alex y. bekker, md, phd associate professor of anesthesiology and neurosurgery new york university...
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Alex Y. Bekker, MD, PhDAlex Y. Bekker, MD, PhDAssociate Professor of AnesthesiologyAssociate Professor of Anesthesiology
and Neurosurgeryand NeurosurgeryNew York University Medical CenterNew York University Medical Center
New York, New YorkNew York, New York
Dexmedetomidine for Monitored Dexmedetomidine for Monitored Anesthesia Care (MAC)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 BrainDamage
Permanent Disabling Temp/Nondisabling
MAC General Regional
*
*
*
*
* P<.025 MAC versus Regional
% o
f cl
aim
s in
ane
sthe
sia
grou
p
Injury Associated with MAC
N=121 %
Respiratory event 24Cardiovascular event 14Equipment failure/malfunctioning 21Related to regional block 2Inadequate anesthesia/patient movement 11Medication related 9Other 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 sites2 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/kgN=134
n (%)
DEX 1 mcg/kgN=129
n (%)
PBON=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 EfficacyMAC Secondary EfficacyAnesthesiologist AssessmentAnesthesiologist 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 ofSedation 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 EfficacyMAC Secondary EfficacySubject Assessment Subject Assessment
MAC Subject Assessment - Higher Scores are Better
0
0.5
1
1.5
2
2.5
3
1 - I
thre
w up o
r felt l
ike it
2 - I
wou
ld use
aga
in
3 - I
itch
ed
4 - I
felt r
elaxed
5 - I
felt p
ain
6 - I
felt s
afe
7 - I
was
too h
ot or c
old
8 - I
was
satis
fied
with a
nesth
esia
9 - I
felt p
ain d
urin
g su
rger
y
10 -
I felt
goo
d
11 -
I hur
t
Ove
rall I
SAS Sco
re
DEX 0.5 mcg/kg
DEX 1 mcg/kg
PBO
*
**
*
*
**
* * ** * *
*p <0.05
Overview of Awake Overview of Awake Fiberoptic Intubation TrialFiberoptic 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 EfficacyAWAKE Primary EfficacyRequirement of Rescue Midazolam (MDZ)Requirement of Rescue Midazolam (MDZ)
Rescue MDZ/No Rescue MDZRescue MDZ/No Rescue MDZDEX (N=55)DEX (N=55)
n (%)n (%)
PBO (N=50)PBO (N=50)
n (%)n (%)p-valuep-value
Required Rescue MDZRequired Rescue MDZ 26 (47.3%)26 (47.3%) 43 (86.0%)43 (86.0%) <0.001<0.001
Did Not Require Rescue MDZDid Not Require Rescue MDZ 29 (52.7%)*29 (52.7%)* 7 (14.0%)7 (14.0%) ––
Characteristics of Cooperative SedationCharacteristics of Cooperative Sedation
In cooperative sedation, In cooperative sedation, patients easily transition patients easily transition from sleep to wakefulness from sleep to wakefulness and task performance when and task performance when arousedaroused
Patients are able to resume Patients are able to resume rest when not stimulatedrest when not stimulated
Cooperative sedation is Cooperative sedation is most useful during most useful during procedures in which procedures in which communication with the communication with the patient must be maintainedpatient 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 The brain is not a sausage, it’s more like a well tuned musical instrument” tuned musical instrument”
Rudolfo Llinas Rudolfo Llinas Endogenous sleepEndogenous sleep
Loss of response to external Loss of response to external stimulistimuli
Sedative component of Sedative component of anesthesiaanesthesia
Arousability From Sedation During Arousability From Sedation During Dexmedetomidine InfusionDexmedetomidine Infusion
BIS indicates Bispectral Index SystemBIS indicates Bispectral Index System
During cognitive and cold pressor testingDuring cognitive and cold pressor testing
Just prior to cognitive and cold pressor testingJust prior to cognitive and cold pressor testing
Dexmedetomidine Dexmedetomidine InfusionInfusion
((mcgmcg/kg/h)/kg/h)
0
20
40
60
80
100
Placebo 0.2 0.6
BIS
Hall JE, Hall JE, Anesth AnalgAnesth Analg 2000 2000
• Patients were infused with Patients were infused with placebo or 1 of 2 doses of placebo or 1 of 2 doses of dexmedetomidine and dexmedetomidine and monitored with the Bispectral monitored with the Bispectral Index System (BIS) before Index System (BIS) before stimulation and immediately stimulation and immediately after being asked to perform after being asked to perform cognitive and cold pressor testscognitive and cold pressor tests
• Patients receiving either Patients receiving either infusion of dexmedetomidine infusion of dexmedetomidine could be completely aroused by could be completely aroused by a mild stimulusa mild stimulus11
Avoid oversedation
Reduce anxiety Maintain
communication Minimize
respiratory depression
Avoid oversedation
Reduce anxiety Maintain
communication Minimize
respiratory depression
Dexmedetomidine in Carotid Dexmedetomidine in Carotid EndarterectomyEndarterectomy
Intraoperative Assessment of Sedation Level Intraoperative Assessment of Sedation Level by the Blinded Observerby the Blinded Observer
Bekker A , Bekker A , J Neurosurg Anesth J Neurosurg Anesth 20042004
The Safety of Dexmedetomidine as The Safety of Dexmedetomidine as Primary Sedative for Awake CEAPrimary Sedative for Awake CEA
Total number of patientsTotal number of patientsN=151N=151
General AnesthesiaGeneral AnesthesiaN=10N=10
Regional/DexRegional/DexN=123N=123
Regional/No DexRegional/No DexN=18N=18
No ShuntNo ShuntN=0N=0
ShuntShuntN=10N=10
No ShuntNo ShuntN=111N=111
ShuntShuntN=12N=12
No ShuntNo ShuntN=12N=12
ShuntShuntN=6N=6
ElectiveElectiveN=10N=10
ObligatoryObligatoryN=0N=0
ElectiveElectiveN=7N=7
ObligatoryObligatoryN=5N=5
ObligatoryObligatoryN=2N=2
ElectiveElectiveN=4N=4
Bekker A, Bekker A, Anesth AnalgAnesth Analg 2006 2006
Clinical Experience with Clinical Experience with Dexmedetomidine for DBS ImplantationDexmedetomidine for DBS Implantation
• Dex (0.3-0.6 mcg/kg/hr) did not impair intensity of movement disorder Dex (0.3-0.6 mcg/kg/hr) did not impair intensity of movement disorder or interfere with MER in PD patientsor interfere with MER in PD patients
• Titration of Dex provided satisfactory sedation for DBS implantationTitration of Dex provided satisfactory sedation for DBS implantation
• Dex provided HD stability and decreased the use of antihypertensivesDex provided HD stability and decreased the use of antihypertensives11
• Propofol induced dyskinesia was controlled with DEX during DBS Propofol induced dyskinesia was controlled with DEX during DBS placementplacement22
11 Rozet I, Rozet I, Anesth Analg Anesth Analg 2006. 2006. 22 Deogaonkar A , Deogaonkar A , AnesthesiologyAnesthesiology 2006. 2006.
Dexmedetomidine and Respiratory Depression
• Minimal effects on ventilation is well documented in human volunteers 11
• Lack of respiratory depression was demonstrated in ICU patients 22
11 Belleville JP, Anesthesiology, 1992; Ebert TJ, Anesthesiology, 2000. 2 2
Venn RM, Crit Care , 2000; Martin E, J Intensive Care Med 2004.
Hospira MAC Trial: Respiratory Hospira MAC Trial: Respiratory DepressionDepression
Definition of Respiratory Depression: Definition of Respiratory Depression:
Respiratory rate < 8 bpm or oxygen saturation < 90% Respiratory rate < 8 bpm or oxygen saturation < 90%
Dex 0.5Dex 0.5 Dex 1.0Dex 1.0 PcbPcb
5 (3.7%) 3 (2.3%) 8 (12.75 (3.7%) 3 (2.3%) 8 (12.7P<0.018P<0.018
Both Dex groups: neither respiratory depression nor interventionBoth Dex groups: neither respiratory depression nor interventionPlb group: respiratory depression or a need for intervention 13.1% Plb group: respiratory depression or a need for intervention 13.1% and 16.1% respectivelyand 16.1% respectively
Dexmedetomidine and Hemodynamic Dexmedetomidine and Hemodynamic StabilityStability
Arain SR, Anesth Analg 2002 Bekker A, J Neurosurg Anesth 2004
50
70
90
110
130
150
Baseline Infusion Period PACU
Blo
od
Pre
ssu
re (
mm
Hg
)
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
80H
eart
Rat
e (
bp
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
Blo
od
Pre
ssu
re (
mm
Hg
)
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
80H
eart
Rat
e (
bp
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 RateMAC 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
20
30
40
100
VA
S P
ain
0
40
60
80
100
VA
S S
edat
ion
PropofolDexmedetomidine
5 20 35 50 65SurgEnd
Pre-surg Time After Surgery, minutes
* †
* †
Arain SR, Anesth Analg, 2002
Improved Improved postoperative pain postoperative pain and greater sedation and greater sedation with with dexmedetomidine dexmedetomidine compared with compared with propofolpropofol
Postoperative Effects of DexmedetomidinePostoperative Effects of DexmedetomidineL
ess
Ale
rt
Mor
e A
lert
Les
s P
ain
M
ore
Pai
n
Morphine-Sparing Effects in Morphine-Sparing Effects in Inpatient SurgeryInpatient Surgery
• 34 patients scheduled for 34 patients scheduled for inpatient surgeryinpatient surgery
• Randomized to either Randomized to either dexmedetomidine or dexmedetomidine or morphinemorphine
• Agents were started 30 Agents were started 30 minutes before the end of minutes before the end of surgerysurgery
• Dexmedetomidine Dexmedetomidine reduced the early reduced the early postoperative need for postoperative need for morphine by 66%morphine by 66%
0
2.5
5
7.5
10
12.5
Morphine Dexmedetomidine
Ave
rag
e T
ota
l Mo
rph
ine
U
sed
, mg
P<.01
0
2
4
6
8
10
12
0 10 20 30 40 50 60 70
Minutes in PACU
Cu
mu
lativ
e M
orp
hin
e
Use
d, m
g
MorphineDexmedetomidine
P<.01
Arain SR, Anesth Analg 2004
MAC Trial: Fentanyl UseMAC Trial: Fentanyl Use
Time PeriodTime Period
DEX 0.5 mcg/kgN=134n (%)
p – value
DEX 1 mcg/kgN=129n (%)
p – value
PBON=63n (%)
Infusion PeriodInfusion Period
Required FentanylRequired Fentanyl 79 (59.0) <0.001 55 (42.6) <0.001 56(88.9)
PACU PeriodPACU Period
Required FentanylRequired Fentanyl 5 (3.7) 0.104 5 (3.9) 0.105 6 (9.5)
OverallOverall
Required FentanylRequired Fentanyl 81 (60.4) <0.001 56 (43.4) <0.001 56(88.9)
Pharmacokinetics of IV agentsPharmacokinetics of IV agents
DexDex PropofolPropofol FentanylFentanyl AlfentaAlfenta
Vdcc, lVdcc, l 1616 1616 3030 1010
Vdss, lVdss, l 200200 350350 330330 3030
Cl, l/minCl, l/min 0.60.6 1.81.8 0.80.8 0.30.3
TT1/21/2, min, min 66 44 66 44
TT1/21/2hrhr 22 1.51.5 2.52.5 11
Dexmedetomodine Was Tried as a Dexmedetomodine Was Tried as a Primary Sedative for:Primary Sedative for:
• Sedation in CT and MRI imaging studiesSedation in CT and MRI imaging studiesMason K, Ped Anesth 2008Mason K, Ped Anesth 2008
Koroglu A, Anesth Analg 2006Koroglu A, Anesth Analg 2006
• Outpatient third molar surgeryOutpatient third molar surgeryUstin Y, J Oral Maxilfac Surg 2006Ustin Y, J Oral Maxilfac Surg 2006
Cheung C, Anaesthesia 2007Cheung C, Anaesthesia 2007
• Cataract surgeryCataract surgeryAlhashemi J, Br J Anaest 2006Alhashemi J, Br J Anaest 2006
• Cardiac catheterizationCardiac catheterizationTosun Z, J Card Vasc Anesth 2006Tosun Z, J Card Vasc Anesth 2006
Mester R, Am J Therap 2008Mester R, Am J Therap 2008
Use of Dexmedetomidine in MRIUse of Dexmedetomidine in MRI
• 80 children aged 1-7 years 80 children aged 1-7 years
• Randomly assigned to either Randomly assigned to either dexmedetomidine or midazolamdexmedetomidine or midazolam
– 10-minute loading doses: 10-minute loading doses: 1 1 mcg/kg dexmedetomidine, mcg/kg dexmedetomidine, 0.2 mg/kg midazolam0.2 mg/kg midazolam
– Infusions: 0.5 Infusions: 0.5 mcg/kg/h mcg/kg/h dexmedetomidine, dexmedetomidine, 6 mcg/kg/h midazolam6 mcg/kg/h midazolam11
• The quality of MRI was significantly The quality of MRI was significantly better (better (PP<.001) and the rate of <.001) and the rate of adequate sedation was significantly adequate sedation was significantly higher (higher (PP<.001) with <.001) with dexmedetomidinedexmedetomidine
0
10
20
30
40
1 2 3
Nu
mb
er
of
Pa
tien
ts
MidazolamDexmedetomidine
1 = no motion1 = no motion2 = minor movement2 = minor movement3 = major movement 3 = major movement necessitating another scannecessitating another scan
Quality of MRI
*P<.001 compared with midazolam
*
*
Koroglu A, Br J Anaesth 2005
Dexmedetomidine for GI Dexmedetomidine for GI ProceduresProcedures
Jalowiecki P, Anesthesiology 2005Jalowiecki P, Anesthesiology 2005
Use of Dex was associated with bradycardia, hypotension, Use of Dex was associated with bradycardia, hypotension, vertigo, nausea/vomiting, prolonged recoveryvertigo, nausea/vomiting, prolonged recovery
Muller R, Gastroint Endosc 2008 Muller R, Gastroint Endosc 2008
Clinical efficacy of Dex alone is less than propofol during ERCPClinical efficacy of Dex alone is less than propofol during ERCP
Demiraran Y, Can J Gastroenter 2007Demiraran Y, Can J Gastroenter 2007
Dex may be a good alternative to midazolam for upper Dex may be a good alternative to midazolam for upper endoscopy endoscopy
Dexmedetomidine: SafetyDexmedetomidine: Safety
PropofolPropofol
TI = 3.5TI = 3.5
Harrison N, Anesthetic Harrison N, Anesthetic Pharmacology, 2004Pharmacology, 2004
Dexmedetomidine:Dexmedetomidine:
Jorden V, Ann Pharmacoth, 2004Jorden V, Ann Pharmacoth, 2004
Pt 1 - 60 times the prescribed dosePt 1 - 60 times the prescribed dose
Pt 2 - 10 times the prescribed dosePt 2 - 10 times the prescribed dose
Pt 3 - 60 times the prescribed dosePt 3 - 60 times the prescribed dose
Ramsay M, Anesthesiology, 2004Ramsay M, Anesthesiology, 2004
Pt 1 - Infusion rate 10 mcg/kg/hPt 1 - Infusion rate 10 mcg/kg/h
Pt 2 - Infusion rate 5 mcg/kg/hPt 2 - Infusion rate 5 mcg/kg/h
Pt 3 – Infision rate 5 mcg/kg/h Pt 3 – Infision rate 5 mcg/kg/h
Therapeutic Index = (median lethal dose [LD50] / (mean effective dose [ED50]Therapeutic Index = (median lethal dose [LD50] / (mean effective dose [ED50]
Benzo- Benzo- diazepinesdiazepines PropofolPropofol OpioidsOpioids 2 2 AgonistsAgonists
SedationSedation XX XX XX XX
Alleviate anxietyAlleviate anxiety XX XX
Analgesic propertiesAnalgesic properties XX XX
Promote arousability Promote arousability during sedationduring sedation XX
No respiratoryNo respiratory depressiondepression XX
Control deliriumControl delirium XX
Comparison of Clinical EffectsComparison of Clinical Effects
Benzo- Benzo- diazepinesdiazepines PropofolPropofol OpioidsOpioids 2 2 AgonistsAgonists
Prolonged Prolonged weaningweaning XX XX XX**
Respiratory Respiratory depressiondepression XX XX XX
HypotensionHypotension XX XX XX XX
ConstipationConstipation XX
DeliriogenicDeliriogenic XX XX XX
TachycardiaTachycardia MorphineMorphine
BradycardiaBradycardia FentanylFentanyl X X
Comparison of Adverse EffectsComparison of Adverse Effects
All progress is based upon a universal innate All progress is based upon a universal innate desire on the part of every organism to live desire on the part of every organism to live
beyond its incomebeyond its income