MINI REVIEW

published: 24 June 2022

doi: 10.3389/fmed.2022.901343

Seeking the Light in Intensive Care

Unit Sedation: The Optimal Sedation
Strategy for Critically Ill Patients
Nicola Gitti 1 , Stefania Renzi 1 , Mattia Marchesi 1 , Michele Bertoni 2 , Francisco A. Lobo 3 ,
Frank A. Rasulo 1,2 , Alberto Goffi 4 , Matteo Pozzi 5 and Simone Piva 1,2*
1
Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia,
Italy, 2 Department of Anesthesia, Critical Care and Emergency, Spedali Civili University Hospital, Brescia, Italy, 3 Institute
of Anesthesiology, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates, 4 Interdepartmental Division of Critical Care
Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada, 5 Department of Emergency and Intensive
Care, San Gerardo Hospital, Monza, Italy

The clinical approach to sedation in critically ill patients has changed dramatically
over the last two decades, moving to a regimen of light or non-sedation associated
with adequate analgesia to guarantee the patient’s comfort, active interaction with the
environment and family, and early mobilization and assessment of delirium. Although
deep sedation (DS) may still be necessary for certain clinical scenarios, it should
be limited to strict indications, such as mechanically ventilated patients with Acute
Edited by: Respiratory Distress Syndrome (ARDS), status epilepticus, intracranial hypertension,
Pasquale Buonanno,
or those requiring target temperature management. DS, if not indicated, is associated
University of Naples Federico II, Italy
with prolonged duration of mechanical ventilation and ICU stay, and increased mortality.
Reviewed by:
Francesco Forfori, Therefore, continuous monitoring of the level of sedation, especially when associated
University of Pisa, Italy with the raw EEG data, is important to avoid unnecessary oversedation and to convert
*Correspondence: a DS strategy to light sedation as soon as possible. The approach to the management
Simone Piva
[email protected] of critically ill patients is multidimensional, so targeted sedation should be considered in
the context of the ABCDEF bundle, a holistic patient approach. Sedation may interfere
Specialty section: with early mobilization and family engagement and may have an impact on delirium
This article was submitted to
Intensive Care Medicine assessment and risk. If adequately applied, the ABCDEF bundle allows for a patient-
and Anesthesiology, centered, multidimensional, and multi-professional ICU care model to be achieved,
a section of the journal
Frontiers in Medicine
with a positive impact on appropriate sedation and patient comfort, along with other
Received: 21 March 2022
important determinants of long-term patient outcomes.
Accepted: 20 May 2022
Keywords: ICU—intensive care unit, neuromonitoring, light sedation, dexmedetomedine, propofol
Published: 24 June 2022
Citation:
Gitti N, Renzi S, Marchesi M, INTRODUCTION
Bertoni M, Lobo FA, Rasulo FA,
Goffi A, Pozzi M and Piva S (2022)
Patients admitted to the intensive care unit (ICU) routinely experience pain, agitation and
Seeking the Light in Intensive Care
Unit Sedation: The Optimal Sedation
anxiety, use of invasive monitoring, and need for invasive procedures or mechanical ventilation.
Strategy for Critically Ill Patients. Appropriate analgesia and sedation are therefore essential. In mechanically ventilated patients,
Front. Med. 9:901343. sedation aims to minimize oxygen consumption, keep patients comfortably connected to the
doi: 10.3389/fmed.2022.901343 ventilator, avoid recall of the critical condition and prevent psychological and physical damage.

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Gitti et al. The Optimal Sedation Strategy in ICU

Failure to control pain and agitation can have detrimental effects anxiety, depression, and PTSD, related to the patient’s awareness
both in the short- and long-term perspective. Poorly controlled of their critical situations are claimed against daily sedation
pain and agitation have been associated with worsening of the interruption (DSI), different studies demonstrated that such an
critical condition, increase in sympathetic tone, and increased approach did not impact the recall of ICU stay nor increased the
rate of accidental removal of medical devices such as endotracheal incidence of PTSD (10, 11). Daily sedation interruption (DSI)
tubes and vascular catheters (1–3). Moreover, uncontrolled pain could increase nurse overload, especially in resources limited
during ICU stay is related to a higher incidence of chronic pain, counties where the nurse: patients ratio is frequently less than
post-traumatic stress disorder (PTSD) symptoms, and a lower 1:1, and it should be accompanied by a light sedation (LS)
health-related quality of life (HRQoL). Conversely, deep and approach for the rest of the day, instead of a deep sedation
prolonged sedation has been associated with increased duration approach (12). Indeed, no doubts exist about the impact of deep
of mechanical ventilation, delayed weaning, increased incidence sedation during the first 48 h of ICU and later in ICU stay,
of delirium, and muscle impairment leading to ICU-acquired as demonstrated by Shehabi et al. in the two different studies
weakness (ICU–AW), and higher hospital and 6-month mortality (13, 14). Deep sedation (DS) was an independent predictor of
(1). Different studies have been conducted in the last two decades long-term mortality and time to extubation in mechanically
to clarify the “why” and “how” to sedate patients in ICU. The key ventilated ICU patients. Although early deep sedation and the
concept is that a “calm, comfortable, and collaborative” patient cumulative dose of sedative agents were not associated with
(i.e., lightly sedated) allows active cognitive stimulation, earlier time to delirium after 48 h, patients with lighter sedation had
liberation from the endotracheal tube, active mobilization, and a lower presence of delirium at 48 h, and also significantly
also improved interaction with the healthcare team and the more coma- and delirium-free days at 28 days. These results
family, all of them being important patient-centered outcomes. induced the authors to propose and test the so-called “early
goal-directed sedation” concept (i.e., light sedation, LS) in a
pilot RCT (15). Starting early after mechanical ventilation (MV)
THE “WHY” initiation, this approach refers to goal-directed management to
target a light level of sedation and minimize benzodiazepine
The paradigm of sedation in ICU changed dramatically in usage. Results showed that patients with light sedation received
the last few decades. In the 80s, the common belief was that less benzodiazepine and propofol, had more delirium-free days
patients should adapt to machines, leading to the large use of and required fewer physical restraints, but mechanical ventilation
deep sedation (DS) and prolonged immobility. In the 90s, the (MV) duration, ICU, and hospital LOS or mortality were not
paradigm changed: the machine should adapt to the patients modified. Starting from these contrasting results, the effects
but clinicians should avoid patients’ recall and memory of of light sedation have been examined in different subsequent
critical ill, leading to the use of deep sedation and avoiding RCTs summarized in SRs and MAs (Table 1). Among the most
neuromuscular blocking agent (NMBA). Starting from the early important systematic reviews, Stephens et al. showed as the
twentieth century, the idea of a protocolized sedation with a daily implementation of light sedation in the first 48 h of mechanical
sedation interruption (DSI) modified dramatically the sedation ventilation reduced mortality, mechanical ventilation duration,
approach in mechanically ventilated patients. A protocolized and ICU–LOS (16). The effects of light sedation on outcomes
sedation approach alone (intended as sedation delivered by were also examined in the meta-analysis presented in the PADIS
team members following written and approved procedures and guidelines, showing a reduction in mechanical ventilation (MV)
outlined in a protocol) is not clearly associated with a beneficial duration and the tracheostomy rate, with no effects on 90-
effect in terms of duration of mechanical ventilation, mortality, or day mortality, the occurrence of delirium, depression, PTDS, or
ICU length of stay as highlighted by a recent Cochrane systematic self-extubation (12). The heterogeneity between included RCTs
review (SR) and meta-analysis (MA) review, and confirmed in and their low quality forced the guidelines panel to make use
a recent multicenter cluster-RCT (DESIST trial) (Table 1) (4, of light sedation as a conditional recommendation. At last,
5). Indeed, the association between sedation protocol and daily Aitken et al. (17) examined the effect of depth of sedation in
sedation interruption (DSI) was initially introduced by Kress ICU patients on outcomes that extend across the ICU stay and
et al. (6) leading to a large number of trials aiming to establish beyond, including 7 RCTs and 18 cohort studies. The main
its efficacy and safety (Table 1). Daily sedation interruption findings were that lighter sedation was not associated with the
(DSI) seems to reduce time in coma, ICU and hospital length of reduced ICU or hospital mortality. Moreover, lighter sedation
stay (LOS), sedation time, and mechanical ventilation duration was not associated with a reduced duration of mechanical
and improve the 1-year survival rates (7). Although other trials ventilation, delirium occurrence, and other adverse events among
did not find the same results (8, 9), subsequent systematic the RCTs but it was among the cohort studies. Across studies,
reviews (SRs) and meta-analysis (MA) of RCTs demonstrated a both risks of bias and heterogeneity were high. The different
possible reduction in duration of mechanical ventilation, ICU– results found in the Aitken and PADIS MAs are difficult to
LOS, hospital-LOS, and also a reduction in tracheostomy rate explain, although the inclusion of non-RCTs in Aitken’s study
(Table 1). On the other hand, the main arguments against inevitably introduced heterogeneity in the results, the RCTs
daily sedation interruption (DSI) consist in its side effects, included are different, and Aitken’s study included the results
including agitation, pain, and endotracheal tube or catheter from the NON-SEDA trial (18) that account for 45% of the
self-removal. Although possible psychological sequelae, such as patients included in the MA. NON-SEDA trial (18) is the far

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Gitti et al. The Optimal Sedation Strategy in ICU

TABLE 1 | Summary of studies mentioned in the review.

Title Study type References Outcomes assessed Results Year

Protocol-directed sedation (PDS)

Protocol-directed sedation vs. SR- MA Aitken et al. (4) Duration of MV Unchanged 2015
non-protocol-directed sedation to ICU mortality Unchanged
reduce duration of mechanically Hospital mortality Unchanged
ventilated intensive care patients. ICU LOS Unchanged
Hospital LOS Reduced with PDS
Incidence of self extubation Unchanged
Incidence of reintubation Unchanged
Incidence of tracheostomy Unchanged
Staff education, regular sedation and Cluster- Walsh et al. (5) ICU mortality Unchanged 2016
analgesia quality feedback, and a RCT Hospital mortality Unchanged
sedation monitoring technology for Time to cessation of mechanical ventilation Unchanged
improving sedation and analgesia Time to discharge from ICU Unchanged
quality for critically ill, mechanically Time to discharge from hospital Unchanged
ventilated patients: a cluster
randomized trial.
Daily sedation interruption (DSI)
Sedation of critically ill patients during RCT Kress et al. (6) Time to awaken Decreased in 1996
mechanical ventilation. A comparison of Propofol-group
propofol and midazolam. Time to sedation Unchanged
Reproducibility of bedside assessment of Unchanged
sedation’s level
Change in VO2 from awake to sedated Decreased similarly in
state sedated state
Efficacy and safety of a paired sedation RCT Girard et al. (7) Ventilator free days Increased 2008
and ventilator weaning protocol for ICU LOS Decreased
mechanically ventilated patients in Hospital LOS Decreased
intensive care (Awakening and 28-day mortality Unchanged
Breathing Controlled trial): a 1-year mortality Increased
randomized controlled trial Days of coma Decreased
Days of delirium Unchanged
RASS at first SBT Decreased
Any self extubation Increased
Self-extubation requiring reintubation Unchanged
Reintubation Unchanged
Tracheostomy Unchanged
Daily sedation interruption in RCT Mehta et al. (8) Days to successful extubation Unchanged 2012
mechanically ventilated critically ill ICU LOS Unchanged
patients cared for with a sedation Hospital LOS Unchanged
protocol: a randomized controlled trial ICU mortality Unchanged
Hospital mortality Unchanged
Unintentional device removal Unchanged
Neuroimaging in ICU Unchanged
Physical restraint Unchanged
Delirium Unchanged
Tracheostomy Unchanged
Nurse workload Increased in PS + DSI
Daily sedation interruption vs. RCT Nassar and Ventilator-free days in 28 days Unchanged 2014
intermittent sedation in mechanically Park (9) ICU mortality Unchanged
ventilated critically ill patients: a Hospital mortality Unchanged
randomized trial Incidence of Delirium Unchanged
Delirium or coma-free days Unchanged
Median SAS Decreased in DSI group
Percentage of time on target SAS Unchanged
ICU LOS Unchanged
Hospital LOS Unchanged
Reintubation Increased in DSI group
Self-extubation Increased in DSI group
Accidental removal of catheters Unchanged
Tracheostomy Unchanged

(Continued)

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Gitti et al. The Optimal Sedation Strategy in ICU

TABLE 1 | (Continued)

Title Study type References Outcomes assessed Results Year

The long-term psychological effects of RCT Kress et al. (11) Duration of mechanical ventilation Unchanged 2003
daily sedative interruption on critically ill ICU LOS Unchanged
patients Incidence of new medical illness Unchanged
Recall awakening in the ICU Reduced
Total impact of Events score Reduced
Avoidance subscale score Reduced
Intrusive Thoughts subscale score Reduced
Diagnosis of PTSD Unchanged
SF-36 score Unchanged
Chronic Anxiety levels Unchanged
Acute Anxiety levels Unchanged
Beck Depression Index score Unchanged
PAIS T-score Unchanged
Meta-analysis of randomized controlled SR-MA Augustes et al. Duration of mechanical Ventilation Unchanged 2011
trials on daily sedation interruption for (54) Risk of OT tube removal Unchanged
critically ill adult patients Tracheostomy Reduced
Re-Intubation Rate Unchanged
ICU LOS and H-LOS Unchanged
Mortality Unchanged
Effects of daily sedation interruption in MA Chen et al. (55) Duration of mechanical ventilation Reduced 2021
intensive care unit patients undergoing ICU-LOS Reduced
mechanical ventilation: A meta-analysis sedation Duration Reduced
of randomized controlled trials HLOS Reduced
Re-intubation Rate Unchanged
Unplanned device removal Unchanged
Tracheostomy risk Unchanged
Ventilator-associated pneumonia risk Unchanged
ICU mortality
Daily sedation interruption vs. no daily SR Burry et al. (56) Duration of mechanical ventilation Unchanged 2014
sedation interruption for critically ill adult ICU LOS Unchanged
patients requiring invasive mechanical HLOS Unchanged
ventilation Mortality Unchanged
OT Tube removal Unchanged
Catheter removal Unchanged
Delirium Unchanged
QoL Unchanged
Drugs Dosage Unchanged
Tracheostomy Reduced
Effectiveness of daily interruption of SR Chen et al. (57) ICU-LOS Reduced 2014
sedation in sedated patients with Duration of mechanical Ventilation Reduced
mechanical ventilation in ICU: A OT tube removal Unchanged
systematic review Tracheostomy Reduced
Deep sedation vs. light sedation (DS vs. LS)
Early goal-directed sedation vs. RCT Shehabi et al. Time with RASS −2 to −1 first 48 h Increased 2013
standard sedation in mechanically (15) Time with RASS −3 to −5 first 48 h Decreased
ventilated critically ill patients: a pilot Dexmedetomidine received Increased
study Midazolam received Decreased
Propofol received Decreased
Morphine received Unchanged
Fentanyl received Unchanged
CAM-ICU + ve Unchanged
Days with −ve CAM-ICU Unchanged
Mobilization Unchanged
Neuromuscular blockade Unchanged
Physical restraint Decreased
Extubated within 7 days Increased
Device removal or self-extubation Unchanged
Ventilator-free days at day 28 Unchanged
ICU LOS Unchanged
Hospital LOS Unchanged
Hospital mortality Unchanged
90-day mortality Unchanged

(Continued)

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Gitti et al. The Optimal Sedation Strategy in ICU

TABLE 1 | (Continued)

Title Study type References Outcomes assessed Results Year

Practice patterns and outcomes SR-MA Stephens et al. Hospital mortality rate Decreased in Early light 2018
associated with early sedation depth in (16) sedation group
mechanically ventilated patients: A Delirium incidence Unchanged
systematic review and meta-analysis Tracheostomy incidence Unchanged
Mechanical ventilation days Reduced in Early light
sedation group
ICU LOS Reduced in Early light
sedation group
Hospital LOS Unchanged
PADIS
Inconsistent relationship between depth SR-MA Aitken et al. (17) ICU mortality (RCTs) Unchanged 2021
of sedation and intensive care outcome: Mechanical ventilation duration (RCTs) Unchanged
systematic review and meta-analysis Mechanical ventilation duration (Cohort Reduced in light
studies) sedation group
TIme to extubation (Cohort studies) Reduced in light
sedation group
ICU LOS (Cohort studies) Reduced in light
sedation group
Hospital LOS (Cohort studies) Reduced in light
sedation group
Ventilator associated pneumonia (Cohort Reduced in light
studies) sedation group
Hospital mortality (RCTs and Cohort Unchanged
studies)
Delirium (RCTs and Cohort studies) Unchanged
Adverse events (RCTs and cohort studies) Unchanged
Non-sedation or Light Sedation in RCT Olsen et al. (18) Mortality at 90 days Unchanged 2020
Critically ill, Mechanically Ventilated No. of days until death up to 90 days Unchanged
Patients No. of major thromboembolic events Unchanged
No. of days free from coma or delirium Unchanged
within 28 days
Highest measured RIFLE score within Unchanged
28 days
No. of ICU-free days Unchanged
No. of ventilator free days Unchanged

SEDATIVE DRUGS
Effect of sedation with RCT Pandharipande Delirium-free and coma-free days Increased in dex group 2007
dexmedetomidine vs. lorazepam on et al. (28) Delirium-free days Unchanged
acute brain dysfunction in mechanically Coma-free days Decreased in dex group
ventilated patients: the MENDS Prevalence of delirium or coma Decreased in dex group
randomized controlled trial Prevalence of delirium Unchanged
Prevalence of coma Decreased in dex group
Mechanical ventilator-free Unchanged
Intensive care unit length of stay Unchanged
28-day mortality Unchanged
Dexmedetomidine vs. midazolam or RCT Jakob et al. (29) Time of RASS range between 0 and −3 2012
propofol for sedation during prolonged without rescue therapy
mechanical ventilation: two randomized MIDEX Unchanged
controlled trials PRODEX Unchanged
Duration of mechanical ventilation
MIDEX Reduced in dex group
PRODEX Unchanged
Nurses’ assessment of VAS
MIDEX Increased in dex group
PRODEX Increased in dex group
ICU LOS
MIDEX Unchanged
PRODEX Unchanged

(Continued)

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TABLE 1 | (Continued)

Title Study type References Outcomes assessed Results Year

Early sedation with dexmedetomidine in Cluster- Shehabi et al. 90-day mortality 2021
ventilated critically ill patients and RCT (36) >65 years Decreased
heterogeneity of treatment effect in the ≤65 years Increased
SPICE III randomized controlled trial Cluster 1 (operative diagnosis) Decreased
Cluster 2 (non-operative diagnosis) Increased
Coma and delirium free days
>65 years Increased
<65 years Decreased
Cluster 1 (operative diagnosis) Increased
Cluster 2 (non-operative diagnosis) Increased
Ventilator free days
>65 years Increased
<65 years Decreased
Cluster 1 (operative diagnosis) Increased
Cluster 2 (non-operative diagnosis) Increased
Effect of dexmedetomidine vs. RCT Pandharipande Septic patients: 2010
lorazepam on outcome in patients with et al. (40) Delirium/coma-free days Increased
sepsis: an a priori-designed analysis of Delirium-free days Unchanged
the MENDS randomized controlled trial Coma-free days Increased
MV-free days Increased
ICU days Unchanged
28-day mortality Decreased
Non-septic patients:
Delirium/coma-free days Unchanged
Delirium-free days Unchanged
Com-free days Unchanged
MV-free days Unchanged
ICU days Unchanged
28-day mortality Unchanged
Dexmedetomidine or Propofol for RCT Hughes et al. Days alive without delirium or coma at Unchanged 2021
Sedation in Mechanically Ventilated (42) 14 days
Adults with Sepsis Ventilator-free days at 28 days Unchanged
Death at 90-days Unchanged
GLobal cognition Unchanged
Neuromonitoring
BIS monitoring vs. clinical assessment SR-MA Shetty et al. ICU LOS Unchanged (low quality 2018
for sedation in mechanically ventilated (48) evidence)
adults in the intensive care unit and its Duration of Mechanical ventilation Unchanged (low quality
impact on clinical outcomes and evidence)
resource utilization Risk of adverse events Unchanged (very low
quality evidence)
Amount of sedative agents administered Not assessable

biggest RCT that investigated the effects of a non-sedation be used in all mechanically ventilated patients” (conditional
protocol compared with the light sedation, and the authors did recommendation, low quality of evidence) (Figure 1).
not find any differences in terms of 90-day mortality, ventilator- Some caveats exist in the application of light sedation. At first,
free days, ICU and hospital LOS. A possible explanation for its definition is not universally accepted. The PADIS guidelines
the non-superiority of a non-sedation strategy in the RCT, as define light sedation as a Richmond Agitation Sedation Scale
the authors stated in the discussion, could be that the depth (RASS) score between + 1 (slightly restless) and −2 (awake with
of sedation did not differ between the groups as much as eye contact to voice) or a Riker Sedation–Agitation Scale (SAS)
intended, especially on day 1, configuring the non-sedation score between 4 (calm and cooperative) and 3 (difficult to rouse
approach as light sedation (mean RASS score was −2.3 on and obey simple commands). The SAS does not evaluate arousal
day 1 in light sedation vs. −1.3 in the non-sedation group) and an SAS of 3 points is the only score to assign to a sedated
(18). patient without coma (SAS = 1 or 2) (20). The RASS scale may
Although still under debate, light sedation has been suggested have a positive or negative value (−5 to + 4) and it is an ordinal
by the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and scale, which makes it unuseful to synthesize using an average
Sleep Disruption (PADIS) guidelines (12), and reinforced by the score (21). This is particularly important since the sedation level
eCASH approach (19). In particular, a protocol based, stepwise could variate during the 24 h; for this reason, other methods for
assessment for pain control and sedation management in sedation assessment have been proposed, such as the Sedation
critically ill patients should be adopted, and light sedation “should Index (22), which summarizes the sedation level over 48 h (sum

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Gitti et al. The Optimal Sedation Strategy in ICU

FIGURE 1 | Algorithm for the use of sedation in critically ill patients. ARDS, acute respiratory distress syndrome; RASS, Richmond Agitation–Sedation Scale.

of the negative RASS scores (RASS −1 to −5) divided by the THE “HOW”
total number of RASS measurements performed). When Sedation
Index has been used, the level of sedation was strongly related to When the “why” of sedation in ICU has been explored,
the risk of death, delirium, and delayed time to extubation (22). clinicians want to know “how” to lightly sedate the patients.
The second caveat is that when light sedation is not integrated On this topic, there is no doubt that benzodiazepines
into a bundle of patient-centered outcomes, could not be as should be avoided to minimize the risk of delirium (27–
useful. The eCASH–early Comfort using Analgesia, minimal 33). As a result, dexmedetomidine and propofol remain the
Sedatives and maximal Humane care–as well as the ABCDEF-R possible choices.
bundle (where R = respiratory-drive-control has been proposed Dexmedetomidine is a highly selective α2 adrenergic
recently) (12, 23), suggest the integration of light sedation receptor antagonist that produces dose-dependent sedation
into a bundle to avoid pain, anxiety, agitation, delirium, and with no respiratory depression and modest hemodynamic
immobility, to reduce the post-intensive care syndrome (PICS) effects (34). Dexmedetomidine may promote sleep via more
incidence. These targets could be achieved by treating pain first physiological pathways in comparison with GABAergic
and by accompanying light sedation to communications aids, sedatives (i.e., benzodiazepines, propofol), favoring the
noise reduction to promote sleep, early mobilization, delirium N3 (or slow wave sleep) stage (35). Propofol is a gamma-
monitoring, and family involvement. aminobutyric acid (GABA) receptor agonist, by binding
Occasionally, deep sedation may be required. In the case to the β subunit of the postsynaptic GABA–A receptor, it
of patients with ARDS, historically deep sedation along with induces postsynaptic membrane hyperpolarization and inhibits
NMBA continuous infusion has been considered the best clinical neuronal depolarization.
practice (24). Following recent evidence (25), practical clinical Pain, Agitation/Sedation, Delirium, Immobility, and Sleep
guidelines (26) suggest avoiding routine use of NMBA infusion Disruption guidelines recommend the use of propofol or
in adults with ARDS before optimizing mechanical ventilation dexmedetomidine over the benzodiazepine for sedation in
and assessing ARDS severity. Moreover, the authors suggest critically ill, mechanically ventilated adults, as a conditional
against using an NMBA infusion (Suggestion, low certainty of recommendation with low quality of evidence (12). Different
evidence) in patients who tolerate ventilation using a lighter RCTs have investigated the effects of dexmedetomidine as
sedation strategy; whenever an NMBA is required to facilitate sedative agents, only one of them compared dexmedetomidine
lung-protective ventilation, it should be used intermittently with propofol (29). The SPICE III trial is the most recent
(Suggestion, low certainty of evidence) (26). and biggest RCT on this topic, including approximately 8

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Gitti et al. The Optimal Sedation Strategy in ICU

times as many patients as the other trials (36). It compared studies, dexmedetomidine has demonstrated anti-inflammatory
the use of dexmedetomidine with usual care (propofol or and bacterial killing properties superior to those of
midazolam or a combination of the two) for sedation gamma-aminobutyric acid (GABA) agonists, thereby, reducing
therapy in mechanically ventilated patients. This open-label, the incidence of subsequent infections and 28-day mortality
randomized trial enrolled 3,904 patients, with mortality at in patients with sepsis (28, 40). Although indirectly correlated,
90 days as the primary outcome. Secondary outcomes included another secondary analysis of the SPICE III trial (41) was
mortality, cognitive function, and HRQoL assessed at 180 days. carried out in patients with septic shock. On multivariable-
Results from the study revealed no difference in 90- and adjusted analysis, dexmedetomidine appeared to be associated
180-day mortality, nor in cognitive function and HRQoL with lower vasopressor requirements to maintain the target
(17). MAP.
The explanation for such unexpected results should be Despite the immunomodulatory and anti-inflammatory
found in the high proportion of patients (60% on day properties of dexmedetomidine, in a recent multicenter,
1 and 50% on day 2) who required deep sedation (not double-blind, randomized, controlled trial that enrolled
allowed in all the other trials), which may have independently adult mechanically ventilated patients with sepsis, the use of
influenced outcomes, as discovered previously by the same dexmedetomidine for light sedation did not demonstrate more
authors (14, 22). Moreover, more than 70% of patients in days of life without acute brain dysfunction (coma or delirium)
the dexmedetomidine arm received propofol or midazolam to compared with propofol. In addition, no differences were found
reach goal sedation in the first 48 h following randomization, in ventilator-free days at 28 days, death at 90 days, or global
and more than 50% of the dexmedetomidine cohort continued cognition at 6 months (42).
to receive propofol at the study day 10 (with only 30%
of patients requiring deep sedation). The inadequacy of
dexmedetomidine to maintain light sedation has been reported
also in MIDEX (29) and PRODEX (29) trials, with, respectively, NEUROMONITORING TO GUIDE
43.8 and 72.5% of patients requiring rescue sedation in SEDATION
the dexmedetomidine arm. Another interesting result of the
SPICE III trial is the higher rate of adverse events in the As mentioned earlier, light sedation aims to obtain the minimum
dexmedetomidine cohort compared with the usual care cohort depth of sedation required to keep the patient free from
(9.6 vs. 1.8%, respectively, P < 0.0001), although lower than in agitation and anxiety, avoiding oversedation. Traditionally, the
the other trials. most widespread method to monitor the depth of sedation is
A subsequent Bayesian secondary analysis of the SPICE clinical, using Richmond Agitation Sedation Scale (RASS) or
III trial (36) found that dexmedetomidine exhibited a Riker Sedation-Agitation Scale (SAS). However, clinical scales
high probability of reduced 90-day mortality in older require awake patients and are not useful to monitor deep
patients (more than 65 years) and a high probability sedation (43). Therefore, other methods have been developed in
of increased 90-day mortality in the younger patients of the recent times to evaluate sedation depth through processed-
non-operative status. and raw-EEG signals. Processed-EEG signal (Bispectral Index,
An important topic is the cost of sedation. Park and Jeong (37) PSI, Entropy) has been proved, both in OR and ICU, to be
carried out a cost-minimization analysis based on MIDEX and related to the depth of sedation measured with clinical scales
PRODEX studies, demonstrating that patients on a mechanical (43, 44) and to reduce sedative dosages (45). Low values of
ventilator and treated with midazolam and propofol had medical a processed-EEG index (corresponding to unnecessary deep
costs (related drug costs, ICU care costs, and costs of treating sedation, burst-suppression or isoelectric EEG) are associated
adverse events), respectively, 17.6 and 15.2% more than patients with a higher incidence of delirium and mortality (46).
treated with dexmedetomidine. A secondary analysis of the Moreover, processed-EEG monitoring systems can also show
SEDCOM trial (27) (an RCT comparing dexmedetomidine and the raw EEG traces and spectral quantitative array, allowing
midazolam for sedation in critically ill patients) (38) showed clinicians to identify specific electroencephalographic signatures
a median total intensive care unit cost savings of $9,679 of sedative drugs in addition to the general benefits of raw EEG
using dexmedetomidine in patients ventilated for more than monitoring (47).
24 h. The primary cost drivers were reduced costs of ICU Concerning the impact of objective measurement of the
stay and reduced costs of mechanical ventilation. Aggarwal level of sedation on outcomes, the literature is scarce on
et al. (39) conducted a cost-minimization analysis for short high-quality studies. A recent systematic review and meta-
sedation in ICU, demonstrating that dexmedetomidine was analysis (48) included four RCTs and found no benefits
associated with significant cost savings of ∼$6,000 compared of BIS monitoring on the clinical outcomes or resource
with propofol and midazolam in mechanically ventilated, adult utilization. A possible explanation of this conflicting and
patients undergoing short-term sedation (<24 h). Although the insufficient evidence may rely on the intrinsic limitations of
limited generalizability of cost data outside the US, the cost- the numerical dimensionless scales of alertness/unconsciousness
saving was mainly related to the reduced ICU length of stay and derived from the electroencephalographic signal (49–51) rather
the required monitoring. than the electroencephalogram itself which presents a strong
An important area of research involves mechanically neurobiological background supporting its use (47, 52) which
ventilated septic patients. In many basic and translational should be promoted by the validated educational programs (53).

Frontiers in Medicine | www.frontiersin.org 8 June 2022 | Volume 9 | Article 901343

Gitti et al. The Optimal Sedation Strategy in ICU

CONCLUSION evaluating their possible contraindications. Moreover, whenever

clinical evaluation of the level of sedation is not feasible, a
The approach to the management of critically ill patients is processed and raw EEG signal could be useful to avoid the
multidimensional, and targeted sedation should be considered in detrimental effects of over-sedation (Figure 1).
the context of the ABCDEF bundle. No doubt exists about the
need to limit deep sedation to restricted clinical circumstances,
while the light sedation (or non-sedation) approach could not AUTHOR CONTRIBUTIONS
explicit its beneficial effects when taken alone and not in the
context of an ABCDEF bundle approach. When light sedation is All authors contributed to the literature review, drafting, and
applied, propofol or dexmedetomidine should be used, carefully critical revision of the manuscript.

REFERENCES prospective longitudinal multicentre cohort study. Intensive Care Med. (2013)
39:910–8. doi: 10.1007/s00134-013-2830-2
1. Temesgen N, Chekol B, Tamirie T, Eshetie D, Simeneh N, Feleke A. Adult 14. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, et al. Early
sedation and analgesia in a resource limited intensive care unit – a systematic intensive care sedation predicts long-term mortality in ventilated critically ill
review and evidence based guideline. Ann Med Surg (Lond). (2021) 66:102356. patients. Am J Respir Crit Care Med. (2012) 186:724–31. doi: 10.1164/rccm.
doi: 10.1016/j.amsu.2021.102356 201203-0522OC
2. Pun BT, Balas MC, Barnes-Daly MA, Thompson JL, Aldrich JM, Barr J, et al. 15. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, et al. Early
Caring for critically ill patients with the ABCDEF bundle: results of the ICU goal-directed sedation versus standard sedation in mechanically ventilated
liberation collaborative in over 15,000 adults. Crit Care Med. (2019) 47:3–14. critically ill patients: a pilot study∗ . Crit Care Med. (2013) 41:1983–91. doi:
doi: 10.1097/CCM.0000000000003482 10.1097/CCM.0b013e31828a437d
3. Prabhakar H, Tripathy S, Gupta N, Singhal V, Mahajan C, Kapoor I, et al. 16. Stephens RJ, Dettmer MR, Roberts BW, Ablordeppey E, Fowler SA, Kollef
Consensus statement on analgo-sedation in neurocritical care and review of MH, et al. Practice patterns and outcomes associated with early sedation
literature. Indian J Crit Care Med. (2021) 25:126–33. doi: 10.5005/jp-journals- depth in mechanically ventilated patients: a systematic review and meta-
10071-23712 analysis. Crit Care Med. (2018) 46:471–9. doi: 10.1097/CCM.00000000000
4. Aitken LM, Bucknall T, Kent B, Mitchell M, Burmeister E, Keogh SJ. Protocol- 02885
directed sedation versus non-protocol-directed sedation to reduce duration 17. Aitken LM, Kydonaki K, Blackwood B, Trahair LG, Purssell E, Sekhon M,
of mechanical ventilation in mechanically ventilated intensive care patients. et al. Inconsistent relationship between depth of sedation and intensive care
In: The Cochrane Collaboration editor. Cochrane Database of Systematic outcome: systematic review and meta-analysis. Thorax. (2021) 76:1089–98.
Reviews. Hoboken, NJ: John Wiley & Sons, Ltd (2015). doi: 10.1002/14651858. doi: 10.1136/thoraxjnl-2020-216098
CD009771.pub2 18. Olsen HT, Nedergaard HK, Strøm T, Oxlund J, Wian K-A, Ytrebø LM, et al.
5. Walsh TS, Kydonaki K, Antonelli J, Stephen J, Lee RJ, Everingham K, et al. Nonsedation or light sedation in critically ill, mechanically ventilated patients.
Staff education, regular sedation and analgesia quality feedback, and a sedation N Engl J Med. (2020) 382:1103–11.
monitoring technology for improving sedation and analgesia quality for 19. Vincent JL, Shehabi Y, Walsh TS, Pandharipande PP, Ball JA, Spronk P, et al.
critically ill, mechanically ventilated patients: a cluster randomised trial. Lancet Comfort and patient-centred care without excessive sedation: the eCASH
Respir Med. (2016) 4:807–17. doi: 10.1016/S2213-2600(16)30178-3 concept. Intensive Care Med. (2016) 42:962–71. doi: 10.1007/s00134-016-
6. Kress JP, O’Connor MF, Pohlman AS, Olson D, Lavoie A, Toledano A, et al. 4297-4
Sedation of critically ill patients during mechanical ventilation. A comparison 20. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the sedation-
of propofol and midazolam. Am J Respir Crit Care Med. (1996) 153:1012–8. agitation scale for adult critically ill patients. Crit Care Med. (1999) 27:1325–9.
doi: 10.1164/ajrccm.153.3.8630539 doi: 10.1097/00003246-199907000-00022
7. Girard TD, Kress JP, Fuchs BD, Thomason JWW, Schweickert WD, Pun 21. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA,
BT, et al. Efficacy and safety of a paired sedation and ventilator weaning et al. The Richmond agitation-sedation scale: validity and reliability in adult
protocol for mechanically ventilated patients in intensive care (awakening intensive care unit patients. Am J Respir Crit Care Med. (2002) 166:1338–44.
and breathing controlled trial): a randomised controlled trial. Lancet. (2008) doi: 10.1164/rccm.2107138
371:126–34. doi: 10.1016/S0140-6736(08)60105-1 22. Shehabi Y, Bellomo R, Kadiman S, Ti LK, Howe B, Reade MC, et al. Sedation
8. Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, et al. Daily intensity in the first 48 hours of mechanical ventilation and 180-day mortality:
sedation interruption in mechanically ventilated critically ill patients cared a multinational prospective longitudinal cohort study. Crit Care Med. (2018)
for with a sedation protocol: a randomized controlled trial. JAMA. (2012) 46:850–9. doi: 10.1097/CCM.0000000000003071
308:1985–92. doi: 10.1001/jama.2012.13872 23. Chanques G, Constantin J-M, Devlin JW, Ely EW, Fraser GL, Gélinas C, et al.
9. Nassar AP Jr, Park M. Daily sedative interruption versus intermittent sedation Analgesia and sedation in patients with ARDS. Intensive Care Med. (2020)
in mechanically ventilated critically ill patients: a randomized trial. Ann 46:2342–56. doi: 10.1007/s00134-020-06307-9
Intensive Care. (2014) 4:14. doi: 10.1186/2110-5820-4-14 24. Papazian L, Forel J-M, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al.
10. Burry L, Cook D, Herridge M, Devlin JW, Fergusson D, Meade M, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J
Recall of ICU stay in patients managed with a sedation protocol or a sedation Med. (2010) 363:1107–16. doi: 10.1056/NEJMoa1005372
protocol with daily interruption. Crit Care Med. (2015) 43:2180–90. doi: 10. 25. National Heart, Lung, and Blood Institute Petal Clinical Trials Network,
1097/CCM.0000000000001196 Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, et al. Early
11. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-term neuromuscular blockade in the acute respiratory distress syndrome. N Engl
psychological effects of daily sedative interruption on critically ill patients. Am J Med. (2019) 380:1997–2008.
J Respir Crit Care Med. (2003) 168:1457–61. doi: 10.1164/rccm.200303-455OC 26. Alhazzani W, Belley-Cote E, Møller MH, Angus DC, Papazian L, Arabi
12. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande YM, et al. Neuromuscular blockade in patients with ARDS: a rapid practice
PP. Clinical practice guidelines for the prevention and management of pain, guideline. Intensive Care Med. (2020) 46:1977–86. doi: 10.1007/s00134-020-
agitation/sedation, delirium, immobility, and sleep disruption in adult patients 06227-8
in the ICU. Crit Care Med. (2018) 46:e825. 27. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F,
13. Shehabi Y, Chan L, Kadiman S, Alias A, Ismail WN, Tan MA, et al. Sedation et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a
depth and long-term mortality in mechanically ventilated critically ill adults: a randomized trial. JAMA. (2009) 301:489–99. doi: 10.1001/jama.2009.56

Frontiers in Medicine | www.frontiersin.org 9 June 2022 | Volume 9 | Article 901343

Gitti et al. The Optimal Sedation Strategy in ICU

28. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, the Ramsay score in sedated ICU patients. J Clin Monit Comput. (2007)
et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain 21:295–302. doi: 10.1007/s10877-007-9087-7
dysfunction in mechanically ventilated patients: the MENDS randomized 45. Kaplan LJ, Bailey H. Bispectral index (BIS) monitoring of ICU patients
controlled trial. JAMA. (2007) 298:2644–53. doi: 10.1001/jama.298.22.2644 on continuous infusion of sedatives and paralytics reduces sedative drug
29. Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock utilization and cost. Crit Care. (2000) 4:190.
SJ, et al. Dexmedetomidine vs midazolam or propofol for sedation during 46. Lobo FA, Vacas S, Rossetti AO, Robba C, Taccone FS. Does
prolonged mechanical ventilation: two randomized controlled trials. JAMA. electroencephalographic burst suppression still play a role in the
(2012) 307:1151–60. doi: 10.1001/jama.2012.304 perioperative setting? Best Pract Res Clin Anaesthesiol. (2021) 35:159–69.
30. Ho KM, Ng JY. The use of propofol for medium and long-term sedation doi: 10.1016/j.bpa.2020.10.007
in critically ill adult patients: a meta-analysis. Intensive Care Med. (2008) 47. Rubinos C, Alkhachroum A, Der-Nigoghossian C, Claassen J.
34:1969–79. doi: 10.1007/s00134-008-1186-5 Electroencephalogram monitoring in critical care. Semin Neurol. (2020)
31. Porhomayon J, El-Solh AA, Adlparvar G, Jaoude P, Nader ND. Impact of 40:675–80. doi: 10.1055/s-0040-1719073
sedation on cognitive function in mechanically ventilated patients. Lung. 48. Shetty RM, Bellini A, Wijayatilake DS, Hamilton MA, Jain R, Karanth S,
(2016) 194:43–52. doi: 10.1007/s00408-015-9820-9 et al. BIS monitoring versus clinical assessment for sedation in mechanically
32. Fraser GL, Devlin JW, Worby CP, Alhazzani W, Barr J, Dasta JF, et al. ventilated adults in the intensive care unit and its impact on clinical outcomes
Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically and resource utilization. Cochrane Database Syst Rev. (2018) 2:CD011240.
ventilated, critically ill adults: a systematic review and meta-analysis of doi: 10.1002/14651858.CD011240.pub2
randomized trials. Crit Care Med. (2013) 41:S30. doi: 10.1097/CCM. 49. Lobo FA, Schraag S. Limitations of anaesthesia depth monitoring. Curr Opin
0b013e3182a16898 Anaesthesiol. (2011) 24:657–64.
33. Azimaraghi O, Wongtangman K, Wachtendorf LJ, Santer P, Rumyantsev S, 50. Dahaba AA. Different conditions that could result in the bispectral index
Ahn C, et al. Differential effects of gamma-aminobutyric acidergic sedatives indicating an incorrect hypnotic state. Anesth Analg. (2005) 101:765–73. doi:
on risk of post-extubation delirium in the ICU: a retrospective cohort study 10.1213/01.ane.0000167269.62966.af
from a New England health care network. Crit Care Med. (2022) 50:e434–44. 51. Palanca BJA, Mashour GA, Avidan MS. Processed electroencephalogram in
doi: 10.1097/CCM.0000000000005425 depth of anesthesia monitoring. Curr Opin Anaesthesiol. (2009) 22:553–9.
34. Li A, Yuen VM, Goulay-Dufaÿ S, Sheng Y, Standing JF, Kwok PCL, et al. 52. Riviello JJ Jr, Erklauer J. Neurocritical care and brain monitoring. Neurol Clin.
Pharmacokinetic and pharmacodynamic study of intranasal and intravenous (2021) 39:847–66. doi: 10.1016/j.ncl.2021.04.006
dexmedetomidine. Br J Anaesth. (2018) 120:960–8. 53. Taran S, Ahmed W, Pinto R, Bui E, Prisco L, Hahn CD, et al. Educational
35. Delaney LJ, Van Haren F, Lopez V. Sleeping on a problem: the impact of sleep initiatives for electroencephalography in the critical care setting: a systematic
disturbance on intensive care patients – a clinical review. Ann Intensive Care. review and meta-analysis. Can J Anaesth. (2021) 68:1214–30. doi: 10.1007/
(2015) 5:3. doi: 10.1186/s13613-015-0043-2 s12630-021-01962-y
36. Shehabi Y, Neto AS, Howe BD, Bellomo R, Arabi YM, Bailey M, et al. 54. Augustes R, Ho KM. Meta-analysis of randomised controlled trials on daily
Early sedation with dexmedetomidine in ventilated critically ill patients and sedation interruption for critically ill adult patients. Anaesth Intensive Care.
heterogeneity of treatment effect in the SPICE III randomised controlled trial. (2011). 39:401–9. doi: 10.1177/0310057X1103900310
Intensive Care Med. (2021) 47:455–66. doi: 10.1007/s00134-021-06356-8 55. Chen T-J, Chung Y-W, Chen P-Y, Hu SH, Chang C-C, Hsieh S-H, et al.
37. Park JH, Jeong JH. A cost-minimization analysis comparing dexmedetomidine Effects of daily sedation interruption in intensive care unit patients undergoing
with midazolam and propofol for sedation in mechanically ventilated intensive mechanical ventilation: a meta-analysis of randomized controlled trials. Int J
care unit patients. Int J Technol Assess Health Care. (2016) 4:75–81. Nurs Pract. (2021). 28:e12948. doi: 10.1111/ijn.12948
38. Dasta JF, Kane-Gill SL, Pencina M, Shehabi Y, Bokesch PM, Wisemandle 56. Burry L, Rose L, McCullagh IJ, Fergusson DA, Ferguson ND, Mehta S. Daily
W, et al. A cost-minimization analysis of dexmedetomidine compared with sedation interruption versus no daily sedation interruption for critically ill
midazolam for long-term sedation in the intensive care unit. Crit Care Med. adult patients requiring invasive mechanical ventilation. Cochr Database Syst
(2010) 38:497–503. doi: 10.1097/CCM.0b013e3181bc81c9 Rev. (2014). 2018:CD009176. doi: 10.1002/14651858.CD009176.pub2
39. Aggarwal J, Lustrino J, Stephens J, Morgenstern D, Tang WY. Cost- 57. Chen H-B, Liu J, Chen L-Q, Wang G-C. Effectiveness of daily interruption of
minimization analysis of dexmedetomidine compared to other sedatives for sedation in sedated patients with mechanical ventilation in ICU: a systematic
short-term sedation during mechanical ventilation in the United States. review. Int J Nurs Sci. (2014). 1:346–51. doi: 10.1016/j.ijnss.2014.10.011
Clinicoecon Outcomes Res. (2020) 12:389–97.
40. Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Conflict of Interest: The authors declare that the research was conducted in the
Shintani AK, et al. Effect of dexmedetomidine versus lorazepam on outcome in absence of any commercial or financial relationships that could be construed as a
patients with sepsis: an a priori-designed analysis of the MENDS randomized potential conflict of interest.
controlled trial. Crit Care. (2010) 14:R38. doi: 10.1186/cc8916
41. Cioccari L, Luethi N, Bailey M, Shehabi Y, Howe B, Messmer AS, et al. Publisher’s Note: All claims expressed in this article are solely those of the authors
The effect of dexmedetomidine on vasopressor requirements in patients with and do not necessarily represent those of their affiliated organizations, or those of
septic shock: a subgroup analysis of the Sedation Practice in Intensive Care the publisher, the editors and the reviewers. Any product that may be evaluated in
Evaluation [SPICE III] trial. Crit Care. (2020) 24:441. doi: 10.1186/s13054- this article, or claim that may be made by its manufacturer, is not guaranteed or
020-03115-x endorsed by the publisher.
42. Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, et al.
Dexmedetomidine or propofol for sedation in mechanically ventilated adults Copyright © 2022 Gitti, Renzi, Marchesi, Bertoni, Lobo, Rasulo, Goffi, Pozzi and
with sepsis. N Engl J Med. (2021) 384:1424–36. doi: 10.1056/NEJMoa2024922 Piva. This is an open-access article distributed under the terms of the Creative
43. Consales G, Chelazzi C, Rinaldi S, De Gaudio AR. Bispectral Index compared Commons Attribution License (CC BY). The use, distribution or reproduction in
to Ramsay score for sedation monitoring in intensive care units. Minerva other forums is permitted, provided the original author(s) and the copyright owner(s)
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Casanova E, Criado A. Comparing entropy and the bispectral index with which does not comply with these terms.

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