0.35; 95% CI 0.180.68, P 0.002) and within the
first 365 days (OR 0.41; 95% CI 0.210.81, P 0.01).
They had more ventilator-free days at 60 days
(32.5
29.2 vs 23.2
28.2 days, P 0.03) and more hospital-free days at 180 days (62.1
59.5 vs 44.1
64.8 days,
P 0.04). Interestingly, long-term mortality differences
remained significant in an additional analysis of the full
cohorts, including all age groups, and also in sensitivity
analyses.
This study is not without limitations. The decision to
initiate isoflurane sedation was at the discretion of the
physician on call and there were only two sets of equipment

available. The authors further state that German Health

Insurance requirements were such that only patients
continuously ventilated for more than 96 h had detailed
medical data in the hospital information system database,
making it impossible to include patients with shorter
ventilation and sedation times. Despite the limitations, this
study is of special note because no other has investigated
long-term mortality after prolonged volatile anaesthetic
sedation. Although the study is retrospective, nonrandomised and single centre, the results remain highly provocative.
The authors report mortality from all causes only, without
subdivision. How mortality might be affected by the
choice of ICU sedative remains speculative. One such
speculation might be that isoflurane induced some form
of organ protection, and there is a body of preclinical
evidence suggesting that volatile anaesthetics can do this.
Several intracellular preconditioning and postconditioning mechanisms have been described.1,2 Apart from preclinical data, clinical studies indicate that volatile
anaesthetics have organ-specific benefits for the liver,3
kidney,4 heart57 and brain.8,9 A major difference
between these studies and that of Bellgardt et al.
(pp. 613) is that they describe several days of low-dose
treatment, in contrast to that administered in most
studies of volatile anaesthetic-induced organ protection.
Is there a general or specific organ-protective effect of
isoflurane sedation, mediated via one or several postulated preconditioning or postconditioning mechanisms?
Or does such long-term exposure pose toxicity risks?
There is a paucity of data on the potential positive or
negative effects of long-term low-dose exposure in
critically ill patients arising from this expanding off-label
method of sedation (pp. 613). Bellgardt et al. (pp. 613)
do not tell us the mechanisms for improved survival but
their contribution is stimulating and hopefully will provoke larger randomised, controlled trials to shed more
light on possible short or long-term effects of long-term
isoflurane sedation in addition to possible mediators of
improved survival.

From the Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Correspondence to Peter Sackey, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden
E-mail: peter.sackey@karolinska.se
0265-0215 Copyright 2015 European Society of Anaesthesiology. All rights reserved.

DOI:10.1097/EJA.0000000000000351

Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

Isoflurane for ICU sedation 5

Acknowledgements relating to this article

Assistance with the Invited Commentary: none.

Financial support and sponsorship: none.
Conflicts of interest: the author has received honoraria from
Abbvie AB in respect of lectures given and has been a consultant
for Baxter Global and for Scandinavian Development Services,
Stockholm.
Comment from the Editor: this Invited Commentary was checked
and accepted by the editors but was not sent for external peer review.

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Eur J Anaesthesiol 2016; 33:45

Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.