Distress is common amongst critically ill patients in ICU, especially those who are intubated or have difficulty communicating with their caregivers [1]. Distress in ICU generally presents as agitation. It needs to be treated for patient comfort & if left untreated increases sympathetic tone with untoward physiologic effects [2]. Before a sedative agent is initiated to manage agitation, the cause of distress should be identified & treated. Common causes of distress in critically ill patients include:-anxiety, pain, delirium, dyspnoea and neuromuscular paralysis. These etiologies may occur separately or in combination.

1. Principles and Practice of Sedation in Intensive Care Unit
(ICU)

2. Review Article
Anxiety
Is defined as a sustained state of apprehension &
autonomic arousal in response to real or perceived threats
[1]. Fear of suffering, fear of death, loss of control &
frustation due to inability to effectively communicate are
typical causes of anxiety in critically ill patients. Symptoms
& signs include headache, nausea, insomnia, anorexia,
dyspnoea, palpitations, dizziness, dry mouth, chest pain,
hyperventilation, pallor, tachycardia, tremulousness and /
or hyper vigilance.
Pain
Routine patient care (suctioning, repositioning,
physiotherapy), immobility, trauma, surgery, endotracheal
tubes & other monitoring devices can all produce pain.
Clinical evidence of pain may include grimacing,
withdrawal, combativeness, diaphoresis, hyperventilation
&/or tachycardia.
Delirium
Is an organic mental syndrome defined as an acute,
potentially reversible impairment of consciousness &
cognitive function that fluctuates in severity [1]. Delirium
is rather common in ICU patients but is frequently under
recognized especially in older individuals & is mostly
under treated [3,4]. Delirious patients have impaired short
term memory, abnormal perception & intermittent
disorientation which is usually worse at night. EEG may
show diffuse slowing of electrical activity of brain. It is a
risk factor for prolonged hospitalization & mortality in
critically ill patients [5]. Risk factors for delirium include:
13 Apollo Medicine, Vol. 8, No. 1, March 2011
PRINCIPLES AND PRACTICE OF SEDATION IN INTENSIVE CARE UNIT (ICU)
AJIT VIGG
Head, Department of Respiratory Medicine & Director, Institute of Sleep Medicine,Apollo Hospitals,
Jubilee Hills, Hyderabad 500 033,India.
e-mail:drajitvigg@gmail.com
Distress is common amongst critically ill patients in ICU, especially those who are intubated or have difficulty
communicating with their caregivers [1]. Distress in ICU generally presents as agitation. It needs to be treated
for patient comfort & if left untreated increases sympathetic tone with untoward physiologic effects [2].
Before a sedative agent is initiated to manage agitation, the cause of distress should be identified & treated.
Common causes of distress in critically ill patients include:- anxiety, pain, delirium, dyspnoea and
neuromuscular paralysis. These etiologies may occur separately or in combination.
Key words: Anxiety, Pain, Delirium, Dyspnoea, Neuromuscular Paralysis,Sedation Protocol control agitation.
Electrolyte disturbances (hyponatremia, hypocalcemia),
hyper-glycemia, hyper amylasemia, azotemia, hepatic
disease, infections, drug withdrawal, alcohol withdrawal,
mal-nutrition, cancer, cerebrovascular disease, cardiopul-
monary disease, advanced age & certain drugs (benzo-
diazepines, corticosteroids, antihistamines, betablockers,
anti arrhythmics, atropine, digoxin) [6].
Dyspnoea
Is a sensation of air hunger or a feeling of suffocation.
Clinical evidence of dyspnoea include tachypnea, shallow
breathing, diaphoresis, tachycardia, hypoxemia. It may
exist despite acceptable blood gas parameters.
Neuromuscular paralysis
All patients undergoing neuromuscular blockade
require pharmacological sedation because neuromuscular
paralysis without sedation or adequate pain control is an
extremely frightening & unpleasant sensation. Identifying
distress in patients on neuromuscular blocking agents is
often difficult because the typical physiological responses
associated with stress may not correlate with patient
discomfort in this setting.
Treat the cause of distress
Initial treatment of agitation should target the presumed
cause of underlying distress. As an example, a patient who
is agitated due to hypoxemia should receive supplemental
oxygen as a priority.
Non pharmacological strategies
For managing agitation should begin simultaneously

3. Apollo Medicine, Vol. 8, No. 1, March 2011 14
Review Article
with therapy targeting the cause of distress. These include
reassurance, frequent communication with the patient,
regular family visits, establishment of normal sleep cycle in
the ICU & cognitive – behavioral therapies (music therapy,
relaxation techniques, guided imagery) [7].
This strategy of using non pharmacological
intervention to control agitation rather than immediately
initiating pharmacological sedation is supported by
evidence from literature. A randomized trial of 140
mechanically ventilated patients compared no sedation
with continuous sedative infusion with daily interruption
[8]. It found that patients managed with a strategy of no
sedation (and continuous verbal comforting & reassurance)
had more ventilator free days & decreased length of ICU
stay, decreased length of hospital stay and decreased
incidence of delirium [8].
Initiation of sedation protocol
Sedative analgesic medication is indicated when
treatment of the cause of distress & nonpharmacological
interventions cannot sufficiently control the agitation.
Commonly used agents
Drugs commonly used to control agitation in the ICU
include Benzodiazepines, Opoid analgesics, propofol and
neuroleptics (Table 1). They differ in their amount of
anxiolysis, analgesia, amnesia & hypnosis.
Barbiturates (thiopental, methohexital) could be used to
manage agitation in critically ill patients if patient is not
tolerating or responding to any of the above agents.
However, they are not ideal because they do not have potent
sedative effects & can cause profound cardiovascular &
respiratory depression as well as diminished cerebral blood
flow.
Selection of an agent
No sedative – analgesic agent is sufficiently superior to
other agents to warrant its use in all clinical situations.
Therefore selection of an agent must be individualized
according to patient characteristics & the given clinical
situation. Important considerations when selecting an ideal
sedative include the etiology of the distress, expected
duration of therapy & potential interaction with other drugs
[9].
Etiology of the distress
The appropriate sedative to be used is determined by the
underlying cause of distress. Thus, for distress due to
anxiety, benzodiazepines are optimal. For distress due to
dyspnoea or pain, opoids are the agents of choice whereas
for distress due to delirium, neuroleptics (Haloperidol) are
preferred. Combination therapy is appropriate for patients
with more than one cause of distress; has an example, a
benzodiazepine & an opoid is appropriate for a patient
whose agitation is due to anxiety & pain.
Duration of therapy
Drugs with a shorter duration of effect (midazolam,
propofol) should be used if a brief duration of sedation (<
24 hours) is anticipated or if patient needs to be frequently
awakened for neurological evaluation. In contrast, drugs
with a longer duration of action (eg. Lorazepam) are
preferred if a longer duration of sedation (>48 hrs) is
expected [10]. Pharmacokinetic modifying variables (e.g.,
age, body weight, renal & hepatic function) and the desired
depth of sedation should be considered whenever a sedative
analgesic agent is selected. Abnormal pharma-cokinetic
modifying variables can magnify differences among the
sedative agents (eg; onset, peak, duration of sedation)
especially during deep sedation.
Initial loading dose
The initial dose of a sedative should account for the
desired level of sedation as well as factors that may affect
drug metabolism (i.e patient age, body weight, renal
function, hepatic function, h/o. alcoholism, drug abuse).
For exact initial doses of various sedatives see Table 2
[11,12].
The advantages & disadvantages of various sedatives
used in ICU are shown below
Fentanyl
Advantages: Potent analgesic sedative with immediate
onset, minimal Venodilation, less hypotension; Hepati-
cally metabolized by Cytochrome P 450 3A4 to inactive
metabolites.
Disadvantages: Highly Lipophilic; tolerance may develop
Table 1 Drugs for sedation in critically ill patients
Analgesics : Fentanyl, Morphine,
Hydromorphone
Remifentanil
Sedative – Hypnotics : Diazepam, Lorazepam,
Midazolam
Benzodiazepines
Anesthetic – Sedatives : Propofol
Alpha -2-Agonists : Dexmedetomidine
Neuroleptics : Haloperidol, Olanzepine,
Quetiapine, Risperidone

4. Review Article
15 Apollo Medicine, Vol. 8, No. 1, March 2011
requiring dose escalation. Withdrawal syndrome upon
abrupt discontinuation; Chest wall rigidity can occur
occasionally.
Morphine
Advantage: No consistent advantage over Fentanyl.
Disadvantage: Hepatically metabolized to active &
inactive metabolites which can accumulate in organ failure;
May precipitate bronchospasm due to histamine release.
Remifentanil
Advantage: Ultra short acting; cleared by nonspecific
plasma esterases. No accumulation in renal or hepatic
insufficiency.
Disadvantage : Pain & discomfort upon abrupt cessation.
Midazolam
Advantage: Potent amnestic & anxiolytic agent with
immediate onset of action & short duration of effect when
administered for short term (<48 hrs). Only IV
benzodiazepine not delivered in propylene glycol.
Disadvantage : Metabolized to active metabolites that may
accumulate & cause prolonged sedation if administered
long term. Drug interaction with multiple ICU drugs & one
must be aware about these drug interactions.
Lorazepam
Advantage: Sedative, annestic, potent anxiolysis with anti
convulsant properties. Hepatically metabolized. Low risk
of drug interactions; safe in mild to moderate hepatic &
renal insufficiency.
Disadvantage: Relatively slow onset of action; Risk of
over sedation when titrating due to delayed response
& accumulation in peripheral tissues; IV incompatibilities
& risk of line precipitate; Propylene glycol solvent
may accumulate with high dosing & cause metabolic
acidosis.
Table 2 Drugs for various sedatives & their initial doses
Drug Loading Maintenance Onset Duration of
dose dose (Min.) action
Fentanyl 1-2 microgram/kg 0.7-10 microgram/ <0.5 30-60 mins
(50-200 micrograms) kg/hr infusion
Morphine 0.05-0.2 mg/kg 0.1-0.5 mg/ 5-10 mins 240 mins
Sulphate (2-10 mgm) kg/hr infusion
Remifentanil None 0.6-15 micrograms/ 1-3 min 5-10 mins
kg/hr infusion
Midazolam 0.02-0.08 mg/kg 1-2 mg intermittent 1-5 min 30 mins
(1-5 mgs) infusion or 2-8 mg/hr
continuous infusion
Lorazepam 0.02-0.06 mg/kg 0.02-0.06 mg/kg 5-20 mins 360 to 480 mins
(1-4 mgs) every 3-6 hrs
or
0.5010 mg/hr as
continuous infusion
Propofol Loading dose 5-80 micrograms/ < 1 min 3-10 min
not recommended kg/min. Initiate at
5 micrograms/kg/
min & titrate every
10 min. in increments
or 5 micrograms/kg/min
Dexmede- Not 0.2 to 1.4 microgram/ > 5-10 60-120 min
tomidine recommended kg/hr initiate at 0.2
micrograms/kg/hr &
titrate every 30 minutes
Haloperidol 0.03-0.15 0.03-0.15 mg/kg 30-60 min 30-360 min
mg/kg (2-10 mg) every 30 min. to to 6 hrs

5. Apollo Medicine, Vol. 8, No. 1, March 2011 16
Review Article
Maintenance: Once initiation of sedative agent achieves a
calm state, attention should be directed towards monitoring
& avoiding excess sedation.
Monitoring of sedation: Patients should be reassessed
daily to determine whether their agitation & underlying
distress are being adequately managed. To facilitate this
evaluation, various scoring systems have been developed.
Scoring systems: Are used to assess pain, sedation &
delirium. They use multiple criteria to determine the
amount of pain, depth of sedation and severity of delirium.
An important limitation of scoring systems is that reference
standards do not exist [14].
Pain scales: There are unidimensional scales (verbal rating
scale, visual analogue scale, numeric rating scale) & multi
dimensional scales (McGill pain questionnaire, Wisconsin
brief pain questionnaire) to assess a patient’s level of pain.
The unidimensional scales can be quickly & easily applied
in ICU if patient is communicative. Multidimensional
scales are more complex & take longer to administer &
often not appropriate for ICU use.
Sedation scales: There are numerous scoring systems to
assess the depth of sedation. The Riker Sedation-Agitation
scale (SAS), motor activity assessment scale (MASS),
Minnesota sedation assessment tool (MSAT) & Richmond
Agitation-Sedation Scale (RASS) (Table 3) are all valid &
reliable in adults who are mechanically ventilated &
critically ill [15-19]. Alternative scoring systems include
Ramsay Sedation Scale, Comfort Scale, Sheffield Scale &
BizekAgitation Scale [20-22)]. The comfort scale is a valid
& reliable system for children [21].
Delirium scales: Many scales & diagnostic instruments
have been developed to identify & evaluate delirium but
most exclude critically ill patients due to difficulty
communicating with them [10]. However a rapid bedside
instrument that can identify delirium in critically ill patients
is the confusion assessment method for the ICU (CAM-
ICU) [23]. Another validated scoring system used in
Europe is the ICDSC tool (Intensive Care Delirium
Screening Checklist). Both assess patients for acute mental
status changes or fluctuating mental status changes,
inattention, disorganized thinking &/or altered level of
consciousness. The CAMICU can identify new or
persistent delirium, but does not quantify the severity of
delirium.
Limitations of scoring systems: For patients who are
pharmacologically paralyzed, monitoring is challenging
because scoring systems cannot determine level of pain,
depth of sedation or delirious state. Heart rate & blood
pressure have historically been used as indicators of
Propofol
Advantage : Potent sedative hypnotic with immediate
onset & rapid awakening upon discontinuation. Un altered
metabolism in renal or hepatic insufficiency; no major drug
interactions.
Disadvantage : With long term use, no specific advantage
over midazolam regarding the duration of vent weaning;
can cause hypotension, hypertriglyceredemia, propofol
infusion syndrome, which is characterized by refractory
brady-cardia, severe metabolic acidosis cardiovascular
collapse, rhabdomyolysis & renal failure.
Dexmedetomidine
Advantage: Effective sedative, sympatholytic (central,
alpa-2-agonist), moderate anxiolysis & analgesia; no
significant effect on respiratory drive; less likely to cause
delirium than other sedatives.
Disadvantage: Hypotension, bradycardia, Hypertension,
hepatically metabolized by cytochrome P450 -2A6; dose
reduction required in renal & hepatic insufficiency.
Haloperidol
Advantage: Sedative dopamine 2-antagonist; controls
positive symptoms of delirium & ICU psychosis. Minimal
cardio respiratory effects in hemodynamically stable
patients.
Disadvantage: Complex hepatic metabolism by
cytochrone P450-3A4 & 2D6; transformations can cause
dose dependent QT prolongation & hypotension.
Administration: The evidence indicates that continuous
infusion of a sedative prolongs the duration of mechanical
ventilation [13]. As a result, current practice favors
intermittent infusions or daily interruption of continuous
infusions. The Society of Critical Care Medicine’s 2002
clinical practice guidelines for the sustained use of
sedatives & analgesics in critically ill adults endorse the
initial use of intermitted infusion, with the initiation of
continuous infusions with daily interruption in patients who
require intermittent infusions more often than every two
hours [10].
Sedation goal: A goal depth of sedation should be
determined prior to beginning the sedation, since this is the
target to which initial therapy is titrated. The goal depth of
sedation should be frequently reassessed & adjusted as the
patient’s sedation requirement becomes more apparent.As
examples, lighter sedation may be desired when serial
neurological exams are required, while deeper sedation
may be desired during severe hypoxemic respiratory
failure.

6. Review Article
17 Apollo Medicine, Vol. 8, No. 1, March 2011
cardiovascular depression. Co administration with an opoid
analgesc may potentiate respiratory & cardiovascular
depression.
Properties
Potency is determined by its binding affinity for GABA
receptor. Lorazepam has highest binding affinity & greatest
potency. Midazolam has lower binding affinity & lower
potency when compared to Lorazepam [31].
Rapidity of action
Is related to how quickly it crosses the blood brain
barrier. Midazolam is highly lipophilic & readily crosses
the blood brain barrier & therefore rapid onset of action (2-
5 mins.) Lorazepam is less lipophilic & has a slower onset
of action (5-20 minutes).
Duration of effect
Initially both lorazepam & midazolam have a short
duration of effect because there is rapid redistribution from
CNS to peripheral tissue sites. With repeated dosing,
however both accumulate in adipose tissue & this increase
the duration of effect because there is more drug that needs
to be mobilized for elimination. Obese patients may store
more drug than lean patients & are at greater risk for
prolonged effects. Midazolam has a short duration of effect
(2-4 hrs) when it is given short term (<48 hrs) by
intermittent infusion to a patient with intact hepatic
function because it has rapid hepatic clearance & there is
rapid redistribution to peripheral tissue sites. However, if
Table 3 Richmond agitation - sedation scale (RASS)
SCORE TERM DESCRIPTION
+ 4 Combative Overtly combative/violent, immediate danger to ICU staff
+ 3 Very agitated Pulls on or remove tubes/catheters aggressive behaviour towards staff
+ 2 Agitated Frequent nonpurposeful movement. Patient ventilator asynchrony
+ 1 Restless Anxious orApprehensive but movements are not aggressive or vigorous
0 Alter & calm
– 1 Drowsy No fully alert, sustained (>10secs) awakening has eye contact to voice
– 2 Light sedation Briefly awakens (<10 secs) with eye contact to voice
– 3 Moderate sedation Any movement to voice but no eye contact
– 4 Deep sedation No response to voice, any movement to physical Stimulation
– 5 Unrousable No response to voice or physical stimulation
distress in this situation, but these vital signs are neither
sensitive nor specific. I am of the opinion that there are two
reasonable approaches. Firstly, pharmacologically
paralyzed patients can be given higher than usual doses of
both an anxiolytic/amnestic and an analgesic to ensure deep
sedation. Secondly, a newer EEG form of Bispectral index
(BIS) monitoring can be used. Although there are
conflicting data regarding its benefit [24-29], I believe, BIS
monitoring is a reasonable approach to assess depth of
sedation in ICU patients receiving neuromuscular
paralysis. However, BIS monitoring cannot replace the
clinical assessment of sedation in routine management of
ICU patients until further favorable data are available from
the literature.
Since midazolam, lorazepam and dexmedetomidine are
the most commonly used sedatives in ICU, further details
about their mechanism of action & their properties shall be
discussed.
Both Midazolam & Lorazepam can be administered by
either intermittent or continuous infusion & have a
relatively short duration of effect.
Mechanism of action
They blind to specific receptors in the Gamma
aminobutyric acid (GABA) receptor complex which
enhances the binding of this inhibitory neurotransmitter
[30].Anxiolysis is achieved at low doses. Higher doses are
associated with sedation, muscle relaxation, anterograde
amnesia, anti convulsant effects & both respiratory &

7. Apollo Medicine, Vol. 8, No. 1, March 2011 18
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midazolam is administered over a longer duration (> 48 hrs)
it may cause prolonged sedation because it has a large
volume of distribution, binds to peripheral tissues & has an
active metabolite alpha hydroxy midazolam [32]. This
active metabolite is most likely to accumulate in patients
with poor hepatic or renal function or in those patients who
are receiving drugs that inhibit cytochrome CYP 3A4
metabolism (fluconazole, macrolide antibiotics,
amiodarone, & metronidazole).
Lorazepam has a moderate duration of effect (6-8 hrs)
when administered over short term (<48 hrs) by
intermittent infusion.This reflects lorazepam’s low hepatic
clearance, small volume of distribution & absence of active
metabolites [33]. Lorazepam is a good choice for longer
term sedation because of its low risk of drug interactions &
because its metabolism does not form active metabolites
[10]. Tolerance i.e. the need for an increased dose to
achieve the same therapeutic effect with continued
administration, occurs with all benzo diazepines. It may
reflect changes in volume of distribution, binding affinity
&/or occupancy of bendiazepine receptor.
Adverse effects
Respiratory& cardiovascular depression are well
known dose dependent complications of both lorazepam &
midazolam. Delayed awakening occurs in those patients
who are sedated for > than 48 hrs. This is associated with
prolonged mechanical ventilation [34]. Delirium may occur
with both lorazepam & midazolam [35-38]. In an
observational study of 198 mechanically ventilated patients
receiving pharmacologic sedation, lorazepam was
identified as an independent risk factor for delirium [35]. It
appears to be more common among those who receive deep
sedation, elderly ICU patients, & those who have dementia
[36,38]. Delirium is associated with a longer duration of
mechanical ventilation, ICU stay, hospital stay & increased
mortality [37].
Propylene glycol toxicity
Propylene glycol is the carrier (solvent) that is used to
administer intravenous lorazepam or diazepam. Infusion of
either drug may be complicated by propylene glycol
toxicity [39-42], which is characterized by hyper-
osmolality and an anion gap metabolic acidosis which is
often accompanied by kidney injury & can progress to
multi system organ failure if severe [39-42].
Dexmedetomidine is a highly selective centrally acting
alpha-2 agonist with anxiolytic, sedative & mild analgesic
effects. It has no deleterious effects on respiratory drive.
According to FDA, dexmedetomidine is indicated for
initial sedation of mechanically ventilated patients for upto
24 hrs. The rationale for 24 hrs limit is that the longer use
may increase the risk of withdrawal effects (hyper-tension)
although these effects have not been consistently found in
other studies [43,44]. The evidence from literature suggests
that dexmedetomidine decreases the need for alternative
sedatives [45]. It increases days without delirium [46] &
decreases time to extubation [47] when compared to
midazolam.
COMPARISONS
There is insufficient evidence to recommend any
sedation regimen over another since relatively few trials
have directly compared sedative agents. Comparing agents
across trials is invalid because there are differences in the
severity of illness, type of cases, therapeutic goals, duration
of therapy & techniques to assess sedation [48]. The
following direct comparisons are among the few that have
been reported in the recent literature:-
Midazolam Vs Propofol
Several studies have compared midazolam to propofol
with both drugs providing adequate sedation[48-53].
Recovery time was longer for midazolam than propofol
after short term use; however the recovery time was
prolonged for both drugs with long term administration.
Lorazepam Vs Propofol
In an open label study, 132 mechanically ventilated
patients were randomized to receive lorazepam by
intermittent IV bolus or propofol by continuous infusion
[54]. Median days on ventilator were lower in the propofol
group (6 vs 8 days).There was no mortality difference.This
trial has been criticized for its design because it is unclear
whether the results are due to different drugs or different
types of administration (intermittent boluses vs continuous
infusion).
Dexmedetomidine Vs Propofol
A randomized trial assigned 89 post operative patients
with an expected length of intubation of < 24 hours to
receive dexmedetomidine or propofol for sedation [55].
The dexmedetomidine group was less deeply sedated &
had a shorter duration of intubation but also had more
discomfort.
Dexmedetomidine Vs Midazolam
A multicentre trial randomized 375 patients expected to
be mechanically ventilated for more than 24 hrs to receive
midazolam or dexmedetomidine for either 30 days or until
extubation [48]. There was no difference in the amount of
time spent within the goal sedation range, the trials primary

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19 Apollo Medicine, Vol. 8, No. 1, March 2011
end point. The dexmedetomidine group had a significantly
lower prevalence of delirium (54 vs 77%) & shorter
duration until extubation (3.7 vs 5.6 days) although these
came at a cost of more frequent bradycarda (42% vs 19%)
[48].
Dexmedetomidine Vs Lorazepam
In a double blind trial, 106 adults who were being
mechanically ventilated in a medical & surgical ICU were
randomized to receive Dexmedetomidine or lorazepam for
upto 120 hrs [48]. The dexmedetomidine group were less
agitated, & had more days without delirium or coma.
Dexmedetomidine Vs Haloperidol
In an open label trial, 20 medical or surgical ICU
patients with agitation and delirium that prevented
extubation were randomized to receive haloperidol or
dexmedetomidine [56]. Dexmedetomidine shortened the
median time to extubation & decreased the ICU length of
stay.
AVOID EXCESS SEDATION
Sedative agent should not be overused because excess
sedation may prolong duration of mechanical ventilation
[13]. Two strategies have been shown in randomized trials
to reduce duration of mechanical ventilation & reduce
complication related to prolonged ventilation :-
(a) Intermittent infusions [13,57].
(b) daily interruption of continuous infusions [58-60].
INTERMITTENT INFUSIONS
An observational study of 242 patients compared the
duration of mechanical ventilation among patients who
received a continuous infusion to those who received either
intermittent sedative infusion or no sedative [48,57]. The
group that received intermittent infusion or no sedation had
a shorter duration of mechanical ventilation (median of 56
hours) than the group that received a continuous infusion
(median 185 hrs).
DAILY INTERRUPTION OF SEDATION
Refers to discontinuing the continuous sedative
infusion until the patient is awake & is following
instructions or until the patient is uncomfortable or agitated
& deemed to require resumption of sedation. The rationale
for daily interruption of sedation is that it facilitates
assessment of patient’s underlying neurologic status as well
as the patient’s need for ongoing sedation. This practice is
supported by evidence from recent robust clinical trials
mentioned below.
In a trial of 128 patients on mechanical ventilation and
continuous sedative infusion, patients were randomly
assigned to continue conventional management or to
undergo daily spontaneous awakening trials [60]. The
group whose continuous sedative infusion was interrupted
daily had a shorter duration of mechanical ventilation (4.9
Vs 7.3 days) and shorter length of ICU stay (6.4 Vs 9.9
days). Limitations of the trial (which were criticized by
many) include that it was performed in a single centre,
ventilator weaning protocol was not standardized &
spontaneous awakening techniques were monitored closely
by study personnel, which is not practically feasible in most
ICU’s.
A similar trial (ABC trial) randomly assigned 336
patients to a daily spontaneous breathing trial & either a
daily spontaneous awakening trial or conventional sedation
management [61]. The daily spontaneous awakening trial
group had decreased one year mortality (but not 28 day
mortality), increased number of vent free days, decreased
length of ICU & hospital stay. The group also had less
cognitive impairment at three months (ARR: 20%)
although there was no difference at 12 months [62].
While these trials indicate that daily interruption of
continuous sedative infusion are beneficial, the benefit may
be less or absent if a sedation protocol is also being used.
This was illustrated by a 3-centre trial in which 65 patients
were randomly assigned to receive either protocolized
sedation (PS) alone or Ps plus daily interruption of
continuous sedative infusion (DI) [63]. Although the
patients in the PS & DI group received significantly lower
doses of midazolam, than patients in the Ps group, there
were no significant differences in duration of ventilation,
ICU stay, hospital length of stay, mortality rates & organ
dysfunction [63].
Despite the evidence that daily interruption of
continuous sedative infusion is beneficial, may intensivists
have not incorporated this into daily clinical practice in
most of the ICUs [64,65]. Concerns related to patient safety
remain a significant obstacle to routine implementation
[66,67]. These concerns include the possibility of long-
term psychological sequelae (post traumatic stress
disorder) [68] & myocardial ischemia [69]. There is little
evidence to support these concerns as demonstrated by
various trials [70].
WITHDRAWAL
When pharmacologic sedation is no longer necessary,
the sequence & rate of discontinuing the sedation must be
determined: For patients receiving more than one sedative
analgesic medication (e.g. a benzodiazepine & an opioid),
the opioid should be tapered last so that the patient doses

9. Apollo Medicine, Vol. 8, No. 1, March 2011 20
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not wake up in pain. The rate of reduction should be
individualized. Abrupt discontinuation is acceptable if
sedation has been given for a short duration (less than 48
hrs), but a gradual reduction over several days is required if
sedation has been given for a longer duration (> than 7
days).
During the reduction of sedative dose, patient should be
closely observed for withdrawal symptoms. Acute
withdrawal symptoms are common. In an observational
study of 28 mechanically ventilated patients in ICU for
more than one week, nine patients (32%) developed acute
withdrawal symptoms when their sedative was reduced
[71]. Higher doses of benzodiazepines & opiates are more
commonly associated with acute withdrawal symptoms.
Benzodiazepine withdrawal symptoms include agi-
tation, confusion, anxiety, tremors, tachycardia, hyper-
tension & fever. Administration of intermittent intra-
venous or oral lorazepam (1mg every 6-12 hrs) often helps
to protect patients from developing withdrawal symptoms
as the continuous benzodiazepine infusion is reduced.
Opiate withdrawal symptoms include agitation, anxiety,
confusion, rhinorrhoea, lacrimation, mydriasis, stomach
cramps, diarrhoea, tremor, nausea, vomiting, tachycardia,
hypertension & fever. Several strategies have been
proposed to prevent opioid withdrawal, including de-
escalation of dose, addition of alpha -2-agonist (clonidine,
dexmedetomidine) converting to a long acting barbiturate
[72]. However, there is no consensus as to the best available
strategy.
SUMMARY
• Distress in critically ill patients is common in the ICU
setting, particularly amongst those who are intubated
or who have difficulty communicating with their care
givers.
• Before a sedation is initiated to treat agitation due to
distress, the underlying cause of distress should be
identified & treated appropriately. Non pharma-
cological strategies should be implemented
simultaneously.
• Pharmacological sedation is necessarily indicated
when treatment of the cause of distress & non-
pharmacological interventions cannot sufficiently
control the agitation.
• Sedative agent & its initial dose are selected on the
basis of several factors: the etiology of the distress,
expected duration of sedation, potential drug
interations, desired depth of sedation and
pharmacokinetic modifying variables.
• There is a strong recommendation from current
guidelines to prefer intermittent infusions or daily
interruption of continuous infusions (Grade 1B
Recommendation)
• All patients should be frequently reassessed to
determine whether their underlying distress and
agitation are being adequately managed scoring
systems should be routinely used to assess the degree
of pain, level of sedation & state of delirium.
• Once the decision has been made to begin reducing
sedation, the rate of reduction must be individua-
lized; for those patients on more than one sedative
analgesic combination it is prudent to taper the opioid
last so that the patient dose not wake up in pain.
During the reduction of sedation, special attention
should be paid for withdrawal symptoms.
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