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