In intensive care, sedation of patients is frequently used for their management. Combined
with analgesia, it provides the comfort essential for the implementation of certain therapies
such as mechanical ventilation.
Classically, sedation is based on the combination of a hypnotic and an injectable morphine,
most often midazolam and sufentanil. Midazolam is a benzodiazepine with many advantages: few
hemodynamic effects, no limited duration of use and good workability. However, its use
presents several difficulties in resuscitation:
Some patients have accelerated metabolism and resistance to benzodiazepines, either
through chronic use of psychotropic or narcotic drugs. These patients develop tolerance
phenomena due to enzyme induction. This tachyphylaxis leads to an increased need for
midazolam to achieve the therapeutic goal.
Some pathologies, such as ARDS, require deep sedation in the initial phase, which may
last several days. After this phase, prolonged sedation may be necessary before
achieving sufficient improvement to allow sedation to be stopped.
The metabolism of midazolam is dependent on liver function and its elimination from
renal function. Alteration of these functions, common in resuscitation, results in
impaired elimination with accumulation of midazolam and 2 active metabolites,
1-hydroxy-midazolam and 1-hydroxy-midazolam-glucuronide.
These three difficulties may lead to an undesirable prolongation of the sedation period
beyond the cessation of midazolam infusion, which is associated with an increase in morbidity
such as neuromyopathies, ventilator-associated pneumopathies (VAPP), deliriums and withdrawal
syndromes. These complications increase the length of stay and mortality in intensive care
units.
For 30 years there has been a growing interest in the use of sedation in resuscitation with
volatile halogenated agents (VHAs). These agents, administered by inhalation, have many
advantages: short onset of action, good workability, effect not dependent on renal or hepatic
function, almost exclusive and predictable respiratory elimination, absence of tachyphylaxis
and metabolism not sensitive to enzyme induction. For these reasons, AVHs are widely used in
anesthesia in the operating room. The hypnotic action of HVAs is closely correlated with the
expired fraction of HVAs. Measured by gas analysers, it allows precise monitoring of the
therapeutic effect. In contrast to resuscitation ventilators, all anesthesia ventilators are
equipped with evaporation tanks and administration circuits, gas analyzers and associated
facilities for their disposal. These technical constraints mean that, despite their many
theoretical advantages, AVHs have not been used in resuscitation area.
In the early 2000s, a new device made it possible to use AVH in intensive care: the AnaConDa®
system. It made it possible to administer AVH using an evaporator inserted into the patient
circuit at the intubation catheter, completely independent of the ventilator. However, this
device had several shortcomings in terms of user safety and cost due to the short service
life of the consumables.
Since 2016, a new device is available in France: the MIRUS® (Pall Medical, Dreieich,
Germany). It has several advantages over AnaConDa® :
It is equipped with an integrated gas analyzer that allows the automatic adjustment of
the AVH flow rate for a concentration target (FeAVH target). This results in greater
safety and AVH savings,
For each AVH with an MA (isoflurane, sevoflurane or desflurane), there is a MIRUS
controller with a tank model with a coding and color-coding system to avoid medication
errors,
Filters and reflectors can be used for several days, thus reducing the cost of use.
Among the recent AVHs and as for its use in anesthesia, isoflurane has shown a safety of use
in resuscitation on longer uses up to 96 hours without side effects. A recent retrospective
study showed no excess mortality after prolonged use of isoflurane (minimum 96 hours, average
506 hours) in post-operative, mainly digestive surgery in patients with sepsis with an
average age of 71 years. After medium-length sedation (average duration 52 hours, maximum 96
hours), the recovery and extubation times are shorter than with intravenous sedation with
midazolam: 10 minutes versus 250 minutes for the extubation time, but with significant
differences in sedation and analgesia protocol compared to our practices. The AVHs have
moreover been included in the German recommendations on sedation in resuscitation.
This monocentric, prospective, controlled, randomized, single-blind study will be conducted
in surgical resuscitation at the Rouen University Hospital. The aim of our research project
is to evaluate the time to extubation after sedation with inhaled isoflurane compared to
conventional intravenous sedation with midazolam, in patients requiring prolonged sedation (3
to 28 days) in a context of septic shock. This population is particularly at risk of hypnotic
accumulation due to the prolonged duration of use and the increased risk of developing renal
or hepatic impairment in connection with septic shock.
Based on data from the literature on shorter durations of up to 96 hours of sedation, the
investigators expect a decrease in the time to extubation in patients sedated with isoflurane
as well as a better quality of awakening with a decrease in resuscitation delirium. This
shortened duration of mechanical ventilation could have beneficial effects on the morbidity
associated with prolonged sedation and ventilation: reduction of pneumopathies acquired under
mechanical ventilation, reduction of the length of stay in resuscitation and hospitalization.