Alex Y.

Bekker, MD, PhD

Associate Professor of Anesthesiology
and Neurosurgery
New York University Medical Center
New York, New York

Dexmedetomidine for Monitored
Anesthesia Care (MAC)

We have completed our review of this application, as amended,
and it is approved, effective on the date of this letter, for use as
recommended in the enclosed agreed-upon labeling text.

Monitored Anesthesia Care: Definition
Monitored Anesthesia Care (MAC) may include
varying levels of sedation, analgesia, and anxiolysis
as necessary. The provider of MAC must be
prepared and qualified to convert to general
anesthesia when necessary.

Position on Monitored Anesthesia Care, ASA 2005
Continuum of Depth of Sedation
Minimal
Sedation
(Anxiolysis)
Moderate
Sedation/
Analgesia
(Conscious
Sedation)
Deep Sedation/
Analgesia
General
Anesthesia
Responsiveness Normal
Response to
verbal
Stimulation
Purposeful
response to
verbal or tactile
stimulation
Purposeful
response after
repeated or
painful
stimulation
Unarousable,
even with
painful
stimulation
Airway Unaffected No intervention
required
Intervention
may be required
Intervention
often required
Spontaneous
ventilation
Unaffected Adequate May be
inadequate
Frequently
inadequate
Cardiovascular
function
Unaffected Usually
maintained
Usually
maintained
May be
impaired
Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists, Anesthesiology 2002


Injury and Liability Associated with Monitored
Anesthesia Care
Bhananker and colleagues assessed the
patterns of injury and liability associated
with monitored anesthesia care (MAC; n =
121) as compared with general (n = 1519)
and regional anesthesia (n = 312)
Bhananker S, Anesthesiology 2006
0
10
20
30
40
50
60
Death/Perm Brain
Damage
Permanent Disabling Temp/Nondisabling
MAC General Regional
*
*
*
*
* P<.025 MAC versus Regional
%

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Injury Associated with MAC
N=121 %

Respiratory event 24
Cardiovascular event 14
Equipment failure/malfunctioning 21
Related to regional block 2
Inadequate anesthesia/patient movement 11
Medication related 9
Other events 20

Bhananker S, Anesthesiology 2006
Characteristics of an Ideal Sedative
Cooperative sedation
Minimal depression of ventilation
Hemodynamic stability
Analgesic effects
Wide therapeutic window
Minimal risks of side effects
Favorable pharmacodynamic/ pharmacokinetic
profile
Amnesia (?)
Study Design: Monitored
Anesthesia Care
325 Patients: 260 Dex; 65 Placebo receiving MAC for surgical
procedures; 25 US sites
2 Precedex Arms: 0.5 mcg/kg/10 min load or 1.0 mcg/kg/10 min
load; 0.6 mcg/kg/hr maintenance titrated 0.2 1.0 mcg/kg/hr.
OAA/S Scale: Midazolam rescue for > 4.
Primary Endpoint: % of pts not requiring MDZ based on OAA/S.
Secondary Endpoints: total MDZ, fentanyl, sedation failures; pt
satisfaction; anesthesiologist assessment; PONV
Safety: respiratory depression; hemodynamic stability
MAC Primary Efficacy
Requirement of Rescue Midazolam (MDZ)

Rescue MDZ/
No Rescue MDZ
DEX 0.5 mcg/kg
N=134

n (%)
DEX 1 mcg/kg
N=129

n (%)
PBO
N=63

n (%)
Did Not Require Rescue
MDZ
54 (40.3) 70 (54.3) 2 (3.2)
Required Rescue MDZ 80 (59.7) 59 (45.7) 61 (96.8)
p-value <0.001 <0.001


MAC Secondary Efficacy
Anesthesiologist Assessment

MAC Anesthesiologist Assessment - Lower Scores are Better
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Ease of Maintenance of
Sedation Level (cm)
Hemodynamic Stability (cm) Respiratory Stability (cm) Subject Cooperation (cm)
DEX 0.5 mcg/kg
DEX 1 mcg/kg
PBO
* *
*p <0.05


MAC Secondary Efficacy
Subject Assessment

MAC Subject Assessment - Higher Scores are Better
0
0.5
1
1.5
2
2.5
3
1

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DEX 0.5 mcg/kg
DEX 1 mcg/kg
PBO
*
*
*
*
*
*
*
* * *
*
* *
*p <0.05




Overview of Awake
Fiberoptic Intubation Trial
Double-blind, randomized, placebo-controlled
100 patients: 50 Precedex; 50 Placebo; 18 US sites
Precedex: 1.0 mcg/kg/10 min; 0.7 mcg/kg/hr maint
Rescue is Midazolam(0.5 mg doses) based on Ramsay Sedation Scale of
1.
Primary Endpoint: % of patients requiring Midazolam
Secondary Endpoints: Total MDZ dose; other rescue meds; patient
satisfaction; anesthesiologist assessment
Safety Endpoints: hemodynamic stability; respiratory depression

AWAKE Primary Efficacy
Requirement of Rescue Midazolam (MDZ)


Rescue MDZ/No Rescue MDZ
DEX (N=55)

n (%)
PBO (N=50)

n (%)
p-value
Required Rescue MDZ 26 (47.3%) 43 (86.0%) <0.001
Did Not Require Rescue MDZ 29 (52.7%)* 7 (14.0%)


Characteristics of Cooperative Sedation
In cooperative sedation,
patients easily transition
from sleep to wakefulness
and task performance
when aroused
Patients are able to resume
rest when not stimulated
Cooperative sedation is
most useful during
procedures in which
communication with the
patient must be
maintained


Facilitates participation in
therapeutic maneuvers
Allows for patient
interaction in care
decisions
May contribute to shorter
recovery room
convalescence
Reduces risk of
developing drug-induced
complications

The brain is not a sausage, its more like a well
tuned musical instrument
Rudolfo Llinas
Endogenous sleep


Loss of response to external
stimuli


Sedative component of
anesthesia
Arousability From Sedation During
Dexmedetomidine Infusion
BIS indicates Bispectral Index System
During cognitive and cold pressor testing
Just prior to cognitive and cold pressor testing
Dexmedetomidine
Infusion
(mcg/kg/h)
0
20
40
60
80
100
Placebo 0.2 0.6
B
I
S
Hall JE, Anesth Analg 2000
Patients were infused with
placebo or 1 of 2 doses of
dexmedetomidine and
monitored with the Bispectral
Index System (BIS) before
stimulation and immediately
after being asked to perform
cognitive and cold pressor tests
Patients receiving either infusion
of dexmedetomidine could be
completely aroused by a mild
stimulus
1


Avoid
oversedation
Reduce anxiety
Maintain
communication
Minimize
respiratory
depression


Dexmedetomidine in Carotid
Endarterectomy
Intraoperative Assessment of Sedation Level
by the Blinded Observer
Bekker A , J Neurosurg Anesth 2004
The Safety of Dexmedetomidine as
Primary Sedative for Awake CEA
Total number of patients
N=151
General Anesthesia
N=10
Regional/Dex
N=123
Regional/No Dex
N=18
No Shunt
N=0
Shunt
N=10
No Shunt
N=111
Shunt
N=12
No Shunt
N=12
Shunt
N=6
Elective
N=10
Obligatory
N=0
Elective
N=7

Obligatory
N=5


Obligatory
N=2

Elective
N=4
Bekker A, Anesth Analg 2006
Clinical Experience with
Dexmedetomidine for DBS Implantation
Dex (0.3-0.6 mcg/kg/hr) did not impair intensity of
movement disorder or interfere with MER in PD patients

Titration of Dex provided satisfactory sedation for DBS
implantation

Dex provided HD stability and decreased the use of
antihypertensives
1

Propofol induced dyskinesia was controlled with DEX
during DBS placement
2


1
Rozet I, Anesth Analg 2006.
2
Deogaonkar A , Anesthesiology 2006.
Dexmedetomidine and Respiratory
Depression
Minimal effects on ventilation is well documented in
human volunteers
1


Lack of respiratory depression was demonstrated in ICU
patients
2





1
Belleville JP, Anesthesiology, 1992; Ebert TJ, Anesthesiology, 2000.
2
Venn RM, Crit Care , 2000; Martin E, J Intensive Care Med 2004.
Hospira MAC Trial: Respiratory
Depression
Definition of Respiratory Depression:

Respiratory rate < 8 bpm or oxygen saturation < 90%

Dex 0.5 Dex 1.0 Pcb

5 (3.7%) 3 (2.3%) 8 (12.7%) P<0.018

Both Dex groups: neither respiratory depression nor intervention
Plb group: respiratory depression or a need for intervention 13.1%
and 16.1% respectively
Dexmedetomidine and Hemodynamic
Stability
Arain SR, Anesth Analg 2002 Bekker A, J Neurosurg Anesth 2004


50
70
90
110
130
150
Baseline Infusion Period PACU
B
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P
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(
m
m
H
g
)
SBP Placebo
SBP DEX 1.0 mcg/kg
SBP DEX 0.5 mcg/kg
DBP Placebo
DBP DEX 1.0 mcg/kg
DBP DEX 0.5 mcg/kg
50
60
70
80
H
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(
b
p
m
)
HR Placebo
HR DEX 1.0 mcg/kg
HR DEX 0.5 mcg/kg
50
70
90
110
130
150
Baseline Infusion Period PACU
B
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P
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(
m
m
H
g
)
SBP Placebo
SBP DEX 1.0 mcg/kg
SBP DEX 0.5 mcg/kg
DBP Placebo
DBP DEX 1.0 mcg/kg
DBP DEX 0.5 mcg/kg
50
60
70
80
H
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(
b
p
m
)
HR Placebo
HR DEX 1.0 mcg/kg
HR DEX 0.5 mcg/kg
MAC Trial: Mean Changes in Systolic and Diastolic Blood Pressure and Heart Rate


*P<.05 difference over time compared with baseline

P<.05 difference between groups

0
10
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40
100
V
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P
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40
60
80
100
V
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Propofol
Dexmedetomidine
5 20 35 50 65 Surg
End
Pre-
surg
Time After Surgery, minutes
*

*

Arain SR, Anesth Analg, 2002
Improved
postoperative pain
and greater sedation
with
dexmedetomidine
compared with
propofol
Postoperative Effects of Dexmedetomidine
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Morphine-Sparing Effects in
Inpatient Surgery
34 patients scheduled for
inpatient surgery
Randomized to either
dexmedetomidine or
morphine
Agents were started 30
minutes before the end of
surgery
Dexmedetomidine
reduced the early
postoperative need for
morphine by 66%

0
2.5
5
7.5
10
12.5
Morphine Dexmedetomidine
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P<.01
0
2
4
6
8
10
12
0 10 20 30 40 50 60 70
Minutes in PACU
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M
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m
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Morphine
Dexmedetomidine
P<.01
Arain SR, Anesth Analg 2004


MAC Trial: Fentanyl Use

Time Period
DEX 0.5
mcg/kg
N=134
n (%)
p value
DEX 1
mcg/kg
N=129
n (%)
p value
PBO
N=63
n (%)
Infusion Period
Required Fentanyl 79 (59.0) <0.001 55 (42.6) <0.001 56(88.9)
PACU Period
Required Fentanyl 5 (3.7) 0.104 5 (3.9) 0.105 6 (9.5)
Overall
Required Fentanyl 81 (60.4) <0.001 56 (43.4) <0.001 56(88.9)
Pharmacokinetics of IV agents
Dex Propofol Fentanyl Alfenta
Vdcc, l

16 16 30 10
Vdss, l 200 350 330 30
Cl, l/min 0.6 1.8 0.8 0.3
T
1/2a
, min 6 4 6 4
T
1/2b
, hr 2 1.5 2.5 1
Dexmedetomodine Was Tried as a
Primary Sedative for:
Sedation in CT and MRI imaging studies
Mason K, Ped Anesth 2008
Koroglu A, Anesth Analg 2006
Outpatient third molar surgery
Ustin Y, J Oral Maxilfac Surg 2006
Cheung C, Anaesthesia 2007
Cataract surgery
Alhashemi J, Br J Anaest 2006
Cardiac catheterization
Tosun Z, J Card Vasc Anesth 2006
Mester R, Am J Therap 2008


Use of Dexmedetomidine in MRI
80 children aged 1-7 years
Randomly assigned to either
dexmedetomidine or midazolam
10-minute loading doses:
1 mcg/kg dexmedetomidine,
0.2 mg/kg midazolam
Infusions: 0.5 mcg/kg/h
dexmedetomidine,
6 mcg/kg/h midazolam
1

The quality of MRI was significantly
better (P<.001) and the rate of
adequate sedation was significantly
higher (P<.001) with
dexmedetomidine

0
10
20
30
40
1 2 3
N
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P
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Midazolam
Dexmedetomidine
1 = no motion
2 = minor movement
3 = major movement
necessitating another scan
Quality of MRI
*P<.001 compared with midazolam
*
*
Koroglu A, Br J Anaesth 2005
Dexmedetomidine for GI
Procedures
Jalowiecki P, Anesthesiology 2005
Use of Dex was associated with bradycardia, hypotension,
vertigo, nausea/vomiting, prolonged recovery

Muller R, Gastroint Endosc 2008
Clinical efficacy of Dex alone is less than propofol during
ERCP

Demiraran Y, Can J Gastroenter 2007
Dex may be a good alternative to midazolam for upper
endoscopy
Dexmedetomidine: Safety
Propofol

TI = 3.5


Harrison N, Anesthetic
Pharmacology, 2004
Dexmedetomidine:

Jorden V, Ann Pharmacoth, 2004
Pt 1 - 60 times the prescribed dose
Pt 2 - 10 times the prescribed dose
Pt 3 - 60 times the prescribed dose

Ramsay M, Anesthesiology, 2004
Pt 1 - Infusion rate 10 mcg/kg/h
Pt 2 - Infusion rate 5 mcg/kg/h
Pt 3 Infision rate 5 mcg/kg/h


Therapeutic Index = (median lethal dose [LD50] / (mean effective dose [ED50]


Benzo-
diazepines
Propofol Opioids a
2
Agonists
Sedation X X X X
Alleviate anxiety

X X
Analgesic properties

X X
Promote arousability
during sedation

X
No respiratory
depression

X
Control delirium X
Comparison of Clinical Effects





Benzo-
diazepines
Propofol Opioids a
2
Agonists
Prolonged
weaning

X X X
*

Respiratory
depression

X X X
Hypotension

X X X X
Constipation

X
Deliriogenic X X X
Tachycardia Morphine
Bradycardia

Fentanyl X

Comparison of Adverse Effects


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