Trends in Evaluation and Management of Agitation in ICU

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Awake or Sedated
Trends in the Evaluation and Management of Agitation in the Intensive

Care Unit
Erin M. DeBiasi, MD; Kathleen M. Akgün, MD, MS; Margaret Pisani, MD, MPH
Semin Respir Crit Care Med. 2015;36(6):899-913.
Abstract and Introduction

Abstract
Critically ill intensive care unit (ICU) patients often require sedation to tolerate life-saving interventions such as mechanical
ventilation. Pain, anxiety, and delirium all contribute to patient distress and agitation which can interfere with ICU medical care if
not addressed and treated appropriately. Sedation practices to treat pain, anxiety, and delirium that deviate from established
practice guidelines affect mechanical ventilation duration, ICU and hospital length of stay, functional impairment, and mortality.
Historically patients were kept deeply sedated in the ICU. However, considerable research has demonstrated that minimizing
sedation with the goal to achieve comfortable wakefulness is preferred in most ICU patients and is associated with improved
clinical outcomes. This review will focus on changes in sedation practice in the ICU over the past three decades. With the
implementation of validated sedation assessment scales, a multidisciplinary treatment model, and development of daily
awakening protocols, no or minimal sedation can be achieved in the majority of ICU patients. Frequent, careful consideration of
the environmental stimuli that contribute to patient discomfort and agitation and judicious use of sedative medications
individualized to each patient are important in achieving this goal.
Introduction
The modern intensive care unit (ICU) was developed in the 1950s in response to the polio virus epidemic. It was not until the
1980s that the first systematic assessments of sedation practices in ICUs were performed. At that time, sedation was routinely
applied for nearly all ICU patients and modeled on general anesthesia practices.[1] Most ICU clinicians preferred to deeply sedate
their patients. In addition to the sedative classes of medications commonly used in the ICU today, neuromuscular blocking (NMB)
agents, barbiturates, and nonbarbiturate sedatives were routinely used on the basis of small observational studies in mixed
medical and surgical ICU populations.[2–6]
Surveys done in the United States and internationally demonstrated the high degree of variability in ICU sedation practices,
without expert guidelines or organized clinical trials to inform practice. A single-center study from a U.S. academic medical ICU in
1990 reported that sedation was almost universally given to mechanically ventilated patients.[7] There was considerable variation
in the choice of drug, route of administration, and use of NMB. There was no standardized approach to the depth of sedation.
Sedation was usually given by intermittent intravenous bolus rather than continuous infusion. In another study performed across
34 ICUs in Great Britain during the same time period, clinicians preferred a depth of sedation to "allow detachment from the ICU
environment."[8] In addition to a wide variety of continuous opiate and benzodiazepine sedatives, NMB agents were frequently
and routinely used in all of the ICUs included in the study.
During this time, the potential side effects of sedation such as prolonged weakness after NMB,[9] adrenal suppression with
repeated or continuous etomidate use,[10] and increased mortality were increasingly recognized.[11] In 1995, the Society of Critical
Care Medicine (SCCM) released their first executive summary guidelines about the use of analgesia and sedation in the ICU.[12]
The guidelines included six general recommendations about the use of intravenous analgesia and anxiolytics as well as
identification and treatment of delirium. However, these recommendations did not include specifics regarding sedative dosages,
depth of target sedation, or tools for monitoring sedation.
Since the publication of these guidelines, there have been evolving practice guidelines for ICU sedation strategies. In this review,
we will present the major shifts in management of agitation and sedation practices in the ICU over the past three decades.
Specifically, we will review the following:
Causes of agitation
Sedation assessment methods
Outcomes of inappropriate sedation
Nonpharmacologic sedation treatment options
Pharmacologic sedation treatment options

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Multidisciplinary sedation practices
Sedation protocols
Early mobilization
Causes of Agitation in Critically Ill Patients: Pain, Anxiety, and Delirium
Agitation is characterized by excessive motor activity and is frequently reported in ICU patients. The incidence of observed
agitation ranges from 16 to 71%.[13–15] Severe agitation has been documented in 16 to 46% of patients.[13,14] The etiology of
agitation in critically ill patients may be difficult to elucidate given barriers such as mechanical ventilation impairing communication.
Agitation can be due to a variety of common and uncomfortable conditions such as underlying pain, anxiety, and/or delirium in
critically ill patients. Risk factors for agitation include underlying infection, prior drug and/or alcohol abuse, and electrolyte
abnormalities.[13] Specific causes of agitation range from acute, life-threatening conditions such as hypoxemia, hypercarbia,
hypoglycemia, acidosis, ischemia (myocardial, cerebral, intestinal), infections, drug intoxication or withdrawal, and endotracheal
tube malpositioning to non–life-threatening conditions that affect comfort such as ventilator dyssynchrony, fear, bed positioning,
sleep deprivation, restraints, nausea, constipation, dry mouth, or side effects of medications[16,17] ().
Table 1. Common causes of agitation in the ICU
Potentially life threatening Not (or less) life threatening

Respiratory failure Patient–ventilator dyssynchrony
Hypoxemia Inadequate flow rates
Hypercarbia Low/high tidal volumes
Metabolic Uncomfortable bed position

Fear
Acidosis Sleep–wake disturbance
Full–bladder/constipation
Hypoglycemia Nausea
Nicotine withdrawal
Drug intoxication or withdrawal Dry mouth
Infection Pain
Catheter discomfort
Central nervous system Drug side-effects
Sepsis Anticholinergic
Ischemia
Paradoxical reaction to benzodiazepines
Myocardial Drug–drug interactions
Intestinal
Cerebral
Ventilator related
Malpositioned endotracheal tube
Tension pneumothorax
Inadequate pain control is frequently reported by patients following their ICU stay and can be an additional source of stress.[18]
Pain associated with the endotracheal tube was reported in up to 82% of patients and 72% of patients classified their overall pain
in the ICU as moderate to severe.[19,20] Uncontrolled pain, like agitation, can lead to negative physiologic outcomes including
tachycardia, ventilator dyssynchrony, increased oxygen consumption, and immunosuppression.[21]
Anxiety is also a common symptom in the ICU, particularly in mechanically ventilated patients.[20,22] Anxiety is characterized by
autonomic excitability, fearful withdrawal, nervousness, and increased motor activity. Uncontrolled anxiety can also lead to
deleterious physiological responses that include myocardial oxygen demand, sympathetic nervous system stimulation, and
increased work of breathing.[23,24]
Delirium affects 50 to 80% of ICU patients.[25,26] Delirium is an acute change in mental status that is associated with impaired
attention, disorganized thinking, and altered level of consciousness. By definition, delirium is secondary to an acute medical
condition. Delirious patients can present with hypoactive states and reduced levels of consciousness, or hyperactive states and
psychomotor agitation. Delirium is particularly prevalent in older patients (older than 65 years) and patients with dementia, more
severe illness, mechanical ventilation, alcohol use, hypertension, and elevated creatinine.[27–29] Additionally, benzodiazepines are
associated with increased incidence of delirium in critically ill patients and the risk increases with benzodiazepine dose.[28,30,31]
Drug and alcohol withdrawals are also important and common causes of hyperactive delirium in ICU patients.[32]
Pain, anxiety, and delirium can be difficult to differentiate from each other, especially for critically ill patients who may be unable to
express themselves due to life-sustaining therapies such as mechanical ventilation. In addition, ICU patients frequently
experience other common symptoms such as dyspnea or thirst that may not be routinely assessed or treated.[33] Uncomfortable
physical or psychological symptoms can perpetuate other symptoms. For example, uncontrolled pain can escalate and, if left
undertreated, lead to anxiety as the patient tries to find a way to express their symptom experience. Uncontrolled pain and anxiety
as well as attempts to pharmacologically treat these symptoms can also contribute to delirium risk. Clinician awareness of the
array of causes of agitation in the ICU population as well as knowledge of the interventions and treatments directed at the
underlying etiology is paramount to minimizing or eliminating uncontrolled pain, anxiety, and delirium and thus agitation in the ICU.
Methods to Assess Patient Agitation and Comfort in the ICU
Sedation scales were first described by Ramsay in 1974 to quantify the degree of agitation in ICU patients and to guide sedation
titration by ICU teams.[34] An effective sedation scale allows a user to (1) accurately document patients' level of sedation; (2)
communicate with other ICU providers with good interuser reliability; (3) titrate sedation to a clearly defined goal; and (4) learn and
record ratings easily.[35] Since the development of the Ramsay score, numerous other sedation scales including the Sedation
Agitation Scale (SAS), Motor Activity Assessment Scale (MAAS), Vancouver Interactive and Calmness Scale, Richmond
Agitation-Sedation Scale (RASS), Adaptation to Intensive Care Environment instrument, and the Minnesota Sedation Assessment
Tool have been developed.[36–41] In a prospective, controlled study, the use of SAS in the ICU was associated with fewer
mechanical ventilation days, fewer nosocomial infections, and decreased agitation.[42]
The 2013 SCCM recommendations on the validity and reliability of the aforementioned sedation scales in ICU patients found that
the RASS and SAS scales were superior to other scales.[18] These two scales had high inter-rater reliability between various
members of the ICU team.[43,44] Users of these scales are able to easily distinguish between different levels of sedation, and the
sedation scores from these two scales had a high level of correlation with brainwave activity measurements gathered from
electroencephalogram (EEG) or Bispectral index (BIS).[45–47] Regardless of which sedation scale is used in the ICU, sedation
goals should be individualized for each patient, bearing in mind that most patients can tolerate light or no sedation.
In addition to minimizing sedation, the SCCM guidelines also recommend routine assessment of pain and delirium in ICU patients.
Reliable scales have been developed for assessment of both pain and delirium.[26,48–51] The most reliable assessment of pain
requires patient's verbal input, which may not be possible in ICU patients. The numerical rating scale was developed to allow for
patients to report their perceived pain level and can be used in nonverbal but interactive patients.[49] For patients who are not
interactive, the behavioral pain scale and the critical-care pain observation tool (CPOT) use observation of patient activity to
interpret pain level.[50–52] reviews the most common and recommended instruments to assess pain, agitation/sedation, and
delirium in the ICU.
Table 2. Scales used to assess pain, agitation, and delirium in the ICU
Patient Score Target

Scale Description
requirements range score
Pain NRS49 Continuous numerical scale of patient-reported pain Self-report 0–10 <4
Scores of 1 (no discomfort) to 3 (most discomfort) assigned to
BPS50 three observational features: facial expression, upper limb Observational 3–12 <5
movement, and ventilator compliance
Scores of 0 (no discomfort) to 2 (most discomfort) assigned to
CPOT51 four observational features: facial expression, body movement, Observational 0–8 <3
ventilator compliance or vocalization, and muscle tension
Agitation RASS39 Ten levels of observable responses to physical/verbal stimuli Observational −5 to 4 −2 to 0
Seven levels with multiple descriptors ranging from dangerously
SAS37 Observational 1–7 3–4
agitated (7) to unarousable (1)
Delirium Assesses four features: acute change in mental status, Requires Positive
CAM-
inattention, altered level of consciousness, and disorganized patient or Negative
ICU26
thinking interaction negative
ICDSC48 Eight-item checklist of features of delirium including altered level Requires 0–8 <3
of consciousness, inattention, disorientation, patient
hallucinations/delusions, psychomotor retardation/agitation, interaction
inappropriate speech/mood, sleep–wake cycle disturbance, and
symptom fluctuation
Abbreviations: BPS, behavioral pain scale; CAM-ICU, confusion assessment method for the ICU; CPOT, critical care pain
observation tool; ICDSC, intensive care delirium screening checklist; NRS, numeric rating scale; RASS, Richmond Agitation-
Sedation Scale; SAS, sedation agitation scale.
Deeper sedation and/or NMB may be required for some patients, such as those with severe asthma; acute respiratory distress
syndrome with difficulty oxygenating, ventilating, or inability to tolerate lower tidal volumes; head trauma; or neurosurgical
catastrophes. When NMB is used, patients should be sedated to unconsciousness with analgesics and sedative hypnotics. There
should also be daily interruption of NMB and sedation to allow for patient assessment.[18,53] All patients receiving NMB should
have objective monitoring of brain function to monitor level of consciousness. The BIS, auditory-evoked potentials, median
somatosensory-evoked responses, Narcotrend index (NI), patient state index (PSI), and state entropy (SE) are examples of tools
that can be used to measure neurologic activity. The BIS, NI, SE, and PSI all process raw EEG data to a numerical index scale,
which can be correlated to brain activity. For example, the BIS gives a score between 0 (no brain activity) and 100 (awake) based
on EEG frequency and amplitude.[54] Neurologic monitoring tools can distinguish generally between deep and light sedation;
however, the main limitations in the use of these measurement tools included interference from electromyographic signals and
variable correlation with validated sedation scales.[45,55–61] After review of 18 studies evaluating the effectiveness and reliability
of these tools, the 2013 SCCM guidelines recommended that this level of monitoring should be limited to patients who are
comatose or patients receiving NMB. They recommended against the substitution of sedation scoring scales with neurologic
monitoring in noncomatose, nonparalyzed patients.[18]
Outcomes of Inappropriate Sedation: The Importance of Targeted Sedation
A common misperception or myth in the ICU is that all patients receiving mechanical ventilation require sedation.[62] However,
there is compelling evidence to suggest that no sedation is the better strategy for many patients on mechanical ventilation for
more than 24 hours.[63] In a Danish trial of medical and surgical ICUs, 140 patients were randomized 1:1 to either a no sedation
protocol or sedation with daily interruptions. Patients who were randomized to the daily interruption of sedation arm were sedated
to Ramsay scores of 3 to 4 with propofol followed by midazolam. Compared with patients receiving daily interruption of sedation,
patients who received no sedation had an average of 4.2 fewer days of mechanical ventilation and shorter ICU and hospital length
of stay (LOS) (all p < 0.05). Delirium was significantly more common in the no-sedation group with more frequent use of
haloperidol. Importantly, patients in both groups continued to receive treatment for pain, and there was no significant difference
between the two groups in morphine dose per hour of mechanical ventilation. These data challenge the myth of automatic
sedation for all mechanically ventilated ICU patients.[62] Future studies are required to determine whether these results are
generalizable.
While sedation may not be required for all mechanically ventilated ICU patients, a significant proportion will still require sedation at
some point during their ICU stay. Proper assessment of sedation for these patients is key to preventing adverse outcomes both
from under- or oversedation. For example, mechanically ventilated patients who have untreated agitation are at risk for adverse
events. Several studies have demonstrated that agitation significantly contributes to the risk of self-extubation and patient–
ventilator dyssynchrony, and that proper sedation for agitated patients can reduce that risk.[14,64,65] Additionally, agitated patients
are at risk for unintentional or unplanned removal of other devices such as central venous lines and urinary catheters.[66] ICU
LOS is also prolonged in agitated patients.[64]
While there are negative effects for extreme agitation in critically ill patients, oversedation is also a major problem. Oversedation
contributes to increased duration of mechanical ventilation as well as ICU and hospital LOS.[67–70] There has been overwhelming
evidence in the past 15 years to suggest that targeting a lighter sedation goal improves patient outcomes in several significant
ways. Minimizing sedation through daily awakenings by sedation interruption and targeting lighter levels of sedation, for example,
a RASS score of −2 to +1, compared with deep levels of sedation, for example, RASS scores of −3 to −5, is associated with
decreased length of mechanical ventilation and ICU LOS, regardless of sedation medication choice or protocol.[67–74] Additionally,
patients with lighter sedation targets required fewer tracheostomy placements.[67,73] Patient mortality was improved in patients
with lighter sedation goals.[73,74] In a prospective, longitudinal, multicenter study from New Zealand of 251 medical and surgical
ICU patients requiring mechanical ventilation, patients who were deeply sedated early in the ICU course (first 48 hours) had an
8% increased risk of 180-day mortality after adjusting for age, demographics, severity of illness, and admission diagnosis.[74]
These results are highly suggestive of the negative impact of early deep sedation in the ICU, but clinical trials are warranted to
confirm these associations.
While multiple research studies have documented that ICU outcomes were improved with lighter or no sedation, there was
concern that lighter sedation could lead to increased psychological and physical stress on patients. A prospective cohort study
found that patients who had a lighter level of sedation were more likely to remember a bothersome ICU experience after their
discharge.[75] However, in a randomized controlled trial, Treggiari and colleagues demonstrated that deeper sedation was
associated with increased posttraumatic stress disorder (PTSD) and recollection of disturbing or false ICU memories.[70] There
was no difference between level of sedation and the association with anxiety or depression. Overall, it is uncertain what level of
sedation is optimal to minimize the psychological sequelae of ICU admission.
It has been postulated that lighter sedation can lead to greater physiologic stress with unwanted consequences due to excessive
catecholamine release contributing to myocardial ischemia and increased oxygen consumption. Deeper sedation may lead to
decreases in these physiologic responses to stress.[76,77] On the other hand, studies have demonstrated that there is no increase
in urine and serum catecholamines and cortisol and no increase in adverse outcomes such as myocardial infarction with lighter
sedation.[72,78] These studies suggest an overall low risk of negative outcomes with lighter sedation targets and considerable
reduction in the harmful outcomes associated with deeper sedation.
Nonpharmacologic Interventions for Sedation Management
Several nonpharmacologic interventions aimed at improving the patient's ICU environment, and ICU experience can benefit in
treating agitated, delirious patients. These interventions may reduce the need to use sedating medications.
Addressing Patient–Ventilator Dyssynchrony
Patients who experience dyssynchrony or asynchrony with the ventilator can be uncomfortable and may appear agitated.[79]
Addressing ventilator settings in agitated mechanically ventilated patients by adjusting inspiratory flow rates, tidal volumes, and/or
ventilator modes may effectively relieve agitation from patient–ventilator dyssynchrony.[80–82] Whether strategies to quickly
identify and treat patient–ventilator dyssynchrony can decrease sedation requires further study.
Control of ICU Environment and Sleep Cycles
Almost half of ICU patients report marked sleep disturbance commonly due to noise, light, or in-room interruptions such as
bathing and turning.[83–85] In studies utilizing polysomnography in the ICU, up to 50% of patient sleep during daytime.[85] This
shift in sleep patterns contributes to circadian rhythm disruption. Lack of bright daytime lighting and increased light overnight can
disrupt circadian alignment and lead to the development of delirium and sleep abnormalities.[86] Simple interventions such as
providing earplugs or reducing alarm volumes can reduce noise levels which could improve sleep quality in the ICU.[87] Dedicated
quiet hours in the ICU or "nap times" can also increase duration of observed sleep.[88] Adherence to natural lighting cycles and
avoidance of bright lights at night is recommended.[21]
Complementary and Alternative Medicine
Therapeutic back massage can improve relaxation and sleep quality in the ICU.[89] Music therapy can also improve patient's ICU
experiences and reduce stress.[90,91] In mechanically ventilated patients, music therapy can reduce anxiety, heart rate, and
respiratory rate.[92,93] Music that is chosen should be based on the patient's preference, ideally without words and used for at
least 30 minutes daily.
Pharmacologic Approach to Sedation
Drug classes commonly used for sedation are opiates, benzodiazepines, and nonbenzodiazepines. Medication selection should
be individualized for each patient. Underlying causes of agitation such as pain or other distressing physical symptoms and
assessment of comorbid disease states (e.g., renal or hepatic disease) should be considered, and ideal duration of sedation
should be tailored to the clinical condition of the patient (Fig. 1). The following section will provide an overview of the classes of
medications used for sedation in the ICU and review the literature regarding medication selection. A summary of common
medications used for sedation in the ICU is presented in .
Table 3. Common medications used for sedation in the ICU
Dose
Mechanism of Half-life (t
(loading; Onset Metabolism Special considerations
action ½)
maintenance)
μ opioid receptor 25–100 μg Hepatic phase I Accumulates with hepatic
agonists IVP 1–2 CYP3A4/5; no impairment
Fentanyl 2–4 h
20–100 μg/h min active Causes bradycardia
ggt metabolites Less hypotension
Hepatic phase
2–5 mg IVP II Causes histamine release
5–10
Morphine 1–10 mg/h 3–4 h glucuronidation; Accumulates with
min
ggt active hepatic/renal impairment
metabolites
Hydromorphone 0.4–1.5 mg 5–15 2–3 h Hepatic phase Accumulates with
IVP min II hepatic/renal impairment
0.5–3 mg/h glucuronidation;
ggt
no active
metabolites
Hydrolysis by
1.5 μg/kg
plasma
IVP; 1–3
Remifentanil 3–10 min esterases; no No accumulation
0.5–15 min
active
μg/kg/h ggt
metabolites
Increase GABAA Accumulation with hepatic
Hepatic phase I
receptor activation impairment; Active
0.5–3 mg IVP 2–5 metabolism;
Midazolam 3–11 h metabolite accumulates
1–5 mg/h ggt min Active
with renal impairment;
metabolites
Lipophilic
Hepatic and
extrahepatic
15–
0.5–2 mg IVP phase II Propylene glycol-related
Lorazepam 20 8–15 h
1–5 mg/h ggt metabolism; toxicities; nephrotoxicity
min
No active
metabolites
Hepatic phase I
2–5 metabolism; Accumulates with hepatic
Diazepam 1–5 mg IVP 24–120 h
min Active impairment
metabolites
Binds to β3 of 30–60 Hepatic phase I
0.5 mg/kg Hypertriglyceridemia;
GABAA; effects on min; and II
IVP; 1–2 pancreatitis; propofol-
Propofol NMDA and dependent metabolism; no
50–200 mg/h min related infusion
cannabinoid on length active
ggt syndrome; Lipophilic
receptors of infusion metabolites
Phase I and II
1 μg/kg IV;
5–10 metabolism
Dexmedetomidine α2 agonist 0.2–1.5 2–3 h Bradycardia, hypotension
min No active
μg/kg/h ggt
metabolites
Hepatic
30– Electrocardiogram QT
metabolism,
Haloperidol Blocks D2 receptor 2–10 mg IV 60 14 h prolongation
renal >> biliary
min Extrapyramidal symptoms
excretion
Abbreviations: ggt, drip; IVP, intravenous push.
Figure 1.
Suggested algorithm for management of sedation in the ICU.
Opiates
Opiates, which work via the mu-receptor in the central nervous system, are used to treat pain and dyspnea in critically ill patients.
They can be used to treat the feeling of air hunger in the setting of respiratory failure. Opiates can be administered by several
routes, with intravenous and enteral being the most common. Morphine, fentanyl, hydromorphone, and remifentanil are the most
common opiates used in the ICU. Side effects from opiate medications are dose-dependent respiratory depression, hypotension,
urinary retention, emesis, constipation, and ileus. Meperidine is generally avoided in the ICU population because it lowers seizure
threshold.[94] Morphine can lead to histamine release and subsequent pruritus and/or bronchospasm. Fentanyl has been
associated with bradycardia but tends to cause less hypotension compared with other systemic opioids.[95]
The choice of opiate medication should be individualized based on the drug's pharmacokinetic properties and the patient's
underlying disease states. Opiates undergo hepatic metabolism and renal excretion, so caution must be used when dosing these
drugs in patients with hepatic or renal failure. Owing to its rapid onset of action and short half-life, fentanyl is often administered as
a continuous intravenous infusion or when rapid onset for symptom management is needed. In Europe, newer and faster acting
opiates such as remifentanil are gaining popularity. Remifentanil is metabolized to an inactive metabolite via rapid hydrolysis by
plasma and tissue esterases.[96] This property limits the drug's duration of action and allows for rapid titration and eliminates
concerns over delayed or unpredictable recovery. When remifentanil was compared with fentanyl for analgesia-based sedation in
ICU patients, both provided effective levels of sedation.[97] However, remifentanil's rapid elimination led to poorer control of pain
when used as the primary drug for sedation, especially during the titration stages. When combined with propofol, remifentanil may
shorten duration of mechanical ventilation when compared with midazolam/fentanyl protocols.[98]
Although opiates do not have any anxiolytic or amnestic properties, a recent interest in analgesia-first sedation (termed
analgosedation) has led to many studies about the use of opiate medications as the primary medication for sedation in agitated
patients.[99,100] Analgosedation protocols focus on the use of opiate-based sedation with additional medications used as needed.
Based mainly on studies done in Europe, the SCCM guidelines in 2013 offered a weak recommendation for the use of
analgosedation protocols.[18] The four studies that were reviewed for these guidelines were not consistent in their choice of
opiate, study population, and reported outcomes. However, a larger meta-analysis of 10 randomized controlled trials including
1,155 mechanically ventilated patients from medical and surgical ICUs recommended the use of analgosedation protocols as the
primary means for sedation.[99] Nine of these studies examined the use of remifentanil to other opiates, benzodiazepines, and
nonbenzodiazepine sedatives and one examined the use of morphine compared with propofol or midazolam. The opiate-based
sedation protocols were found to be associated with shorter duration of mechanical ventilation, more rapid ventilator weaning, and
shorter ICU LOS without any significant negative outcomes in this heterogeneous group of medical and surgical ICU patients. In
addition, the morphine-based protocol, termed the no sedation protocol, found no difference 2 years after randomization in
outcomes such as PTSD compared with the sedation with daily interruption protocol. However, an increase in ICU delirium was
noted in the no-sedation group.[63,101] Recently in the United States, a small retrospective study of 100 ICU patients examined a
protocol of continuous infusion of fentanyl versus propofol for primary sedation.[100] Pain, agitation, and delirium were routinely
assessed using the CPOT, RASS, and confusion assessment method for the ICU (CAM-ICU). This study found that the use of
fentanyl alone was safe and effective in sedating patients on mechanical ventilation. There was no difference found in length of
mechanical ventilation, ICU LOS, or development of delirium between the different drug regimens. Overall, the use of opiates for
sedation in ICU patients should be considered, especially when pain is thought to be a significant source of agitation.[18,99] Future
research on opiate-only sedation, specifically comparing different opiate-based protocols with no sedation protocols, will be helpful
in guiding this practice.
Anxiolytics—Benzodiazepines
Benzodiazepines are commonly used for anxiolysis in the ICU. This class of medications activates the gamma-aminobutyric acid
A (GABA) central nervous system receptors. In addition to anxiolytic properties, these medications also have amnestic, hypnotic,
sedative, and anticonvulsant effects. When used with opiates, they can have a synergistic effect. Side effects from
benzodiazepines include respiratory depression and hypotension. Recently, several studies have demonstrated an increased risk
of delirium associated with benzodiazepine use in critically ill patients,[28,30,31,102] although these associations are not
consistently demonstrated.[103]
Benzodiazepines are highly protein bound and metabolized by the liver. Therefore, their clearance is reduced in patients with
underlying hepatic disease. Hepatic dysfunction has a smaller impact on the metabolism of lorazepam compared with other
benzodiazepines commonly used in the ICU, as it undergoes hepatic glucuronidation rather than cytochrome P450 metabolism.
[104,105] Glucuronidation is less impacted by hepatic dysfunction, age-related changes, and drug–drug interactions than the
cytochrome P450 system. After undergoing hepatic metabolism, all of the benzodiazepines are excreted by the kidneys. Patients
with renal dysfunction may experience a longer half-life and duration of action with benzodiazepine use.[106] Accumulation of the
active metabolites of midazolam, especially in obese patients due to its high solubility in lipids, can become a particularly
important consideration when using it as an intravenous infusion. Elderly patients also clear benzodiazepines more slowly and are
therefore more at risk for drug accumulation.[105] Patients on prolonged infusion of lorazepam are at risk of developing propylene
glycol toxicity, the solvent used for lorazepam infusions. Propylene glycol toxicity is characterized by renal dysfunction, altered
mental status, metabolic acidosis, and an elevated osmolar gap.[107]
There are limited studies comparing different benzodiazepines for sedation in critically ill patients. In addition, many of the studies
available have been in small, relatively homogenous patient populations with mixed results.[108–110] In particular, time for patients
to return to an awakened mental status has not been consistent across studies comparing lorazepam with midazolam. One study
demonstrated a greater achievement of desirable level of sedation with lorazepam as compared with midazolam (87 vs. 66%,
respectively).[108] In general, because of midazolam's faster onset of action, it may be the preferred agent for short time periods,
whereas lorazepam may be selected for longer-term sedation given its metabolism.[18] See for common benzodiazepines used in
the ICU.
Table 3. Common medications used for sedation in the ICU
Dose
Mechanism of Half-life (t
(loading; Onset Metabolism Special considerations
action ½)
maintenance)
μ opioid receptor 25–100 μg Hepatic phase I Accumulates with hepatic
agonists IVP 1–2 CYP3A4/5; no impairment
Fentanyl 2–4 h
20–100 μg/h min active Causes bradycardia
ggt metabolites Less hypotension
Hepatic phase
2–5 mg IVP II Causes histamine release
5–10
Morphine 1–10 mg/h 3–4 h glucuronidation; Accumulates with
min
ggt active hepatic/renal impairment
metabolites
Hydromorphone 0.4–1.5 mg 5–15 2–3 h Hepatic phase Accumulates with
IVP min II hepatic/renal impairment
0.5–3 mg/h glucuronidation;
ggt no active
metabolites
Hydrolysis by
1.5 μg/kg
plasma
IVP; 1–3
Remifentanil 3–10 min esterases; no No accumulation
0.5–15 min
active
μg/kg/h ggt
metabolites
Increase GABAA Accumulation with hepatic
Hepatic phase I
receptor activation impairment; Active
0.5–3 mg IVP 2–5 metabolism;
Midazolam 3–11 h metabolite accumulates
1–5 mg/h ggt min Active
with renal impairment;
metabolites
Lipophilic
Hepatic and
extrahepatic
15–
0.5–2 mg IVP phase II Propylene glycol-related
Lorazepam 20 8–15 h
1–5 mg/h ggt metabolism; toxicities; nephrotoxicity
min
No active
metabolites
Hepatic phase I
2–5 metabolism; Accumulates with hepatic
Diazepam 1–5 mg IVP 24–120 h
min Active impairment
metabolites
Binds to β3 of 30–60 Hepatic phase I
0.5 mg/kg Hypertriglyceridemia;
GABAA; effects on min; and II
IVP; 1–2 pancreatitis; propofol-
Propofol NMDA and dependent metabolism; no
50–200 mg/h min related infusion
cannabinoid on length active
ggt syndrome; Lipophilic
receptors of infusion metabolites
Phase I and II
1 μg/kg IV;
5–10 metabolism
Dexmedetomidine α2 agonist 0.2–1.5 2–3 h Bradycardia, hypotension
min No active
μg/kg/h ggt
metabolites
Hepatic
30– Electrocardiogram QT
metabolism,
Haloperidol Blocks D2 receptor 2–10 mg IV 60 14 h prolongation
renal >> biliary
min Extrapyramidal symptoms
excretion
Abbreviations: ggt, drip; IVP, intravenous push.
Anxiolytics—Nonbenzodiazepines
Nonbenzodiazepine sedative–hypnotic medications, mainly propofol and dexmedetomidine, have increasingly been used to treat
anxiety and agitation in the ICU. Propofol, similar to benzodiazepines, has anxiolytic, amnestic, hypnotic, sedative, anticonvulsant,
and bronchodilator properties.[111,112] It acts through activation of GABA receptors and inhibition of N-methyl-d-aspartate
receptors. Propofol has a rapid onset and offset of action. Metabolism of propofol is not dependent on renal or hepatic function.
[112] These properties make this drug an attractive choice for sedation in the setting of requirements to actively monitor a patient's
underlying neurological status. Side effects from propofol include respiratory depression, systemic vasodilation leading to
hypotension, bradycardia, hypertriglyceridemia, and acute pancreatitis with prolonged use over several days. Propofol infusion
syndrome (PRIS) characterized by metabolic acidosis, hypertriglyceridemia, hypotension, and arrhythmias can also develop.[113]
PRIS incidence is unknown but seems to be very rare. Based on case series, PRIS is more commonly seen in patients with
traumatic brain injury, those being treated for refractory status epileptics, and patients on significant doses for a prolonged period
of time (>80 mcg/kg/min for 4–5 days).[114]
Dexmedetomidine is a newer nonbenzodiazepine that acts as a selective central α-2 (α2) agonist. While it acts as a sedative, it
also has sympatholytic effects and tends to be analgesic sparing. Dexmedetomidine undergoes hepatic metabolism and has
minimal effect on respiratory drive. It has a slower onset of action (10–15 minutes) and peak effectiveness time (60 minutes)
compared with other sedatives used in the ICU.[115] However, the quality of sedation produced by dexmedetomidine is
considerably different than other medications, as patients sedated with this drug tend to be more awake and interactive.[116] This
could make dexmedetomidine the preferred sedative agent in morbidly obese patient who may be more susceptible to opiate-
[117]
induced respiratory depression.[117] Side effects of dexmedetomidine include hypotension or hypertension with loading doses as
well as hypotension and bradycardia with infusion.[118,119]
There has been considerable debate over whether the use of nonbenzodiazepine drugs is preferable over benzodiazepines for
sedation in the ICU. outlines the major studies that have compared benzodiazepine with nonbenzodiazepine medications in the
ICU. The 2002 SCCM guidelines recommended that benzodiazepines be used for sedation in ICU patients.[21] Midazolam was
recommended only for short-term use because of previous studies demonstrating unpredictable awakening; lorazepam was
recommended for longer durations of sedation. Propofol was recommended only for a subgroup of patients requiring rapid
awakening for frequent neurologic assessment or early extubation.[21] The revised 2013 SCCM guidelines addressed these
questions by evaluating several studies in addition to performing their own meta-analysis. This resulted in a subsequent shift in
their recommendations regarding the use of propofol and dexmedetomidine. The 2013 guidelines recommend that
nonbenzodiazepines may be preferred as the first-line agents for mechanically ventilated ICU patients requiring sedation after
analgesic-first strategies have been provided.[18] A separate meta-analysis performed by Fraser et al in 2013 also supported this
recommendation.[120] The shift in their recommendations was based on several factors. First, while there were several neutral
studies,[121–123] there was increasing evidence that the prolonged use of benzodiazepines for sedation was associated with
negative outcomes including delirium, higher number of days on mechanical ventilation, and longer ICU LOS.[124–131] Second, in
the 2013 SCCM meta-analysis, when propofol was compared with benzodiazepines, there was a trend toward shorter duration of
mechanical ventilation in the propofol group, although there was no difference in ICU LOS, self-extubation, or incidence of
delirium across these studies.[121–124,126,127,129–131] Third, when dexmedetomidine was compared with benzodiazepines, one
large study demonstrated significant reduction in length of mechanical ventilation,[125] whereas others were neutral or weakly
supported dexmedetomidine use.[126,128,129] ICU LOS was reduced with dexmedetomidine in one study.[126] Fourth,
dexmedetomidine use was shown to improve outcomes related to delirium. In one study, the incidence of delirium was reduced
from 50% when using propofol or midazolam to 3% when using dexmedetomidine,[126] and a second study indicated that the
prevalence of delirium was reduced from 77% in patients receiving midazolam to 54% in those receiving dexmedetomidine.[125]
Finally, use of nonbenzodiazepines for sedation is not more costly than benzodiazepines and in some studies has been shown to
be more cost-effective by reducing ICU LOS.[126,132,133] As the state of knowledge on sedative options in the ICU becomes more
evidence based, practice guidelines will likely change to reflect the evidence.
Table 4. Recent trials comparing the use of benzodiazepine to nonbenzodiazepine sedation strategies
Author, year Drugs used Design N Scale used Significant outcomes
No difference in duration of sedation,

return of spontaneous breathing
Independently
Weinbroum et Propofol,
RCT 67 designed
al,121 1997 midazolam Propofol associated with increased
scale hypotension, cost, need for dose
adjustment, faster recovery
No difference achievement of target

Searle et al,122 Propofol, level of sedation, number of infusion
RCT 41 Ramsay
1997 midazolam rate adjustments, time to extubation or
awakening
No difference ICU LOS

Hall et al,131 Propofol, Propofol associated with earlier
RCT 99 Ramsay
2001 midazolam extubation, better achievement of target
level of sedation
No difference in achievement of target

Huey-Ling et Propofol,
RCT 60 Ramsay level of sedation, development of
al,123 2008 midazolam
hypotension
Carson et Propofol, RCT 132 Ramsay

al,124 2006 lorazepam No difference hospital mortality, ICU
LOS, hospital LOS, self-extubation,
reintubation
Propofol associated with fewer days on

ventilator
Fong et al,127 Propofol, Propofol associated with fewer days on

Retrospective 287 N/A
2007 lorazepam ventilator
No difference 28-d mortality, 1 y time to

death, cost
Pandharipande Dexmedetomidine Dexmedetomidine associated with
RCT 106 RASS, CAM
et al,128 2007 lorazepam increased days alive without delirium or
coma, achievement of target level of
sedation

level of sedation, ICU LOS
Riker et al,125 Dexmedetomidine,
RCT 366 RASS, CAM
2009 midazolam Dexmedetomidine associated with
decreased delirium, days on ventilator

level of sedation when RASS goal 0–3,
Dexmedetomidine, ICU LOS
Ruokonen et
propofol, RCT 85 RASS
al,129 2009 Dexmedetomidine associated with
midazolam
decreased days on ventilator and
inability to maintain RASS goal 4
Dexmedetomidine, Dexmedetomidine associated with

Maldonado et
propofol, RCT 118 Ramsay decreased delirium, shorter ICU LOS,
al,126 2009
midazolam hospital LOS

level of sedation, LOS, mortality
Dexmedetomidine associated with

decreased time to extubation compared
with midazolam, days of mechanical
Dexmedetomidine, ventilation
Jakob et al,130
propofol, RCT 1001 RASS
2012
midazolam Dexmedetomidine associated with
increased side effects of hypotension
and bradycardia
Dexmedetomidine associated with

improved patient interaction, ability to
report pain
Abbreviations: CAM, confusion assessment method; ICU, intensive care unit; LOS, length of stay; RASS, Richmond Agitation-
Sedation Scale; RCT, randomized controlled trial.
Antipsychotics
Antipsychotics are used to treat acute agitation and delirium in the ICU. Haloperidol has been used most frequently, although
atypical antipsychotics such as olanzapine or quetiapine are increasingly used and may have fewer extrapyramidal side effects
compared with haloperidol.[134,135] Haloperidol may have a role in preventing delirium in older postoperative ICU patients.[136]
However, randomized clinical trials in ICU patients receiving mechanical ventilation have failed to demonstrate efficacy of
antipsychotics, when used routinely compared with placebo, in reducing the incidence of developing ICU delirium, in part due to
small sample size and receipt of haloperidol in the control groups.[137,138] Until ongoing clinical trials demonstrate their efficacy in
treating ICU delirium, judicious use of antipsychotics with careful monitoring for EKG changes and extrapyramidal side effects is
supported by clinical guidelines.[18,21]
Multidisciplinary Care Teams' Roles in Sedative Management
Multidisciplinary care is essential for improving the quality of clinical care delivered in the ICU. In addition to physician providers, a
multidisciplinary team including nurses, pharmacists, respiratory therapists, and consultants is associated with improved survival.
[139] This effect can likely be attributed to better implementation of evidence-based medicine, awareness of potential drug–drug
interactions, and improved communication between team members.
Nonphysician multidisciplinary team members can have a significant impact on patient outcomes through active sedation
management, particularly when they are empowered to ensure compliance with sedation protocols.[67,140] Brook and colleagues
performed a landmark study in 1999 that demonstrated that a nurse-driven sedation protocol targeting a particular Ramsay score
led to similar improvements in ICU outcomes compared with physician-directed orders.[67] In this protocol, nurses used the
Ramsay score to assess level of sedation and pain and select, administer, and titrate the most appropriate medication. They
reassessed the patient at prespecified time intervals. Improvements in mechanical ventilation and ICU and hospital LOS were
also seen in subgroups receiving continuous sedation when nurse-driven protocols were employed. Marshall and colleagues also
demonstrated that pharmacist-directed recommendations on sedation in patients on continuous medications lead to significant
reductions in mechanical ventilation days and both ICU and hospital LOS.[140]
Sedation Protocols: A Method to Achieve Targeted Zero or Light Sedation
In addition to the debates regarding level of sedation and specific drugs used for sedation, there has been no consensus
regarding the ideal method to achieve and maintain lighter levels of sedation while maintaining patient safety. The study by Brook
and colleagues indicated that the use of a protocol for sedation management improves ICU outcomes.[67] In 2002, the SCCM
provided guidelines that directed clinicians to determine the appropriate depth of sedation required to care for a particular patient
and to frequently reassess whether that target is reached.[21] Between 2002 and the society's next guidelines in 2013, there was
considerable research done on this subject. It is now recommended that all patients be targeted to zero or a light level of sedation
with the aid of sedation scales, sedation protocols, consideration of intermittent dosing of medications, and daily interruption of
sedation paired with ventilator weaning trials.[18]
With the aforementioned evidence in mind, there was increasing focus on the optimal approach to achieve an ideal level of
sedation in ICU patients. A prospective observational study in 1997 indicated that continuous sedation in comparison to bolus-
dosed sedation or no sedation increased mechanical ventilation duration and ICU and hospital LOS.[71] This study helped
establish the foundational basis of research focused on reducing sedation with the aid of protocols. One of the first approaches to
reducing sedation was daily spontaneous awakening trials (SAT).[69] A SAT is a daily interruption of sedative medication, with
continuation of analgesics as needed for pain. The goal of a SAT is to have patients open their eyes to verbal stimuli without
sustained anxiety, agitation, tachypnea, respiratory distress, or arrhythmia. Kress and co-worker demonstrated that SATs done on
patients who were on continuous sedation resulted in decreased duration of mechanical ventilation and ICU LOS. Additionally,
fewer diagnostic tests such as brain imaging were ordered to assess a patient's mental status. The SAT protocol also led to
decreases in critical illness complications including ventilator-associated pneumonia, bacteremia, barotrauma, venous
thromboembolic disease, sinusitis, and cholestasis.[141] When paired with a spontaneous breathing trial (SBT), daily SATs can
further reduce days on the ventilator and ICU and hospital LOS.[68] Total doses of sedative medications are also reduced with this
approach. Importantly, while paired SATs and SBTs resulted in more self-extubations, this did not lead to an increased need for
reintubation.
With proven benefit of SATs, de Wit and colleagues sought to determine if the use of a sedation algorithm was superior to daily
SATs.[142] In this randomized controlled trial, patients were assigned to either a nurse-driven protocolized sedation group, in which
level of sedation and sedative dose was frequently evaluated and titrated, or a group in which sedatives were routinely
discontinued each day as per the Kress' SAT protocol.[69] The study demonstrated daily interruption of sedation was associated
with increased mortality compared with a nurse-driven sedation protocol. There were also more days mechanically ventilated and
longer ICU and hospital LOS in the daily interruption group. It should be noted that the study was ended early by a safety
monitoring group after an interim analysis demonstrated increased hospital mortality in the daily awakening group, although no
causal relationship could be identified. The a priori difference in time to extubation between the two groups chosen by the study
investigators had already exceeded 2 days, and this may have explained the excess mortality. Further reducing the evidence to
support daily awakening trials, the Canadian Critical Care Trials Group compared protocolized sedation alone versus protocolized
sedation paired with a SAT.[143] This study found that protocolized sedation alone had similar outcomes compared with
protocolized sedation paired with daily SATs. Finally, a recent Cochrane review did not find strong evidence to support the use of
daily interruptions in sedation compared with other sedation strategies including protocolized sedation targeting a light to
moderate sedation goal and "usual care" as directed by patient's care teams.[144] Considering results from these studies together,
it is unclear whether daily sedative interruption adds to improved clinical outcomes when strategies aimed at targeting light
sedation are employed. Overall, the 2013 SCCM guidelines direct clinicians to use either protocolized sedation with daily
interruptions or zero or light sedation targeted to a sedation goal appropriate for individual ICU patients.[145]
Incorporation of Early Mobilization Into Sedation Strategies
Recently, early mobilization has become a key movement in improving the quality of ICU care. Longer mechanical ventilation
courses and prolonged immobilization are associated with increased ICU-acquired neuromuscular weakness.[146,147] This can
lead to long-term consequences such as inability to return to independent living at home, prolonged functional impairments, and
decreased exercise tolerance. Mobility in ICU patients requires that the patient be awake enough to interact. Early studies
indicated that early mobilization can be achieved with lighter sedation and that early mobilization improves outcomes including
development of pressure sores.[148] Early mobilization leads to reduction in ICU and hospital LOS, delirium, and length of
mechanical ventilation.[149,150] Additionally, early mobilization leads to increases in quality of life, probability of regaining
independent functional status, and improvements in respiratory and peripheral muscle strength.[150,151]
Sedation protocols have aided in efforts to promote early mobilization, with lighter sedation allowing for earlier mobilization.[149–
153] In the first study to examine protocolized initiation of mobilization, patients who were awake enough to participate in a mobility
program with physical therapy had decreased ICU and hospital LOS without an increase in complications.[149] Paired SAT with
mobilization programs decreased the duration of delirium and mechanical ventilation days and increased likelihood of returning to
independent functional status.[150] Protocols such as the Awakening and Breathing Coordination, Delirium management and Early
mobility (ABCDE) bundle which incorporate SATs with SBTs, daily assessment of mobility, and provisions for physical therapy
demonstrated similar outcomes of decreased mechanical ventilation days and length of delirium.[152,153] Overall, these studies
emphasize the importance of early mobility and this is reflected in the 2013 SCCM guidelines recommending either protocolized
sedation with daily interruptions or light sedation goals paired with an early mobility protocol in ICU patients.[145]
Conclusion
Agitation due to untreated pain, anxiety, and/or delirium can have a significant negative impact on clinical and patient-centered
outcomes. Evidence over the past decade has found that deep sedation should not be the default management for the majority of
ICU patients and that ICU patients requiring sedation benefit from a targeted light sedation strategy. Nonpharmacologic
management targeting control of the patient's environment, adjusting ventilator setting to address patient–ventilator dyssynchrony,
and complementary and alternative medicine practices may also play an important role in treating agitation in ICU patients and
could reduce the need for pharmacologic sedation. The appropriate use of individualized medication choices, sedation scales, a
multidisciplinary team approach, and protocolized care can help improve outcomes in critically ill patients.
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4/16/2018 https://www.medscape.

Trends in the Evaluation and Management of Agitation in the Intensive

Semin Respir Crit Care Med. 2015;36(6):899-913.

Abstract and Introduction

Sedation assessment methods

Outcomes of inappropriate sedation

Nonpharmacologic sedation treatment options

Pharmacologic sedation treatment options

Causes of Agitation in Critically Ill Patients: Pain, Anxiety, and Delirium

Table 1. Common causes of agitation in the ICU

Potentially life threatening Not (or less) life threatening

Hypoxemia Inadequate flow rates

Hypercarbia Low/high tidal volumes

Metabolic Uncomfortable bed position

Malpositioned endotracheal tube

Methods to Assess Patient Agitation and Comfort in the ICU

Patient Score Target

Outcomes of Inappropriate Sedation: The Importance of Targeted Sedation

Nonpharmacologic Interventions for Sedation Management

Addressing Patient–Ventilator Dyssynchrony

Control of ICU Environment and Sleep Cycles

Complementary and Alternative Medicine

Pharmacologic Approach to Sedation

Table 3. Common medications used for sedation in the ICU

Abbreviations: ggt, drip; IVP, intravenous push.

Suggested algorithm for management of sedation in the ICU.

Table 3. Common medications used for sedation in the ICU

Abbreviations: ggt, drip; IVP, intravenous push.

Author, year Drugs used Design N Scale used Significant outcomes

No difference in duration of sedation,

No difference achievement of target

No difference ICU LOS

No difference in achievement of target

Carson et Propofol, RCT 132 Ramsay

Propofol associated with fewer days on

Fong et al,127 Propofol, Propofol associated with fewer days on

No difference 28-d mortality, 1 y time to

No difference in achievement of target

No difference in achievement of target

Dexmedetomidine, Dexmedetomidine associated with

No difference in achievement of target

Dexmedetomidine associated with

Dexmedetomidine associated with

Multidisciplinary Care Teams' Roles in Sedative Management

Sedation Protocols: A Method to Achieve Targeted Zero or Light Sedation

Incorporation of Early Mobilization Into Sedation Strategies

82. Petty TL. Suspended life or extending death? Chest 1998;114(2):360–361

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