a.

Intruoduction
Sedation is of paramount importance in the management of patients with acute respiratory
distress syndrome (ARDS). In this chapter, we will present the difficult balance that must be
reached between the need to limit the potential harmful effects of mechanical ventilation
(ventilation induced lung injury [VILI], inflammation, asynchronies, lack of homogeneity) on the
one hand and the need to limit the effects of prolonged deep sedation (hyotension, sepsis,
weakness, delirium) on the other.
Ideally, there are two phases without clear clnical cut-offs-that require different strategies for
sedation targets and monitoring. First, supporting vital functions in the acute phase of acute
respiratory failure management requires deep sedation, both to permit invasive procedures
with the least iatrogenic damage and to control the body stress response. Analgesic and
sedative drugs are necessary to permit pronation, for example, or to decrease work of breathing
and respiratory asynchrony. In this phase, objective methods of monitoring sedation, such as
the simplified electroencephalogram (EEG), should be used.
Once the patient is clinically stable and hypoxia is resolved, pain, agitation, and delirium
symptoms must be adequately controlled, while maintaining the lightest decreasing oxygen
consumption, or controlling anxiety and agitation are some reasons justifying the use of
sedative therapy in this phase.
Optimal sedation management should thus provide the best possible adjustment to the phase of
critical illness while avoiding excessive depression of the conscious state. In this context, the key
intervention is to continuously monitor pain/agitation/delirium using validated tools, so that
neurological status monitoring is even more important than the choice of a particular sedative
agent, because the literature supports only modest differences in outcomes when using non
benzodiazepine based sedation protocols. During weaning from mechanical ventilation, in
addition to early sedation interruption, while maintaining a calm, conscious, and cooperative
patient.
b. The difficult choice between deep and light sedation
Patients with ARDS need special management. From the start of treatment, many strategies
have to be used, including protective ventilation with low tidal volume, use of high positive and
expiratory pressure (PEEP), prone positioning, use of neuromuscular blockers, and
extracorporeal membrane oxygenation (ECMO) in the most severe case. In these patients,
administration of sedative agents is mandatory. They ensure compliance with these procedures
and adjustmen to the hars ICU environment. Moreover, ARDS has serious physical and
psychological implications, and these patients need the most appropriate and individualized
neurological treatment, because among many other vital organ failures, the early and long-term
consequences of ARDS may lead to severe brain dysfungction.
Pain, agitation, delirium, anxiety, and alteration of consciousness are frequently triggered by
treatable causes, such as hypoxemia, hypercarbia, acidosis, hypoglycemia, hypo or
hypernatremia, sepsis, hypovolemia, alcohol or drug withdrawal, or by life saving medical
treatments, including mechanical ventilation, invasive procedures, forced body postures,
uninterrupted noise and light stimulation, or their consequences, such as sleep deprivation or
the inability to all organic and metabolic causes of distress, and minimizing environment linked
 stressors. As a second step, they suggest administration of analgesic, sedative and antipsychotic
drugs to ensur comfort, at all stages of the illness. Adequate levels of sedation, therefore,
represent a primary target for managing patients with ARDS , but these patients do not have
unique sedation target for their whole ICU stay; as soon as possible, the target sedative level
should be changed from deep to light. Because sedative therapy has several important
adverse effects, including hemodynamic instability and cardiac dysritmias, sepsis, ileus, delirium
and prolonged respiratory weaning, it is important to titrate administration to the lowest
effective amounts.
A conscious sedation target is an innovation particularly relevant to ARDS management.
However, some intensivists tend to consider it unfeasible, considering the potential higher risk
of ventilation-related lung damage, the risk of self-removal of invasive devices, and the possible
stress/discomfort for patients. From an ICU staff perspective, it also raises the issue of increased
workload. These beliefs are, however, at least partially unfounded. Despite guidelines
supporting minimal sedation and the fact that between 60 and 0% of ICUs use a specific score to
evaluate the level of sedation, many physicians routinely maintain a deeper than desired level of
sedation, likely causing avoidable adverse effects.
Although the clinical course of each ARDS patient is different, it is useful to distinguished at least
two different scenarios leading to neuroactive drug prescription. In the acute hypoxic phase,
intubation, placement of vascular catheters and other maneuvers devoted to clnical stabilization
require a deep sedation target, similar to general anesthesia. The use of protective ventilation
strategies may necessitate the prolongation of this phase for several days. However, subsequent
to this phase, it is important to change the target toward lighter sedation, using the smallest
possible amount of neuroactive drugs to ensure adequate patient adjustment to critical illness.
This second phase should start as soon as possible, depending on the severity of pulmonary
dysfunction. Other practices, such as adjustment of mechanical ventilation settings, of drug
therapies and of the environtmen to the specific needs of each patient can help reduce
discomfort.
c. Achieving the sedative target
The appropriate target level of sedation primarily depends on a patients acute disease process
and on the therapeutic and supportive interventions requaried. Generally, the use of deep levels
of sedation to facilitate mechanical ventilation or painful procedures should be minimized with
optimization of ventilation settings and adequate analgesia, rather than deepening
unconsciousness. In any case, after hypoxia resolution, the sedation target should be a calm
patient, awake during the day and asleep at night.
The appropriate balance of sedation and analgesia is difficult as achieve and maintain. Without a
rational agreement on target levels of sedation, different members of the healthcare team will
have disparate treatment goals, increasing the risk of iatrogenic complications and potentially
delaying recovery. The target level of sedation for each patient should thus be discussed
between the different ICU staff members, defined at the beginning of each staff shift, and re-
evaluated regularly as the clinical condition of the patient changes. Th pharmacological
treatment should be planned with sufficient flexibility to enable titration to the desired
endpoint, anticipating fluctuations in sedation requirements throughout the day. Frequent
 monitoring with validated tools improves communication among clinicians and plays an
important role in detecting and treating pain, agitation and delirium while avoiding excessive or
prolonged sedation.
d. Continuous neurological assessment with subjective, validation tools
Individual assessment of sedation, performed at the bedside by nurses or physicians, can be
hampered by lack of objectivity. Guidelines recommend establishing a sedation target and
regularly redefining it for each patient, using a validated sedation assessment scale. These scales
provide repeatable and comparable measurements, enabling adequate titration of analgesic,
sedative and antipsychotic therapy and, as such, are a key component of sedation algorithms.
Among the validated tools, the scale with the highest psychometric properties are the verbal
numeric rating (VNR), the behavioral oain scale (BPS) and the critical care pain observation tool
(CPOT) for pain assessment; the Richmond agitation-sedation scale (RASS) and the sedation
agitation scale (SAS) for agitation/sedation assessment; and the confusion assessment method
for the intensive care unit (CAM-ICU) and the intensive car delirium screening checklist (ICDSC)
for delirium assessment. Amongst these validated tools, each ICU should choose t least one for
pain, one for agitation/sedation, and one for delirium.
Proper identification of pain symptoms in critically ill patients presents a challenge because of
difficulty communicating with patients who have an endotracheal tube in situ, those with
altered states of consciousness, and those receiving neuroactive drugs. To address these issues,
specific behavioral scales have been designed and validated in unconscious/sedated and in
conscious/awake patients, and established as valid, reliable, and simple tools to be used in
clinical practice.
Under or over use of sedative drugs may compromise clinical stability. Potentially life
threatening adverse effects of untreated agitation and stress response are evident: self removal
of life sustaining devices, tachypnea, tachycardia, hypertension, sustained hypoxemia and
hypercarbia due to uncoordinated mechanical ventilation. At the same time, deeper than
necessary sedation may increase mortality, length of ICU stay, sepsis severity, and the onset of
new neurological failure both during hospitalization and after discharge.
To obtain the best sedative titration, use of validated tools is mandatory. The RASS describes 10
levels of sedation/agitation using observation, veral and physical stimulation. Score range from -
-5 (unconscious, unresponsive to voice and physical stimuli) to +4 (overtly combative, violent,
immediate danger to staff), adequately describing to possible neurological conditions that
require immediate intervention. Interestingly, the RASS is also validated to asses degree of
sedation over time, both in spontaneously breathing/mechanically ventilated and in
sedated/not-sedated critically ill patients.
Although encouraging results regarding evaluation of pain and agitation have been reported in
the literature, recognition and assessment of delirium are more challenging, because they rely
on effective and continuous staff education. There is a direct relationship between increased
morbidity and mortality and the duration (in days) of delirium. The presence and duration of
delirium also correlated with a significant deterioration in the quality of life after ICU discharge.
Assessments of sedation/agitation must be reported in the clinical chart at least once per shift,
together with an evaluation of the adequacy of sedative treatment. Monitoring of neurological
 status plays a key role in patients with ARDS, and is easy and quick to perform: physicians should
state the desired sedation target for the specific patient at the specific moment of their clinical
course; nurses, for their part, should report the current neurological state, describing pain,
anxiety, agitation, sleep, need for physical restraints, delirium, together with a comprehensive
evaluation of sedative therapy, in order to achieve optimal treatment titration.
Teaching protocols used for implementation of sedation scales have shown good results among
ICU caregivers. Different methods have been used to implement evaluation tools in clinical
practice. Typically, they use an introductory in service training for nurses and physicians
followed by graded, staged educational interventions at regular intervals. Web based, freely
available teaching intervention have also ben proposed.

Some problem remain, particularly regarding the fluctuation of consciousness. Patients with
ARDS are prone to sudden changes in their state of consciousness as a result of effects of drugs,
sleep disruption, organic and metabolic disease or delirium. Assessment of sedation once a shift
is indispensable but not sufficient. Among the different possible values measured
(minimal/maximal level, prevalent level, worst level), it is important to state the duration of
each value within the observed shift. Sedation and agitation need to be reassessed on a regular
basis and during any clinical modification, to promptly capture any changes requiring
intervention. Moreover, it is relatively common for patients to manifest sudden aggressive
behavior when recovering from sedation and without fully wakening. For this reason. It is
important to encourage interdisciplinary communication between nurses and physician in order
to be aware of and prevent these problem.
Finally, assessing sedation during the night is frequently challenging. Most analgesics and
sedatives are known to make patients sleepy, but without achieving restorative, physiological
sleep. If a critically ill patient appears calm and keeps his/her eyes closed during the night,
he/she should not be stimulated just to make a sedation assessment. He/she sould be observed
during unavailable procedures conducted during the night in the ICU, in order to discriminate
normal sleep (with arousals due to noise or light) from sedation or coma.

e. Sedation assessment using objective method

Several objective methods of sedation assessment have been proposed (bispectral index [BIS],
entropy, auditory-evoked potentials [AEPs]), but none is completely satisfactory.
The BIS is a four-channel EEG monitor that generates a single value correlated with the depth of
consciousness during general anesthesia. The four correlation between BIS and validation ICU
sedation scales is related in BIS variability at awake/agitated levels and electromyography (EMG)
interference. Based on the analysis of EEG signal irregularity, the entropy monitor also use the
EMG signal, which may provide useful information for assessing whether a patient is responding
to an external, painful stimulus, but provides no additional information on sedative level. In this
context, the responsiveness index may offer some advantages. AEPs are electrophysiological
responses of the nervous system to standard sensory stimulation transmitted through
headphones. These methods have a role in monitoring sedation levels only in patients needing
deep sedation, or receiving neuromuscular blocking agents, as in this circumstance sedation
scales cannot be used.
Actigraphy provides a continuous measure of body movements and was initially developed to
measure sleep-wake cycles. This small electronic device, containing an accelerometer,
continuously senses and records minimal measurements, summarizing such data in numerical
form. Although wrist actigraphy does not discriminate the effects of lack (or excess) of analgesic
and sedatives form other acute neurological dysfunctions, preliminary observations suggest that
the measurement of body movements could provide a timely indication of acute changes in
neurological status generating motor agitation or hypoactive behavior. This objective method is
relatively new in this context. It presents interesting properties, worthy of future investigation.
f. Clinical practice flowchart for sedation and agitation management in ARDS patients
Recognition that inappropriately heavy sedation may increase mortality and morbidity has led to
a new approach that maximizes patient comfort while they remain awake, interactive and
oriented. This new approach relies on strategies, such as protocolized sedation, analgesia-based
sedation, enteral sedation, avoidance of paralytic agents, early mobilization and use of validated
tools for sedation assessment. In recent years, many giudlines have been proposed, providing a
guide
g. Sedation protocol in the literature
Adoption of local sedation protocol is strongly advised by international guidelines. The protocols
should include daily interruption of short-term sedatives (propofol, dexmedetomidine),
analgesia-based sedation (morphine, fentanyl or remifentanil), use of inhalation halogenated
anesthetic agents in the early phase (sevoflurant) and use of enteral approach during
subsequent phases. Whichever the local protocol, international guidelines highlight the need to
make mechanically ventilated patients calm, conscious and cooperative as soon as possible