Cloni e Dex

Journal of Intensive
Care Medicine
http://jic.sagepub.com/
Dexmedetomidine and Clonidine: From Second-to-First-Line Sedative Agents in the Critical Care
Setting?
C. Pichot, M. Ghignone and L. Quintin
J Intensive Care Med published online 27 April 2011
DOI: 10.1177/0885066610396815
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Dexmedetomidine and Clonidine: From

Second- to First-Line Sedative Agents
in the Critical Care Setting?
Journal of Intensive Care Medicine

000(00) 1-19
The Author(s) 2011
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0885066610396815
http://jicm.sagepub.com
C. Pichot, MD1, M. Ghignone, MD, FRCPC2, and L. Quintin, MD, PhD3
Abstract
In the critical care setting, a-2 agonists present a multifaceted profile: sedation combined with arousability, suppression of delirium,
preservation of respiratory drive, reduced O2 consumption, preserved renal function, and reduced protein metabolism. In
addition, this review details the reduced arterial impedance, improved left ventricular performance, preserved vascular reactivity
to exogenous amines, preserved cardiac baroreflex reactivity, preserved vasomotor baroreflex activity combined with a lowered
pressure set point: these features may explain the good tolerance observed when a-2 agonists are used as continuous infusion
without any loading dose. Reviewing the literature allows one to suggest that a new management appears possible with arousable
sedation. However, it remains to be demonstrated whether this arousable sedation can be combined with the preservation of
spontaneous ventilation, in the setting of severe respiratory distress, as opposed to conventional controlled mechanical ventilation
combined with conventional sedation. Should such a speculative view be confirmed, then a-2 agonists will move from second-line sedative agents to first-line sedative agents. However, key studies are lacking to demonstrate the effect of a-2 agonists on physiological
endpoints and outcome. Presently, the existing body of data suggests a niche for the use of a-2 agonists in the critical care setting.
Keywords
clonidine, dexmedetomidine, critical care medicine, intensive care medicine, sedation, respiratory drive, weaning, O2
consumption, systolic function, vascular reactivity
Introduction
Continuous sedation in the critical care unit (CCU) presents several drawbacks.1 Thus, daily interruption of sedation and new
ventilation techniques reduce the duration of mechanical ventilation and CCU stay.2 Currently, the goals of sedation include
patient comfort and the ability to tolerate the tracheal tube and
cooperate with the staff. Alpha-2 agonists come in at a juncture,
where the new objectives of CCU care include synchronization
of the ventilator to the patient, maintenance of the functioning of
the neuromuscular/ventilatory system early upon ventilatory
support, and minimizing circulatory side effects while balancing
the patients comfort and cognitive abilities.
This review focuses on the following: (a) the recent evolution toward the use of a-2 agonists as first-line sedative agents,
and (b) their unique ventilatory, circulatory, and metabolic profiles, in addition to their sedative properties. This review is
based on PubMed searches with the following key words: clonidine, dexmedetomidine, sedation, critical care medicine,
intensive care medicine, ventilation, circulation, hemodynamics, and head injury. The articles were considered for their
double-blind, randomized prospective design. Unfortunately,
such articles are few: this literature reflects a succession of
serendipitous findings and the absence of any thoroughly
thought-out pharmacological development. Thus, this patchy literature makes the use of case reports and open studies a necessity
when indications, routes, and dosages are considered. Given the
absence of key physiological and epidemiological studies, this
review is not a comprehensive review but is instead an overview
of the existing data, and inferences are strictly separated from the
data. Some data pertaining to the basic science or the anesthesia
settings are included where relevant. Our institutional protocol for
the use of a-2 agonists is included as a supplement.
Effects on the Central Nervous System and

CCU Applications
The pharmacodynamic profiles of clonidine and dexmedetomidine are almost identical. Sedation, analgesia, and hypotension
1
Critical Care Unit, Memorial Hospital, St Lo, France

Critical Care Unit, Columbia Hospital, WPalm Beach, FL, USA
3
Physiology (CNRS UMR 5123), University of Lyon, Lyon, France
2
Corresponding Author:
L. Quintin, Physiology (CNRS UMR 5123), 8 Rue R Dubois, 69 622 LyonVilleurbanne cx, France
Email: quintin@univ-lyon1.fr
Journal of Intensive Care Medicine 000(00)
are mediated via a-2A receptors.3 Dexmedetomidine is more

selective for a-2A receptors (clonidine: 200:1; dexmedetomidine, 1600:1). This selectivity is relative: both drugs evoke
hypertension upon bolus injections, presumably via postsynaptic a-1 receptors (see below) or postsynaptic a-2 receptors.4
Dexmedetomidine produces a larger cardiac parasympathetic
activation (ie, bradycardia), which is of little concern in the
CCU as long as no loading dose is used. Given a nonloading
dose regimen,5-7 a head-to-head comparison is needed to assess
whether a short-acting drug (dexmedetomidine) will minimize
untoward side effects. Conversely, a longer-acting drug (clonidine) may be appropriate in the setting of a CCU stay lasting
days or weeks.
locus coeruleus
Sedation
nucleus ambiguus
rostral ventrolateral medulla

IML
Active bradycardia
PNS heart
SNS
Passive vasodilatation
Passive bradycardia
Sedation
Mechanism. In animals, a-2 agonists are believed to act
through a-2 adrenoceptors, which are located on noradrenergic
(NA) locus coeruleus (LC) cell bodies or dendrites, to inhibit
the release of NA through a negative feedback mechanism
(presynaptic receptors also called autoreceptors)8-10 (Figures 1 and 2). However, functional inactivation of NA terminals
by a neurotoxin (DSP4) or depletion of catecholamine stores
(a-methylparatyrosine, reserpine) do not modify the reduction
in the minimum alveolar concentration (MAC) of halothane that
is evoked by dexmedetomidine.17 Thus, the sedative effect of a-2
agonists may be independent of its action on NA cortical postsynaptic terminals or on NA pontine presynaptic cells bodies.
The arousable sedation observed in the CCU may be accounted
for a low-baseline (tonic) activity and intact (phasic) reactivity of LC neurons, following administration of clonidine15
(Figure 3). In humans, circulatory effects of a-2 agonists are independent of any sedative effect: when a benzodiazepine, nitrazepam, induces more sedation than clonidine, no circulatory
effect is observed.18
Clonidine was synthesized in 1962 as a nasal vasoconstrictor
and the discovery of its sedative and hypotensive effects was serendipitous.19 During the 70s, cardiologists used clonidine as an
antihypertensive, most often at bedtime because of its sedative
effects. This prescription schema blunts the morning increase
in blood pressure.20 Doses ranged from 150 to 1200 mg per oral
(po) in combination with other drugs or up to 3600 mg po when
used as a single antihypertensive agent.21 The drowsiness
recedes in 70% of the patients after 3 or 4 weeks of administration21 with no major evidence of sleep-wake cycle disruption.
Similarly, chronic high doses of clonidine (5400 and 6000 mg/
day po) were not associated with sedation.22 In volunteers,
low-dose clonidine (25 mg) increased rapid-eye-movement
(REM) sleep and decreased non-REM sleep. In contrast,
medium-dose clonidine (150 mg) decreased REM sleep and
increased non-REM sleep.23 Dexmedetomidine induced sedation that closely resembled non-REM sleep in humans.24
In the CCU, clonidine was introduced as an alternative to
chlormethiazol25,26 in the treatment of delirium tremens
(0.45-3 mg/day) or as a supplement (1.4 mg/day) to a
midazolam-fentanyl regimen27 (Table 1).
Figure 1. Impact of a-2 agonists on the noradrenergic dorsal bundle,

catecholaminergic ventral bundle, and cardiac vagal motoneurons:
(a) The a-2 agonists are believed to act through the noradrenergic cell
bodies of the locus coeruleus (LC), a tightly packed nucleus located in
the medial dorsal pons. The sedative effects of a-2 agonists are believed
to be generated through the locus coeruleus (see text). (b) The a-2 agonists inhibit adrenergic presympathetic neurons located in the rostral
ventrolateral medulla (vasomotor center). They do not affect glutamatergic presympathetic neurons: this is in line with the preserved reactivity of the sympathetic system (SNS) following a-2 agonists, despite a
lower set-point.11,12 Adrenergic and glutamatergic presympathetic neurons project onto the intermediolateral cell column (IML), within the
spinal cord, where preganglionic cell bodies are located. Thus, a-2 agonists exert inhibitory effect on the cardiac (slow passive bradycardia)
and vasomotor (slow passive vasodilatation) sympathetic nervous system. (c) Alpha-2 agonists stimulate cardiac vagal motoneurons located
in the nucleus ambiguus external formation (dorsal and medial to the
rostral ventrolateral medulla). They lead to increased cardiac parasympathetic activity (PNS) and increased slope of the cardiac baroreflex,13,14
for example upon brisk increase in pressure (fast active bradycardia).
The combination of increased parasympathetic cardiac baroreflex activity and of inhibited cardiac and vascular sympathetic activity explains the
circulatory properties of a-2 agonists.
Critical care unit delirium. Clonidine suppressed opiate32 and

alcohol25,27 withdrawal. Therefore, its use in the CCU
appears logical; clonidine alone (up to 2.5 mg/day) abated
withdrawal from sedative agents upon weaning from mechanical ventilation.33 Upon tetanus, clonidine (1.2 mg/day then
0.5 mg/day24; or 0.9 mg/day35) supplemented sedation and
magnesium. German intensivists use clonidine liberally as
follows: (a) 35%, 48%, and 56% of the German CCUs use
clonidine for sedation lasting <24, 48, and 72 hours, respectively; (b) clonidine is used during weaning from ventilation
in 62% of German CCUs36; and (c) clonidine is administered
in up to 90% of patients.37 In the late 90s, dexmedetomidine
was introduced as a sedative that was restricted to the
24-hour postoperative period. Following repair of type-A
aortic dissection (in a prospective randomized double-blind
trial, n 15 " 2; clonidine bolus of 0.5 mg/kg followed
by 1-2 mg/kg per hour), the incidence of delirium was similar
between groups but with a lower severity and duration and a
Pichot et al
ketamine
NMDA
++
morphine
diazepam
NA
NA
GABA
clonidine
++
1
chlorpromazine, droperidol
Figure 2. Schematic overview of a noradrenergic (NA) synapse:

presynaptic a-2 autoreceptors located on NA cell bodies, terminals
or dendrites, lead to inhibition of NA cell bodies in the locus coeruleus and inhibition of NA release. The schema holds for sympathetic nerve endings. Thus a-1 postsynaptic receptors are not
excited, either within the synapse or at the vascular level. m-Receptors and GABA receptors inhibit NA cell bodies and NA release: a
synergy exists between opiates, benzodiazepines, and a-2 agonists
to inhibit the NA system. This explains why opiates and benzodiazepines requirements are reduced when a-2 agonists are used as
second-line agents. Conversely, when a-2 agonists are used as firstline agents, opiates or benzodiazepines are to be used at reduced
dosage (#50% to #80%; see text). Glutamatergic projections from the
prepositus hypoglossi (nucleus tractus solitarius) and rostralventrolateral medulla (vasomotor center) activate the locus coeruleus through
NMDA receptors15,16: ketamine acts as an inhibitor on these excitatory
projections. By acting on postsynaptic a-1 receptors, neuroleptics act
synergistically with a-2 agonists. In the CCU, such interaction may be
useful upon delirium tremens or drug withdrawal, when high-dose a2 agonists are used as first-line agents and supplemented with
neuroleptics.
shortened CCU stay in the clonidine group.38 Accordingly,

CCU delirium is reduced by approximately 30% (n 103,
2 centers; lorazepam group: 92% vs dexmedetomidine:
63%; P < .01).7 Agitation was less in the dexmedetomidine
group, in which patients were closer to their Richmond Agitation Sedation Scale target score (P < .04).7 These findings
were replicated in a multicenter trial (n 297).6 Such benefits are also observed when dexmedetomidine is compared
with propofol or midazolam in the postcardiac surgery setting (open randomized study, n 30"3 patients, dexmedetomidine: incidence of delirium: 3%; propofol: 50%;
midazolam: 50%).39
Figure 3. Alpha-2 agonists lead to arousable sedation in the critical

care setting. Middle panel: Upon emergence from halothane anesthesia in paralyzed rats, high phasic activity is observed in the LC. (Contrast a nearly orderly pattern of discharge under anesthesia
comprising primarily tonic activity with little phasic activity [A] and a
pattern under emergence comprising only phasic activity [B]): When
clonidine is administered, the tonic activity is entirely suppressed, but
the phasic activity appears untouched [B] (modified from15). [B])
Lower panel: A glutamergic antagonist, kynurenic acid (Kyn) microinjected in the LC suppresses the phasic reactivity preserved after clonidine administration (modified from15). The prepositus hypoglossi
and paragigantocellularis nucleus project onto the locus coeruleus and
provides phasic, glutamatergic, input to the LC.16Could this histochemical organization16 and pharmacological observations15 observed
in the rat be translated to the sedation observed in the critical care?
under a-2 agonist, when the patient is undisturbed, the patient rests
calmly (no tonic LC activity). By contrast upon stimulus, arousability
is preserved (intact high phasic LC activity).
Reduction in opiates and sedative requirements. Adding a-2

agonists to an existing sedative regimen leads to a large reduction in opiates (50%40 and 75%41) and benzodiazepine requirements (80%40). A rigorous design (60 < Bispectral index
[BIS]<70 upon ventilation; 65 < BIS < 95 upon weaning;
85 < BIS < 95 after extubation) led to a 43% and 73% reduction
of propofol supplementation during ventilation and weaning,
respectively. There was a reduction of 58% in morphine
flunitrazepamclonidine
(n54) vs. chlormethiazolhaloperidol (n50)
vs. flunitrazepamhaloperidol (n55)
30
randomized; clonidine17 vs.

no-clonidine10
total number of patients20
dexmedetomidine15 vs.
placebo15
clonidine
clonidine
clonidine
clonidine then
1
dexmedetomidine
placebo51
clonidine
dexmedetomidine
dexmedetomidine
dexmedetomidine
weaning from
mechanical
ventilation
tetanus
tetanus
tetanus
postoperative
ventilation
and
sedation
postoperative
ventilation
and
sedation
postoperative
ventilation
and
sedation
clonidine
delirium
tremens
delirium
tremens
delirium
tremens
clonidine
clonidine20 vs.
chlormethiazol
haloperidol19
1
clonidine
delirium
tremens
drug
setting
Table 1. Sedative Effects of Alpha-2 Agonists: Overview
thoracic epidural
60-180 mg.h-1*2 days
adjunct : magnesium, morphine,

midazolam up to 70 mg.h-1
adjunct : diazepam 20 mg.h-1; mida- not specified
zolam 30 mg.h-1; morphine 30
mg.h-1; baclofen 75 mg/day,
intermittent vecorunium
clonidine 50 mg.h-1 then dexmedetomidine 0.4

mg.kg-1.h-1
FreshwaterTurner, 2007
Sutton, 1990
Gregorakos,
1997
Liatsi, 2009
Spiess, 1996
Yam,1992
Boher, 1990
Metz, 1980
reference
(continued)
stand-alone vs. placebo; rescue mid- reduction of midazolam (-79%) and Venn, 1999
azolam bolus 0.02 mg.kg-1 then
morphine (-48%); lower respira0.01-0.2 mg.kg-1.h-1 if needed to
tory rate (mean : 14 vs. 21 breaths
Ramsay>2
per min); higher SaO2 (98 vs 96 %)
2.5 mg.kg-1.h-1
0.2-2.5 mg.kg-1.h-1 to Ramsay>2 stand-alone vs propofol 1-3 mg.kg- reduction of alfentanil (-68%);
Venn, 2001
1.h-1, alfentanil 0.25-1.0 mg.kgincreased PaO2/FiO2; increased
1.min-1 to Ramsay>2; no rescue
urine output
medication
6.0 mg.kg-1.h-1*10 min 0.1-0.7 mg.kg-1.h-1 to
stand-alone vs. placebo; rescue pro- reduced propofol (-35%) and
Triltsch, 2002
60<BIS<70 during mechanical
pofol 0.2 mg.kg-1 then 0.5-4
morphine (-63% before extubation;
ventilation, 65<BIS<95 during
mg.kg-1.h-1 to BIS
-100% after extubation) requireweaning, 85<BIS<95 after
ments; difference in norepinephrextubation
ine/dopamine requirements: ns
non-clonidine group : 5 out 10

patients died; clonidine group : 2
out of 17 patients died (p0.04).
recovery
900 mg/day
6 mg/kg/day
stand-alone following previous

weaning from remifentanil
prpofol or fentanylmidazolam
adjunct : diazepam 50 mg/day
increased incidence of pneumonia

and increased duration of
mechanical
ventilation in the chlormethiazolhaloperidol group
positive effect in 25 out of
30 patients
recovery
recovery
reduced duration of
delirium and CCU stay
effect
1.8-2.5 mg/day
up to 1.2 mg until sympathetic

hyperactivity was blocked
associated with fentanyl-midazolam
stand-alone vs. chlormethiazol/

haloperidol
adjunct vs. stand-alone
1.44 mg/70 kg/day
0.45-3.16 mg (mean : 1.11)
maintenance dose
1 mg.kg-1 over 10 min 0.2-0.7 mg.kg-1.h-1 up to

Ramsay>2 whilst intubated
0.9 mg/5 min
0.15-1.2 mg
loading dose
lorazepam51
midazolam122
dexmedetomidine
dexmedetomidine
long-term
ventilation
(up to 120
h)
long-term
ventilation
n20
dexmedetomidine
standard of care41
12
dexmedetomidine
dexmedetomidine
38; spontaneous
ventilation33 vs.
mechanical ventilation5
dexmedetomidine
long-term
ventilation
saline191
dexmedetomidine
postoperative
ventilation
and
sedation
postoperative
ventilation
and sedation in
children
long-term
ventilation
in medical
CCU
long-term
ventilation
drug
setting
Table 1 (continued)
maintenance dose
adjunct vs. stand-alone
up to 1 mg.kg-1 to 8% 0.8 mg.kg-1.h-1 to Richmond

of the
scale -2 to 1
patients
0.15-1.5 mg.kg-1.h-1
0.25-1.4 mg.kg-1.h-1
0.8 mg.kg-1.h-1*1h
no loading dose
0.2-0.7 mg.kg-1.h-1 to
2<Ramsay<4
no loading dose
reference
reduction in propofol (-87 %)

Martin, 2003
requirements; increased calmness,
tolerance to endotracheal tube,
ease to communicate
absence of respiratory depression
Chrysostomou,
2006
effect
ceiling effect for sedation>1.5 mg.kg- Venn, 2003

1.h-1; reduced adrenaline
requirements; reduced creatinine
(p0.03)
stand-alone; rescue midazolam 1 mg median duration of artificial airway: Shehabi, 2004
or morphine 2 mg/fentanyl 20 mg
7.7 days; 4 out 5 patients present a
reduction in noradrenaline
requirements
dexmedetomidinepropofol vs.
duration of mechanical ventilation
Ruokonen, 2009
placeboplacebo; rescue
shorter (p0.025); dexmedetopropofol 2.4 mg.kg-1.h-1*1h then
midine patients more arousable,
0.8-4.0 mg.kg-1.h-1; rescue
cooperative and better able to
midazolam 1-2 mg up to 3/h then
communicate
0.04-0.20 mg.kg-1.h-1; objective
Richmond scale -3 to -4
stand alone vs. lorazepam
more days without delirium or coma Pandharipande,
1-10 mg.h-1 to Richmond scale -3;
in dexmedetomidine patients (7 vs
2007
rescue fentanyl or propofol
3 days;p0.01); improved shortterm and long-term survival (ns)
stand-alone vs. midazolam 0.06
lower incidence of delirium; shorter Riker, 2009
mg.kg-1.h-1; rescue midazolam
duration of endotracheal intubaand fentanyl
tion (3.7 vs 5.6 days, p0.1);
lower incidence of hospitalacquired infections (overall :
p0.02; urinary : p0.02;
pulmonary: p0.07)
0.2-2.5 mg.kg-1.h-1 up to 7 days rescue propofol 0.2 mg.kg-1 then

for Ramsay>2
0.5-4 mg.kg-1.h-1
1 mg.kg-1*10 min
rescue agents : midazolam, lorazepam, fentanyl, etc . . . .
0.1-0.75 mg.kg-1.h-1
no loading dose
1 mg.kg-1 over 10 min 0.2-0.7mg.kg-1.h-1 to Ramsay>3 stand-alone vs. saline; rescue

before extubation, Ramsay>2
propofol 0.2 mg.kg-1 then
after extubation
0.5-4.0 mg.kg-1.h-1
loading dose
requirements,28 which appeared more prominent following

extubation.42 A double-blind, randomized, prospective, multicenter study confirmed these findings in the surgical CCU
(n 401 patients).29 Similar findings were reported in the
pediatric surgical CCU.43
Arousable sedation. With a-2 agonists as stand-alone sedative
agents, the patient lies calmly in bed despite the surrounding
stimuli (noise, tracheal tube, ventilator, etc) but is easily aroused
to full consciousness with the ability to communicate and follow
commands. Following the end of stimulation, the patient returns
to his original indifference to the environment (ataraxia). A large
study (n 79) showed that dexmedetomidine-treated patients
were more arousable, cooperative, and better able to communicate their pain than patients under propofol/midazolam.31
Nurses judged the patients treated with dexmedetomidine as
easier to manage and communicate with.29
Alpha-2 agonists are used either as second-line agents
only31 or as first-line agents.6,7 Two issues are relevant. First,
patients in need of moderate sedation may benefit from a-2
agonists as stand-alone sedative agents. This fits with a daily
assessment of the patient and daily trial of spontaneous breathing. In contrast, patients in need of deep sedation close to
general anesthesia (eg, ARDS-affected patients in the prone
position) may need conventional agents. In this respect, a-2
agonists may also be judiciously supplemented with drugs on
a case-by-case basis to achieve deep sedation and spontaneous
breathing (eg, +hydroxyzine + loxapine + ketamine . . . vs
+ propofol + midazolam + opioid analgesics . . . ). Depending on the dose of clonidine (0.2-2 mg/kg per hour,44 ie, 400 mg3.5 mg/70 kg per day), sedation may be deep (eg, upon
mechanical ventilation and hemodialysis, 3 % Ramsay % 4 or
deeper) or light (eg, upon weaning, after extubation or upon
noninvasive ventilation, 2 % Ramsay % 3). Dexmedetomidine
produced sedation with minimal midazolam in 80% of the
patients5 and, when used alone (up to 2.5 mg/kg per hour, ie,
4.2 mg/70 kg per day), allowed adequate sedation in most
patients in the medical CCU setting. A ceiling effect was
observed above 1.5 mg/kg per hour.45 Second, (a) the drowsiness evoked by clonidine recedes in 70% of the patients after
3 weeks of antihypertensive therapy in the cardiology setting.21
Accordingly, an escape phenomenon occurs after days or
weeks of clonidine sedation (Pichot-Quintin, unpublished
data). (b) Agitation and self-extubation are possible when transitioning from existing sedative regimen to dexmedetomidine.46 However, it should be noted that the patient may
demonstrate spontaneous movements or willingness to communicate under a-2 agonists that are used as first-line
agents.
Amnesia. Clonidine can be used in attention deficit/hyperactivity disorder,47 Tourettes syndrome,48 schizophrenia,49 and
Korsakoff syndrome.50 In keeping with these observations with
clonidine, cognitive function appeared better preserved in
patients
treated
with
dexmedetomidine
(ns).7
Dexmedetomidine-treated patients presented with a higher
incidence of amnesia of their CCU stay,29 but a dose-response

curve is lacking. By contrast, patients treated with dexmedetomidine, but not those treated with propofol, recalled the length of
their CCU stay accurately. Discomfort on the ventilator was a
concern, as opposed to the observation performed in propofoltreated patients.41
Inference. Intensivists are transitioning from the use of a-2
agonists as second-line agents (eg, upon weaning36) to their use
as first-line agents6,7 that are selected as soon as the patients need
noninvasive ventilation51 or invasive ventilation. Little is known
about the use of a-2 agonists alone compared with the various
combinations of other sedative agents used in the CCU.39
Sedation in the Setting of Head Injury

Alpha-2 agonists act as sedative agents in the setting of head
injury. In addition, they act also as sympatholytics, upon rapid
increases in intracranial pressure (ICP) and blood pressure. In
patients with head injury, clonidine (2.5 mg/kg intravenous
[IV] over 10 minutes) leads to a stable carotid blood flow and
arteriojugular O2 difference, despite mild hypotension.52
Accordingly, clonidine (150-450 mg/day through nasogastric
tube) was used in patients with head injury without depression
of consciousness level.53 No overall change in ICP was
observed in patients with head injury receiving clonidine (2.5
mg/kg IV over 10 minutes) when aggregated data are considered. However, an increase in ICP and in arteriojugular O2 difference was reported in 3 out of 12 patients.54 By contrast, the
following was observed in patients with head injury or neurosurgical patients: (a) ICP was slightly lowered, but cerebral
perfusion pressure was slightly increased following dexmedetomidine; and (b) hypotension resulted in patients with head
injury following a loading dose of the a-2 agonist.55 Thus, an
IV loading dose should be avoided in head-injury patients, and
cerebral perfusion pressure must be maintained.
In patients with head injury, the Lund concept is applied
to reduce ICP, prevent the breakdown of the blood-brain barrier, and decrease vasogenic edema56 in patients with lownormal cerebral perfusion pressure (60-70 mm Hg). Therapy
consists of low-dose thiopentone, dihydroergotamine, a bblocker (metoprolol), and clonidine (1.5-8 mg/kg per day, ie,
ca 110-560 mg/70 kg per day). In a retrospective study, this
approach improved outcome (deaths: 47% vs 8%; good recovery: 42% vs 72% in the historical [n 38] vs the Lund concept
[n 53] groups, respectively).57 A retrospective study from
another Swedish group58 confirmed the Lund findings. However, no randomized prospective trials in a large sample of
patients have substantiated these findings.59 Thus, the Lund
concept cannot be viewed as a standard therapy.
Analgesia
In animals, clonidine has antinociceptive activity60 and is 5 to
10 times more potent than morphine at identical doses.61
Analgesia appears primarily linked to a supraspinal site of
Pichot et al
action.62 In conscious healthy volunteers, although

medetomidine did not change heat, dental, or tourniquetinduced pain, it attenuated the unpleasantness produced by
ischemia. Thus, medetomidine lowered the affectivemotivational component (analgognosia) with little influence on
sensory intensity itself.63 In humans, (a) clonidine reduced the
amount of intraoperative opiates by 45% to 75% with improved
beat-by-beat variability in blood pressure;64-66 (b) combined with
proprofol, epidural clonidine, in a dose-dependent manner,
allowed the performance of intraabdominal surgery.67 Similar
observations were reported with dexmedetomidine at high doses
(5-10 mg/kg per hour IV) without opiates.68 High-dose dexmedetomidine (1.4 mg/kg over 10 minutes, followed by 0.7 mg/kg per
hour69; 10 mg/kg per hour followed by 1 mg/kg per hour with sevoflurane 1%70) induced anesthesia without opiates in morbidly
obese patients. Alpha-2 agonists may not be used as the sole agent
in the CCU when pain is anticipated because medical patients
need a little supplementation (5 mg of morphine/day); by contrast, trauma/surgical or dialyzed patients need larger doses (23
or 63 mg/day, respectively).5
Inference. The core effect of a-2 agonists is to modify the
perception of pain and promote ataraxia. Thus, given an a-2
sedation regimen, 2 alternatives are available if pain is a documented issue: (a) selection of nonopiate analgesics to allow for
spontaneous ventilation (eg, pressure support ventilation)
because of the preserved ventilatory drive (see below) or (b)
initial usage of an approximately 80% reduced opiate dose, followed by titration of the opiates to the desired analgesic effect.
Effect on Ventilation and CCU Applications

Mechanism
In vitro studies on the neonate mouse brain stem revealed that
clonidine increases the respiratory frequency and counteracts
the depression caused by midazolam.71 In halothaneanesthetized rats, (a) clonidine induced a transient 15% to
20% decrease in respiratory rate72 with an increase in tidal volume73 (b) dexmedetomidine did not potentiate the respiratory
depression induced by alfentanil.74 In healthy volunteers, clonidine (300-400 mg po) alone did not depress the slope of the
ventilatory response to CO2 rebreathing or the slope of the
occlusion pressure to CO2. Further, clonidine did not worsen
the respiratory depression induced by morphine (210 mg/kg
intramuscular [IM])75; at a dose of 3 mg/kg IV, it changed neither the minute volume nor the end-tidal CO2 but lowered the
response to CO2 rebreathing,76 mimicking the effect of slowwave sleep. Finally, following clonidine, O2 consumption
(VO2) is reduced in healthy volunteers (#12%) at rest77 and
upon shivering in the postsurgical setting.78
Following upper airway surgery in patients with sleep
apnea, the minimal O2 saturation was higher following clonidine (2 mg/kg po).79 When dexmedetomidine was used as a
total intravenous anesthetic agent, O2 supplementation was
not necessary in some instances.68
Noninvasive Ventilation and Weaning

Clonidine (1-5 mg/kg tid, route unspecified) allowed the adaptation of young children to noninvasive ventilation.80 Clonidine
improved ventilatory parameters (frequency/tidal volume,
PaO2/FIO2, duration of weaning, CCU stay, and severity of delirium) in patients presenting with delirium and recovering from
type-A aortic dissection.38 Following unsuccessful weaning, clonidine (0.9-1.8 mg over ca 20 minutes) reduced VO2 by 45%.33
The respiratory rate was lowered from 22 to 14 breaths/min.33
Accordingly, dexmedetomidine (3 mg/kg per hour over 5 minutes
then 0.2-0.7 mg/kg per hour) administered to patients presenting
with agitation under noninvasive ventilation allowed weaning
of noninvasive ventilation without agitation, reduced respiratory
rate from 29 to 22 breaths/min (n 10), and improved PaO2/
FIO2 and PaCO2.51 In a medical/surgical CCU setting, dexmedetomidine sedated patients for an extended period of time,
following extubation (26 hours postextubation).5
Dexmedetomidine had the following effects in the postsurgical setting: lowered respiratory rates (placebo: 21 breaths/
min vs dexmedetomidine: 14 breaths/min) and increased O2
saturation40 after general surgery with routine ventilation;
reduced morphine requirements (#63%) and improved PaO2/
FIO2 when titrated to Ramsay & 3 before extubation (0.4 mg/
kg per hour) and Ramsay & 2 after extubation (0.17 mg/kg per
hour), as shown by retrospective42 and prospective analysis (n
10 " 2);41 reduced the duration of mechanical ventilation
(dexmedetomidine: 77 hours; propofol/midazolam: 110 hours;
n 79; P .025)31; lowered the incidence of atelectasis (n
401 patients, P .01)29; and increased the PaO2/FIO2 ratio
before and after extubation in the surgical CCU setting.42
Finally, a multicenter trial (n 297) that compared highdose dexmedetomidine (up to 1.4 mg/kg per hour) to midazolam reported a reduced duration of intubation (#1.9 day),
although CCU stay was not shortened.6 In the pediatric cardiac
surgical setting, dexmedetomidine was used in spontaneously
breathing children in the immediate postoperative period without any ventilatory side effects.30
Bronchodilatation
Outside the critical care setting, inhaled clonidine (75 mg)
allows an improvement in forced expiratory volume (FEV1)
and peak expiratory flow rate in asthmatic patients.81 These
beneficial effects were not observed when clonidine was administered orally.82 In dogs, IV dexmedetomidine caused minor
bronchodilatation and blocked the histamine-induced bronchoconstriction, but inhaled dexmedetomidine did not.83 In a 4year-old agitated child in whom inhalational therapy was
impossible, dexmedetomidine allowed one to deal with status
asthmaticus.84
Inference
Easy weaning may be a consequence of the following: (a)
arousable sedation, which allows frequent assessment of the
patient; (b) the absence of depression of the ventilatory drive
in vitro71 as well as a large reduction in the requirements for

sedative agents and opiates, which further preserves the
respiratory drive; (c) the reduction in emergence delirium following mechanical ventilation under conventional sedation85;
and (d) the reduction in O2 consumption77,78 upon weaning.33
Thus, a-2 agonists allow sedation to be maintained throughout
mechanical ventilation from intubation6 to weaning and noninvasive ventilation. Sedation under spontaneous ventilation is
suitable to the current requirement for daily spontaneous
breathing trials as the standard of care, supports the trend
toward the synchronization of the ventilator to the patient, and
promotes the maintenance of full functionality of the
respiratory-muscular system from intubation to extubation.
However, the use of a-2 agonists remains speculative if initiated from the start of respiratory assistance (eg, for ARDS),
to reduce shivering or VO2 consumption in the setting of ARDS
or intentional hypothermia (eg, in the neuro-CCU).
Effects on Circulation and Side Effects

Mechanism
In animals, cardiac parasympathetic activation by clonidine is
enhanced after depletion of catecholamines by reserpine-amethyparatyrosine.86 Sympathetic nerve activity is inhibited
by clonidine, even after reserpine-a-methylparatyrosine treatment.87 Thus, a-2 agonists may present circulatory effects
entirely independent of adrenergic mechanisms. Despite these
facts, a-2 agonists are believed to act through a-2 adrenoceptors
located on adrenergic cell bodies (autoreceptors) of presympathetic neurons in the vasomotor center11,88 (Figure 1). In vivo
electrophysiological data89 contradict pharmacological data,
which favor an action through imidazole receptors.90 The reactivity of the sympathetic vasomotor reflex persisted after hypotension.11,12,91 In dogs, following severe coronary stenosis, (a)
clonidine (10 mg/kg IV) suppressed the increased poststenotic
coronary resistance and myocardial lactate consumption92; (b)
dexmedetomidine increased the endocardial/epicardial bloodflow ratio, despite a reduction in myocardial blood flow.93
Alpha-2 agonists are known to blunt tachycardia and hypertension, and to reduce plasma catecholamine concentration.
Thus, the delineation of the clinical applicability of these properties is not needed. By contrast, safety issues are key: inotropism, vascular reactivity, and circulatory side effects.
Inotropism
In in vitro rat studies, an unchanged ejection fraction is
observed, compatible with an absence of intrinsic negative inotropism. The in vivo observations may be the end result of an
afterload reduction combined with a reduced inotropic state;
the reduced inotropism is secondary to the reduced cardiac
sympathetic drive to the heart.94 in vivo studies on the patients
with chronic heart failure (CHF) following clonidine (150 mg
bolus) showed reduced left-filling pressure, bradycardia, and
increased stroke volume and cardiac output.95 These observations were repeated as follows: (a) after clonidine 400 mg
po96 or 300 mg/day for 1 week97 or another a-2 agonist, guanabenz (8-12 mg),98 NYHA III to IV patients showed lowered
pulmonary capillary wedge pressure, bradycardia, increased
stroke index, and constant cardiac output. However, systemic
hypotension (BP < 90 mm Hg) was observed in 3 patients96;
and (b) upon arrival in the CCU, clonidine-treated patients who
were recovering from coronary bypass surgery presented with
higher mixed venous saturation.99 More intriguingly, a greater
improvement in sicker patients was observed.97 These latter
observations were repeated as follows: (a) Despite lower exercise capacity before randomization, improvement in the exercise capacity was larger in the clonidine-treated patients100;
and (b) upon acute myocardial infarction associated with
hypertension and high capillary wedge pressure, clonidine
(5 mg/kg IV over 5 minutes) led to minimal bradycardia,
lowered the wedge and systemic pressure while maintaining
cardiac output. The improved left ventricle (LV) function was
more prominent in the patients with higher wedge pressures.101 In patients with hypertension, clonidine (150 mg
bolus) led to intriguing observations: high cardiac output was
converted into normal cardiac output (7.2-4.9 L/min). By
contrast, low cardiac output was converted to normal cardiac
output (2.6-4.2 L/min). An 11% increase in stroke volume
was observed when the HR was lowered more than the cardiac output.102 In patients with hypertension who presented
with a diastolic pressure of >130 mm Hg, clonidine (5 mg/
kg IV over 20-36 minutes) increased stroke volume and ejection fraction from 59% to 71%.102
Vascular Reactivity
In vitro, clonidine inhibits the activation evoked by isoproterenol. By contrast, clonidine led to a 50% to 60% increase in
isoproterenol-evoked activation. The sensitivity of the b-adrenergic receptor appeared to increase, following clonidine.103 In
healthy volunteers, clonidine (2 mg/kg over 10 minutes) evoked
an increase in the density of b-adrenoceptors on lymphocytes,
with a decrease in affinity. A possible externalization of badrenoceptors following lowered plasma catecholamine concentration was hypothesized. This was not observed in vitro.104
In patients with CHF, clonidine (150 mg IV bolus) lowered the
pressure in the isolated vein segment but increased the pressor
response of the isolated vein segment upon deep breathing.105
In supine hypertensive patients, clonidine (200-400 mg/day)
increased vascular reactivity: the dose of phenylephrine necessary to increase the pressure by 25 mm Hg (PE25) was reduced
from 96 to 39 mg. The chronotropic response to isoproterenol
(increase in HR by 20 beats per minute: CD20) was
increased.106 This upregulation of a-1 and b-receptors agrees
with the increased response to noradrenaline observed after
methyldopa administration in patients with hypertension .107
Upon recovery from major surgery and aortic surgery, respectively, the response to phenylephrine108 and isoproterenol was
increased.109 Following liver transplant, intraoperative noradrenaline and postoperative vasoconstrictor and inotropic
requirements were reduced in the clonidine-treated patients.110
Pichot et al
Reduced Vasopressor Requirements

In the pediatric cardiac surgical CCU setting, dexmedetomidine did not evoke any increase in inotropic requirement.30
In the medical CCU setting, adrenaline requirements were
reduced, following introduction of dexmedetomidine.45
Similarly, following cardiac surgery, dexmedetomidine
administration was associated with a lower incidence of
administration of adrenaline (randomized open label, inclusion: n 148 dexmedetomidine-treated patients vs 147
propofol-treated patients; 18 dexmedetomidine-treated
patients vs 32 propofol-treated patients requiring adrenaline; P .03).111 Furthermore, vasopressor requirements
were decreased and the duration of their administration was
shortened in septic patients. The 2 groups of patients were
unequal in their incidence of vasopressors administration
at enrollment.112 In a patient with sepsis, increases in
plasma concentrations of endogenous noradrenaline and
adrenaline were preserved following clonidine.113 In a
patient with septic shock (SBP < 70 mm Hg despite NA
3 mg/kg per min), SBP increased to '100 mm Hg within
3 hours of clonidine administration, and vasopressor
requirements were reduced up to 20% of baseline within
48 hours of clonidines introduction.114
Other Side Effects

The baseline sympathetic activity was lowered, but the reactivity of the vascular and cardiac sympathetic systems was unaffected.12 However, bradycardia and hypotension are to be
expected, especially in hypovolemic patients.
Bradycardia was observed in children who presented with
head injury and were treated with hypothermia combined with
dexmedetomidine-remifentanil.115 In this observation, differentiating the bradycardia linked to hypothermia or remifentanil
or dexmedetomidine appears elusive.
No hypotension was observed in infants (0-24 months)
recovering from cardiovascular surgery, but one brief episode of sinus bradycardia resolved spontaneously (retrospective study; n 50; clonidine: 0.18-3.6 mg/kg per hour
IV).116 A similar absence of bradycardia and hypotension
was observed in the setting of a medical pediatric CCU
(respiratory failure; n 24; clonidine 3 mg/kg 3 times per
day through the nasogastric tube). This English pediatric
CCU has used clonidine as a first-line sedative agent in
combination with morphine since 2000. Approximately,
85% of the patients receive clonidine during their CCU
stay,117 which agrees with the German data in adults.37,29
In contrast, a retrospective study (n 121) using dexmedetomidine (0.15-0.70 mg/kg per hour) in pediatric patients
observed hypotension in 16% of the patients and bradycardia in 12% of the patients.118 A loading dose of dexmedetomidine that is administered slower than the established
infusion regimen led to a lower incidence of hypotension,
but bradycardia still occurred.119 Furthermore, while a loading dose of dexmedetomidine was followed by
hypertension, then hypotension,40,29 a slow infusion without

loading dose suppressed almost all hypotensive effects.5
This was also observed in patients with head injury54,55 and
a pediatric cardiac surgical CCU.30 In the medical CCU
setting, volume loading and a reduction in the loading
doseof dexmedetomidine appeared to be relevant.45 Of
note, in the setting of long-term mechanical ventilation,
little6 or no7 loading doses of dexmedetomidine were used.
Overdose of a-2 agonists appeared to be surprisingly
well-tolerated.120,121
Hypertension may be observed with a-2 agonists in the following scenarios: (a) loading with a clonidine bolus or dexmedetomidine rapid infusion; (b) oral administration of high-dose
clonidine (5000-6000 mg/day ie, ca 3-4 mg/kg per hour; plasma
concentrations: 14-26 ng/mL)22; and (c) high-dose dexmedetomidine (4 mg/kg per hour for several hours) in a child presenting with head injury. Decreasing the infusion rate normalized
the pressure.122
Arrhythmias
The parasympathomimetic effect is demonstrated in animals
where clonidine increases the excitability of cardiac vagal
motoneurons13 and enhances bradycardia upon stimulation of
the Bezold-Jarisch reflex.123 In humans, a very small dose of
clonidine (0.2 mg/kg over 5 minutes, ie, 14 mg IV/70 kg) leads
to sinus slowing and depression of nodal conduction, which is
of lesser importance than those observed following b-blocker
administration.124 Lengthening of the PR interval is more prominent when the baseline PR interval is long.124 Clonidine
(450 mg po per day) administered chronically for hypertension
may be associated with dizziness, syncope, and short sinus
arrest (4.5 seconds).125 Clonidine (150 mg IV bolus may lead
to isorhythmic atrioventricular dissociation.95 A 2-minute
asystole has been reported upon sternal retraction following
dexmedetomidine (1 mg/kg over 10 minutes then 0.2 mg/kg per
hour) in a patient with a history of vigorous exercise who was
treated with a parasympathomimetic drug, pyridostigmine.126
Inference
In the CCU, a-2 agonists appear surprisingly well-tolerated,
provided that hypovolemia is avoided before and throughout
administration of a-2 agonists. A very slow infusion of an a2 agonist (eg, dexmedetomidine: 0.4 mg/kg hour for 1 hour
without loading dose followed by 0.2 to 0.7 mg/kg per hour
infusion to a 2 < Ramsay < 45; clonidine: 0.2 to 2 mg/kg per
hour without any loading dose or rapid infusion44) appears
satisfactory. These regimens may be combined with very low
doses of noradrenaline or dobutamine if hypotension or bradycardia occurs.5 This would maintain or transiently increase
the perfusion pressure, depending on the organ at risk (eg,
patients with head injury, high perfusion pressure to maintain
an adequate diuresis . . . ) or HR, if venous saturation is low.
10
Effects on the Gastro-Intestinal Tract,

Kidney, and Metabolism
Gastrointestinal Tract
The half-life of clonidine appears to be unchanged in cirrhotic
patients (cirrhotic patients: 25.4 + 3.0 hours; normal individual: 20-25 hours).127,128 Clonidine (150 mg po for 7 days)
reduced hepatic venous pressure and gradient. In cirrhotic
patients with elevated noradrenaline (>300 pg/mL) clonidine
(75 mg twice daily for 3 months; double-blind randomized) led
to the following: increased sodium excretion, loss of body
weight, reduced diuretic requirements, no renal impairment,
reduced number of paracenteses, and delayed readmission for
tense ascites.129 Clonidine 2.5 mg/kg IV reduced cardiac output
but did not affect hepatic flow in cirrhotic patients (mostly with
ascites:30 out of 44 patients). A reduced portal venous pressure
is explained by a reduction in postsinusoidal resistance. Despite
a fall in BP, there was an increase in renal flow, glomerular filtration rate, and urine flow.130
Small bowel transit time is prolonged in volunteers (placebo: 90 + 7 minutes; clonidine 148 + 20 minutes, n
6; randomized single blind)131 and in diabetic patients,132 but
emptying of the gall bladder was accelerated.132 Intestinal
pseudoobstruction has been reported following clonidine
administration in the ambulatory setting133 and in the critical
care setting; this was observed in patients treated for delirium
tremens with high-dose clonidine (up to 3000 mg/day) in addition to midazolam and pethidine.134
Kidney
NYHA III to IV patients treated with clonidine (300 mg/day for
1 week) experienced a halving of their dose of diuretics and a
reduction of edema.97 ASA 1 patients treated with clonidine 5
mg/kg presented a larger intraoperative urine output and sodium
and potassium excretion.135 Patients with hypertension (n
17) who underwent coronary surgery with cardiopulmonary
bypass and were premedicated with clonidine (3 mg/kg po) presented no postoperative changes in serum creatinine, as
opposed to placebo patients.136 A similar preservation was
observed in liver transplant110 and in coronary patients (n
48).137 The incidence of elevated urea (BUN) was lowered
by half in dexmedetomidine-treated patients, following cardiac
surgery.111 In the CCU, dexmedetomidine-treated patients presented with a higher urine output (P .12).41 Lower creatinine
concentrations were observed in the medical CCU setting (nonrandomized design; P .02).45
is achieved after 1 to 3 hours, and half of it is recovered,

unchanged in the urine. However, the half-life of the drug is
increased in renal failure.139 Dexmedetomidines terminal
half-life (t1/2b 3.14 hours) does not appear to be modified
in stable patients presenting to the surgical CCU140 as compared to healthy volunteers. The elimination half-life of dexmedetomidine (0.6 mg/kg IV over 10 minutes) was shorter
(113 + 11 vs 136 + 13 minutes) in volunteers with renal
impairment (creatinine clearance: 21 + 9 mL/min, n 5) compared with healthy volunteers (creatinine clearance: 122 + 31
mL/min, n 5). This supports an hepatic elimination process.
The intensity of the sedation was more prominent in the volunteers with renal impairment.138 No data pertaining to the
reduced requirements of clonidine or dexmedetomidine in
acute renal failure are available. As hemodialysis/filtration is
often required upon acute renal failure, the dosage of a-2 agonist has to be adjusted and titrated to the desired effects on
sedation and circulation.
Metabolism
A nonrandomized retrospective analysis showed that protein
catabolism was almost entirely suppressed in alcohol abusers
who were treated with clonidine, following esophageal cancer
resection; additionally, the length of hospital stay was
reduced.141 Clonidine had the following positive effects in various patient groups: increased gastric intramucosal pH after
cardiopulmonary bypass,142 reduced metabolic acidosis following liver graft declamping,110 and decreased plasma lactate
levels 12 hours after cardiac surgery.143
Sepsis
In septic rats, dexmedetomidine and clonidine improved circulation, reduced mortality (94%-44%), decreased cytokine concentrations,144 and inhibited the aggregation of neutrophils in
the lung.145 This was replicated in a dose-related manner, leading to a reduced acidosis and mortality from 84% to 20% and
preserved blood pressure.146 In humans, following (a) cardiac
surgery performed on clonidine patients (1-3 mg/kg per hour for
6 hours: ca 1.2 mg), early proinflammatory response was attenuated143; (b) major surgery, dexmedetomidine lowered interleukin 6 concentrations but had no effect on cortisol and ACTH
concentrations.147
Inference
Kidney function and peripheral blood flow appear well preserved. Response to sepsis appears improved.
Pharmokinetics
The elimination of clonidine and dexmedetomidine is primarily
through the kidney and liver, respectively, with different elimination half-lives in healthy normotensive participants: 20 to 25
hours for clonidine128 and 136 + 13 minutes for dexmedetomidine.138 Clonidine is absorbed easily after oral administration,
and its bioavailability is close to 100%. Its peak concentration
Miscellaneous
Withdrawal
Withdrawal syndrome after discontinuation of a-2 agonists has
been reported following long-term outpatient treatment in the
cardiology setting but not following acute treatment in the
Pichot et al
11
toxicology,32 anesthesia, or CCU setting. No withdrawal syndrome was observed after using dexmedetomidine for 3 to 4
days in a multicenter study (n 244).6 However, tapering high
doses of a-2 agonists over 2 to 4 days is advisable, after days or
weeks of administration.
Route
In the United States, given the absence of IV preparation, (a)
some intensivists have used the epidural preparation of clonidine for i.v administration (b) via the transdermal route, 3 to
4 days are needed to reach steady-state plasma concentrations.139 To circumvent this problem, a combination of nasogastric and transdermal routes may be used and work is
needed to achieve a simple and efficacious administration
protocol for clonidine when IV clonidine is not available.
Finally, there will be regulatory problems. In France,
although IV clonidine is cheap and available, its CCU44 use
is off-label. The likelihood of the licensing of dexmedetomidine in the European market may warrant its use, regardless of the cost. In the United States, present regulations
allow the use of dexmedetomidine for 24 hours only, at a
dose of %0.7 mg/kg per hour.148 The FDA granted permission
to use dexmedetomidine at dose twice that high, for up to 30
days of mechanical ventilation,148 presumably to assess
safety within a research protocol.
Outcome
The CCU stay of eclamptic patients was shorter for patients
treated with dexmedetomidine (mean stay 45 hours) than for
those treated with midazolam (mean stay 83 hours).149
Improved outcome was observed in the aortic surgery setting,
where the combined incidence of cardiac death and myocardial
infarction was lowered following aortic surgery and a-2 agonist administration.150 Clonidine improved in-hospital and
long-term survival following elective noncardiac surgery in
coronary patients.151 a-2 agonists reduced mortality and myocardial infarction following vascular surgery152 and decreased
the risk of cardiac death by 52%.153 Clonidine was associated
with better survival in the CCU in patients with tetanus (prospective design; nonclonidine patients [n 10]: death: 50%;
clonidine-treated patients [n 17]: death: 11%; P .04).154
Trauma-infected patients with alcohol withdrawal showed a
higher incidence of pneumonia (P .04) and longer duration
of ventilation (P .03) when treated with chlormethiazol/
haloperidol (n 50) as compared with treatment with flunitrazepam/clonidine (n 54).26 Dexmedetomidine was associated
with a trend toward better outcome and longer survival (n
103).7 When an analysis was restricted to septic patients, dexmedetomidine was associated with a reduction in death rate by
70% (dexmetedomidine: n 19; lorazepam: n 20; P
.04).112 A large (n 297), multicenter trial observed a reduction in infections in dexmedetomidine-treated patients (P<.02;
urinary tract infections: P<.02; hospital-acquired pneumonia:
P .07).6
Cost
Dexmedetomidine and lorazepam treatments cost US$4675
and $2335, respectively (median-calculated cost for the study
drug; total pharmacy cost: dexmedetomidine [n 45]
$27 460 vs lorazepam: [n 45] $20 660, P .15)7 (US market: one 2-mL vial of dexmedetomidine, 100 mg/mL$50-$80;
French veterinary market: 1 mL 500 mg of dexmedetomidine, 10 mL vial, 135). On the other hand, the ICU costs are
similar in the 2 groups.7 The estimated costs (2008) in France
for the sedation of 1 patient for 24 hours with clonidine (1 mg/
kg per hour, ie, 3.4 mg/70 kg per day) as a first-line sole sedative agent and other conventional sedation regimens are as follows: clonidine, 5.1 (French market: 1 vial of clonidine 150
mg in 1 mL 0.42); midazolam sufentanil, 6.4; and propofol remifentanil, 55. Such comparison is financially relevant but may be biased because no head-to-head drug
comparison has been performed, for example on the French
market. Nevertheless, these drug regimens are usually combined (eg, propofol remifentanil vs midazolam sufentanil
vs clonidine alone).
Inference
The studies cited in this review show a trend toward a possible
reduction of morbidity and mortality with the use of a-2 agonists in critically ill patients. However, this is based on small,
nonrandomized or retrospective studies.112,153,154 Only Phase
III or IV randomized controlled trials will be able to fully prove
a change in outcome. Two hypotheses may account for the
improved outcome: (a) improved cardioventilatory interactions lead to accelerated recovery: the length of mechanical
ventilation and the iatrogenic complications are reduced; (b)
a-2 agonists are sympathetic inhibitors and parasympathetic
activators: parasympathetic activation increases resistance to
inflammation.155
Furthermore,
clonidine
stimulates
macrophages.156
Conclusion
Alpha-2 agonists evoke sympathetic inhibition combined with
parasympathetic activation. These various sites of action
explain the multifaceted profile of a-2 agonists: sedation combined with arousability, reduced incidence of delirium, preservation of the respiratory drive, allowing the use of modern
ventilatory techniques (eg pressure support) with reduced
intrathoracic pressure, weaning from mechanical ventilation,
and initiation of noninvasive ventilation, reduced O2 consumption, reduced arterial impedance and improved LV performance, preserved vascular reactivity to exogenous amines,
preserved cardiac baroreflex reactivity, preserved vasomotor
baroreflex activity combined with a lower set point, preserved
renal function, improved tissue perfusion, and reduced protein
metabolism. Hypotension and bradycardia appear manageable
if volemia is repeatedly optimized before and throughout the a2 agonist treatment and slow IV infusion without bolus administration is considered as the only therapeutic modality. It
12
appears that a new management strategy is possible148,157

Arousable sedation may be combined with spontaneous ventilation (eg, pressure support ventilation). Accelerated/early
weaning and improved outcome need confirmation
As research was carried out primarily in the cardiology,
anesthesiology, and surgical CCU settings, the literature on
a-2 agonists with respect to physiology and outcome in the
medical CCU setting presents limitations. Double-blind randomized prospective studies are needed to substantiate a niche for
a-2 agonists in the CCU.
Declaration of Conflicting Interests

The author(s) declared a potential conflict of interest as follows: L
Quintin received grants and honoraria from Bohringer-Ingelheim
France, UCB Pharma, and Abbott International (1986-1995).
Funding
The author(s) disclosed receipt of the following financial support for
the research and/or authorship of this article: Block grants from University of Lyon-CNRS to UMR 5123, PICS CNRS and PEPS CNRS to
LQ.
Pichot et al
13
Institutional protocol for the use of alpha-2 agonists as sedative agents in our CCU
Indications (for clonidine according to French Society of Critical Care Medicine [44]):
Weaning from mechanical ventilation.
Hyperdynamic circulation (orage neurovegetatif).
Emergence from sedation in head-injured patients.
Indications (for clonidine according to French regulatory authority and French compendium of specialties : dictionnaire
Vidal):
Malignant hypertension, hypertensive encephalopathya
Aortic dissectionb.
Left ventricular insufficiency in the setting of acute pulmonary oedema.
Pre-eclampsia (2d line agent).
Indications (for alpha-2 agonists according to the literature or the authors):
Tachycardia and/or hypertension.
Head injury (with preserved cerebral perfusion pressure).
Tetanos.
Delirium Tremens.
Weaning from heroin, cocaine.
Weaning from sedation.
CCU delirium.
Preservation of sleep-wake cycle in the CCU.
VO2 reduction.
Suppression of shivering.
Adaptation to intentional hypothermia.
Adaptation to non-invasive ventilation.
Weaning from mechanical ventilation.
Absolute contra-indication:
Absolute or relative hypovolaemia : Adequate volemia is mandatory before and throughout administration of a-2 agonists. As
any loading dose of a-2 agonists appears unwise, volume loading may be performed, then a very slow infusion may be commenced. Daily assessment of volemia is recommended.
Relative contra-indications:
Sick sinus syndrome.
Atrial fibrillation with a low ventricular response.
Atrioventricular block or a P+R interval of over 200 ms.
Prior treatment with beta-blockers resulting in a heart rate below 60 bpm, or prior administration of sympatholytic drugs.
Possible deleterious associations : diltiazem, urapidil.
Administration:
Avoid loading dose : use only continuous infusion over 24 h. Consider nasogastric route only for a limited period of time or
transdermal patch if peripheral perfusion is adequate and venous access or infusion syringes limited.
Clonidine : 0.4-2 mg.kg-1.h-1 [44]. Clonidine 1 mg.kg-1.h-1 without loading dose achieves 3%Ramsay%4 after 3-6 h (see
below : supplementation). If clonidine 2 mg.kg-1.h-1 is inadequate to achieve Ramsay&3 (e.g. delirium tremens) or escape
phenomenon after days or weeks, then supplement the a-2 agonist accordingly (see below).
Dexmedetomidine : 0.8-1.5 mg.kg-1.h-1 [6-7]. Despite the fact that dexmedetomidine is more selective for a-2 receptors, the
dosages collected throughout the literature do not reflect such a difference. A ceiling effect is reported above 1.5 mg.kg-1.h-1[45].
14

Supplemental sedation:
Rescue medication may be needed during 3-6 h i.e. progressive induction of sedation with slow infusion of a-2 agonists and
without loading dose : repeat midazolam 3-5 mg bolus, as needed, bearing in mind the respiratory depression induced by midazolam, e.g. in patients ventilated with pressure support-spontaneous ventilation.
Supplementation of a-2 agonists may be needed when high dose a-2 agonists are inadequate to get 3%Ramsay%4. Select drugs
which do
a)
not affect the respiratory drive (hydroxyzine i.v., loxapine through the nasogastric tube, ketamine, gamma-OH butyrate
[GammaOH1] . . . .). Such choice would be in line with a preserved spontaneous breathing e.g. under pressure support ventilation.
b) affect the respiratory drive : thiopentone, propofol, midazolam, opioid analgesics . . . Such choice implies to monitor closely
the respiratory status. Such combination does not allow one to assess which drug causes circulatory or cognitive disturbances:
a combination of e.g. clonidine-midazolam-sufentanyl-nicardipine is a door open to side effects and misunderstandings. In a
similar manner, adding propofol-remifentanil to clonidine may lead to profound hypotension-bradycardia.
If a clear cut indication exists, maintenance doses of hypnotic or halogenated agents are to be reduced by 80% or more and titrated
to sedation scale, e.g. 3%Ramsay%4 in patients with a tracheal tube.
Supplemental analgesia:
Consider pain medication only when clinically indicated, i.e. documented on pain scale.
Consider first drugs without effect on ventilatory drive : nefopam, low dose ketamine (alone or combined), when pressure
support-spontaneous ventilation is selected. A second choice would be opiates reduced by 80% or more, then titrated to pain scale.
Normothermia:
As a-2 agonists do not mask the respiratory consequences of hyperthermia (tachypnea) in septic patients, intentional
normothermia-mild hypothermia (36-37 ( C) may be warranted to lower respiratory rate. When hemodialysis is necessary, mild
intentional hypothermia is usually unnecessary. The effect of a-2 agonists on the hypothalamus makes the prescription of paracetamol unnecessary to prevent shivering.
Trouble shooting: bradycardia, hypotension, low cardiac output.
Reduce/eliminate halogenated, hypnotics, or other sedative agents.
Passive leg raising+Head-down tilt (beach chair position).
Volume loading upon induction and throughout a-2 agonist administration.
Vasoactive drugs: the requirement for ephedrine, phenylephrine, norepinephrine, isoproterenol, dobutamine are reduced.
As a-2 agonists are sympathetic inhibitors, a degree of hypotension is a possibility. After weighting the benefits of the a-2 agonist
vs. such a side effect, very low dose vasopressors5 may restore cerebral, coronary or renal perfusion pressure.
Military antishock trouser may be an option to reduce volume or vasopressor requirement.
For established bradycardia or low output, dobutamine requirements (titrated to echocardiographic assessment or superior vena
cava/mixed venous O2 saturation>70-75%) may be as low as 1.25 mg.kg-1.min-1.
For transient bradycardia, consider low-dose isoproterenol (titration to effect : boluses : 2-10 mg). If longer effect is needed,
atropine (0.75 to 1.2 mg).
Progressive tapering of clonidine over 2-4 days immediately after severing from non-invasive ventilation or prior to or following discharge from CCU : switching over from i.v. a-2 agonist to po clonidine is a simple option.
If considered, the authors recommend a slow i.v. infusion without bolus administration.
If considered, the authors recommend a slow i.v. infusion without bolus administration.
Pichot et al
15
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Journal of Intensive

The online version of this article can be found at:

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Dexmedetomidine and Clonidine: From

Journal of Intensive Care Medicine

C. Pichot, MD1, M. Ghignone, MD, FRCPC2, and L. Quintin, MD, PhD3

Effects on the Central Nervous System and

Critical Care Unit, Memorial Hospital, St Lo, France

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Journal of Intensive Care Medicine 000(00)

are mediated via a-2A receptors.3 Dexmedetomidine is more

rostral ventrolateral medulla

Figure 1. Impact of a-2 agonists on the noradrenergic dorsal bundle,

Critical care unit delirium. Clonidine suppressed opiate32 and

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Figure 2. Schematic overview of a noradrenergic (NA) synapse:

shortened CCU stay in the clonidine group.38 Accordingly,

Figure 3. Alpha-2 agonists lead to arousable sedation in the critical

Reduction in opiates and sedative requirements. Adding a-2

Downloaded from jic.sagepub.com at CAPES on April 29, 2011

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randomized; clonidine17 vs.

total number of patients20

Table 1. Sedative Effects of Alpha-2 Agonists: Overview

60-180 mg.h-1*2 days

adjunct : magnesium, morphine,

clonidine 50 mg.h-1 then dexmedetomidine 0.4

non-clonidine group : 5 out 10

stand-alone following previous

increased incidence of pneumonia

up to 1.2 mg until sympathetic

associated with fentanyl-midazolam

stand-alone vs. chlormethiazol/

adjunct vs. stand-alone

1.44 mg/70 kg/day

0.45-3.16 mg (mean : 1.11)

1 mg.kg-1 over 10 min 0.2-0.7 mg.kg-1.h-1 up to

0.9 mg/5 min

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adjunct vs. stand-alone

up to 1 mg.kg-1 to 8% 0.8 mg.kg-1.h-1 to Richmond

reduction in propofol (-87 %)

ceiling effect for sedation>1.5 mg.kg- Venn, 2003

0.2-2.5 mg.kg-1.h-1 up to 7 days rescue propofol 0.2 mg.kg-1 then

rescue agents : midazolam, lorazepam, fentanyl, etc . . . .

1 mg.kg-1 over 10 min 0.2-0.7mg.kg-1.h-1 to Ramsay>3 stand-alone vs. saline; rescue

Journal of Intensive Care Medicine 000(00)

requirements,28 which appeared more prominent following

incidence of amnesia of their CCU stay,29 but a dose-response

Sedation in the Setting of Head Injury

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action.62 In conscious healthy volunteers, although

Effect on Ventilation and CCU Applications

Noninvasive Ventilation and Weaning

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Journal of Intensive Care Medicine 000(00)

in vitro71 as well as a large reduction in the requirements for

Effects on Circulation and Side Effects

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Reduced Vasopressor Requirements

Other Side Effects

hypertension, then hypotension,40,29 a slow infusion without

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