Transcript Dexmedetomidine for Monitored Anesthesia Care (MAC)

Dexmedetomidine for Monitored
Anesthesia Care (MAC)
Alex Y. Bekker, MD, PhD
Associate Professor of Anesthesiology
and Neurosurgery
New York University Medical Center
New York, New York
“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
MAC
General
Regional
*
% of claims in anesthesia group
60
50
*
*
40
30
*
20
10
0
Death/Perm Brain
Damage
Permanent Disabling
* P<.025 MAC versus Regional
Bhananker S, Anesthesiology 2006
Temp/Nondisabling
•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)
Injury Associated with MAC
N=121
%
Respiratory event
Cardiovascular event
Equipment failure/malfunctioning
Related to regional block
Inadequate anesthesia/patient movement
Medication related
Other events
24
14
21
2
11
9
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 DEX 1 mcg/kg
N=134
N=129
PBO
N=63
n (%)
n (%)
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)
<0.001
<0.001
–
p-value
MAC Secondary Efficacy
Anesthesiologist Assessment
MAC Anesthesiologist Assessment - Lower Scores are Better
5
4.5
4
3.5
3
*
*
DEX 0.5 mcg/kg
DEX 1 mcg/kg
2.5
PBO
2
*p <0.05
1.5
1
0.5
0
Ease of Maintenance of
Sedation Level (cm)
Hemodynamic Stability (cm)
Respiratory Stability (cm)
Subject Cooperation (cm)
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11
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1
MAC Secondary Efficacy
Subject Assessment
MAC Subject Assessment - Higher Scores are Better
3
*
*
*
*
*
**
*
DEX 0.5 mcg/kg
*
DEX 1 mcg/kg
PBO
1
*p <0.05
0.5
0
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)
DEX (N=55)
PBO (N=50)
Rescue MDZ/No Rescue MDZ
p-value
n (%)
n (%)
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, it’s 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
Just prior to cognitive and cold pressor testing
During cognitive and cold pressor testing
100
BIS
80
60
40
20
0
Placebo
0.2
0.6
Dexmedetomidine
Infusion
(mcg/kg/h)
BIS indicates Bispectral Index System
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
stimulus1
Dexmedetomidine in Carotid
Endarterectomy
 Avoid
oversedation
 Reduce anxiety
 Maintain
communication
 Minimize
respiratory
depression
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
No Shunt
N=0
Elective
N=10
Shunt
N=10
Obligatory
N=0
Regional/Dex
N=123
No Shunt
N=111
Regional/No Dex
N=18
Shunt
N=12
Elective
N=7
Obligatory
N=5
No Shunt
N=12
Elective
N=4
Bekker A, Anesth Analg 2006
Shunt
N=6
Obligatory
N=2
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
antihypertensives1
• Propofol induced dyskinesia was controlled with DEX
during DBS placement2
1
2
Rozet I, Anesth Analg 2006. 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
2
Belleville JP, Anesthesiology, 1992; Ebert TJ, Anesthesiology, 2000. 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
MAC Trial: Mean Changes in Systolic and Diastolic Blood Pressure and Heart Rate
80
Heart Rate (bpm)
HR Placebo
70
HR DEX 1.0 mcg/kg
60
HR DEX 0.5 mcg/kg
50
150
Blood Pressure (mmHg)
SBP Placebo
130
SBP DEX 1.0 mcg/kg
110
SBP DEX 0.5 mcg/kg
90
DBP Placebo
70
DBP DEX 1.0 mcg/kg
50
DBP DEX 0.5 mcg/kg
Baseline
Infusion Period
PACU
More Pain
Less Pain
VAS Pain
Postoperative Effects of Dexmedetomidine
100
40
Propofol
Dexmedetomidine
30
20
*†
10
VAS Sedation
Less Alert
More Alert
0
100
*†
80
60
Improved
postoperative pain
and greater sedation
with
dexmedetomidine
compared with
propofol
40
0
Pre- Surg
surg End
5
20
35
50
65
Time After Surgery, minutes
*P<.05 difference over time compared with baseline
†P<.05 difference between groups
Arain SR, Anesth Analg, 2002
Morphine-Sparing Effects in
Inpatient Surgery
Cumulative Morphine
Used, mg
12
Morphine
Dexmedetomidine
10
8
6
P<.01
4
2
0
0
10
20
30
40
50
60
70
Minutes in PACU
12.5
Average Total Morphine
Used, mg
• 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%
P<.01
10
7.5
5
2.5
0
Morphine
Dexmedetomidine
Arain SR, Anesth Analg 2004
MAC Trial: Fentanyl Use
Time Period
DEX 0.5
mcg/kg
N=134
n (%)
p – value
79 (59.0)
<0.001
5 (3.7)
81 (60.4)
DEX 1
mcg/kg
N=129
n (%)
p – value
PBO
N=63
n (%)
55 (42.6)
<0.001
56(88.9)
0.104
5 (3.9)
0.105
6 (9.5)
<0.001
56 (43.4)
<0.001
56(88.9)
Infusion Period
Required Fentanyl
PACU Period
Required Fentanyl
Overall
Required Fentanyl
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
T1/2a, min
6
4
6
4
T1/2b, 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 midazolam1
•
The quality of MRI was significantly
better (P<.001) and the rate of
adequate sedation was significantly
higher (P<.001) with
dexmedetomidine
Quality of MRI
40
Number of Patients
•
•
30
Midazolam
Dexmedetomidine
*
1 = no motion
2 = minor movement
3 = major movement
necessitating another scan
20
10
*
0
1
2
3
*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
Therapeutic Index = (median lethal dose [LD50] / (mean effective dose [ED50]
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
Comparison of Clinical Effects
Benzodiazepines
Propofol
Opioids
a2 Agonists
Sedation
X
X
X
X
Alleviate anxiety
X
Analgesic properties
X
X
X
Promote arousability
during sedation
X
No respiratory
depression
X
Control delirium
X
Comparison of Adverse Effects
Benzodiazepines
Propofol
Opioids
Prolonged
weaning
X
X
X*
Respiratory
depression
X
X
X
Hypotension
X
X
X
Constipation
Deliriogenic
a2 Agonists
X
X
X
X
X
Tachycardia
Morphine
Bradycardia
Fentanyl
X
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