csa - sedatives for procedures use shift enter to open the

Procedural Sedation

Steven L. Shafer, M.D.Professor of Anesthesia

Stanford University School of MedicineAdjunct Professor of Pharmaceutical Science

University of California at San Francisco

Disclosure

• Sedation is a labeled indication for all of the approved drugs I will be discussing.

• I’ve consulted with Roche (midazolam), AstraZeneca (propofol), Theravance (THRX-918661), Ethicon Endo-Surgery (Sedation Delivery System), and Guilford Pharmaceuticals (Aquavan)

-aminobutyric acid• a.k.a GABA• Most widespread inhibitory neurotransmitter in the CNS• Three classes of receptors

• GABAA

» Ligand gated ion channel» Cl- channel» Site of action of benzodiazepines, barbiturates, and propofol» Not the site of action of inhaled anesthetics

• GABAB

» Slow inhibitory post-synaptic potentials, regulates K+ and Ca++ conductance

» Not a binding site of anesthetic drugs

• GABAC

» Also a Cl- channel» Not a binding site of anesthetic drugs

GABAA Receptor

• Transmembrane pentamer composed of 2 , 2 , and 1 or subunits

– Each has a binding site for GABA

• Benzodiazepines– Bind a cleft of and

subunits– Increases frequency of

channel opening

• Barbiturates, (propofol)– Bind subunit– Increase duration of channel

opening

• Agonist: muscimol• Antagonist: bicuculine

Continuum of Depth of SedationDefinition of General Anesthesia and Levels of

Sedation / Analgesia(Developed by the American Society of Anesthesiologists)

(Approved by ASA House of Delegates on October 13, 1999)

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 following repeated or painful stimulation

Unarousable, even with painful stimulus

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

* Reflex withdrawal from a painful stimulus is NOT considered a purposeful response

Practice Guidelines for Sedation and Analgesia by

Non-Anesthesiologists• Approved by ASA, October 17, 2001

• Endorsed by ASGE, AAOMS, AAR, Adopted by JCAHO – Monitoring

• level of consciousness, ventilation, oxygenation, hemodynamics– Training

• pharmacology, airway, “recognize and manage complications,” ACLS

– Drugs• opioids, benzodiazepines, propofol, methohexital, ketamine

– Miscellaneous• supplemental oxygen, emergency equipment

Clinical Settings Where Sedation is Used

Clinical Settings

Procedures Estimated No. of Procedures

(US, 2003)Gastroenterology Colonoscopy, other

gastrointestinal endoscopies 24 million

Cardiology Cardiac catheterization, Angiography, TEE, Angioplasty,

Cardioversion, Pacemaker

12 million

Minor Surgery Knee arthroscopy, Inguinal hernia repair, Suturing, Excision

of skin lesion or tumor, Dermatological surgeries,

Insertion of lines/catheters, trachs, PEG tubes, Biopsy (breast

and liver)

12 million

Source: NDC; Verispan, Guilford Pharmaceuticals

Worldwide Market Size

US Europe Japan

2003 population

289 million 427 million

127.5 million

Estimated number of procedures

60-80 million

89-118 million

26-35 million

Total: 175-233 million procedures

Source: Population Reference Bureau; NDC

Sedative-Hypnotic Use: Worldwide Propofol and Midazolam Sales

0

10

20

30

40

50

60

70

80

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Mill

ion

s o

f U

nit

s

Propofol

Midazolam

50% Effect Site Decrement Time

Minutes since beginning of infusion

0 120 240 360 480 600

0

30

60

90

120

Min

utes

for

a 5

0% d

ecre

ase

fent

anyl

alfentanil

sufentanil

remifentanil

0 120 240 360 480 600

0

30

60

90

120

midazolam

thio

pent

al

propofol

Sedation and Amnesia:Propofol vs. Midazolam

• 67 volunteers, randomized, open label

• No difference between relative sedative and amnestic profiles for propofol and midazolam

• Big difference with thiopental and fentanyl from propofol or midazolam

• Vesalis et al, Anesthesiology 1997 87:749-64

Sedation50% Memory

LossMidazolam (ng/ml) 64 56Propofol (g/ml) 70 62Thiopental (ug/ml) 2.9 4.5Fentanyl (ng/ml) 0.9 3.2

Sedation and Amnesia:Propofol vs Midazolam

• Randomzed, blinded cross-over trial in 10 voluneers

• Titrated to different levels of sedation:

– Steep change in effect with small change in concentration

• Could not distinguish memory impairment between propofol and midazolam

• de Roode, et al, Anesth Analg 2000 91:1056-61

Propofol MidazolamLethargic 1350 208Asleep 1620 249

Increasing Interest in propofolby GI Community

0

2

4

6

8

10

12

14

16

18

1998 1999 2000 2001 2002

Year

Pe

er

Re

vie

we

d M

an

us

cri

pts

GI Practice Dynamics

• Recommendation colonoscopy screening at age 50– ~80 million Americans over the age of 50– Population is aging– Current waiting times are 4-6 months

• Similar trends for other GI procedures

Propofol Optimal for GI Sedation• Favorable pharmacokinetics

– Rapid onset/offset permits precise titration– Rapid offset permits rapid recovery

• from over sedation• if monitors detect any compromised patient state• after procedure

• Favorable pharmacodynamics– Decreased nausea and vomiting– Clear-headed after procedure

Propofol is Coming to a GI Suite Near You

www.drnaps.org

Propofol is Coming to a GI Suite Near You

www.drnaps.org

• Painless exams with total amnesia • Rapid endo and prep room turnover • Rapid discharge, usually within 15-20 minutes • Rapid return of patients to work or leisure • Improved provider efficiency • Protocol believed to be safer than traditional sedation • Improved ambiance and relaxation of techs and nurses • Better patient comprehension and compliance with discharge instructions • Patients delighted with you and your endo unit • Colonoscopy as a screening procedure gains popularity • Good to excellent patient memory of your findings and recommendations • Practice expansion through patient delight in lack of procedural discomfort

Midazolam Risks

The Introduction of Versed®

OnsetElimination Half-Life Duration

Equipotent Doses

Diazepam "slow" 40 hr "long" 10 mgMidazolam "fast" 4 hr "short" 5 mg

Midazolam and Diazepam Clinical Pharmacology(as originally introduced into clinical practice)

Result of initial dosing guidelines

• 1600 adverse reactions and 86 deaths associated with midazolam in the first 5 years after its introduction in the United States.

» Department of Health and Human Services, Office of Epidemiology and Biostatistics, Center for Drug Evaluation and Research, Data Retrieval Unit HFD-737, June 27, 1989

• Nearly all were associated with midazolam for sedation during endoscopy

FDA’S REGULATION OF THE NEW DRUGVERSED

HEARINGSBEFORE A

SUBCOMMITTEE OF THE

COMMITTEE ON

GOVERNMENT OPERATIONS

HOUSE OF REPRESENTATIVES

ONE HUNDREDTH CONGRESS

SECOND SESSION

MAY 5 AND 10, 1988

Midazolam Sedation for Endoscopy

Adapted from Bell, J Clin Pharmacol 1987 Feb;23(2):241-3

Age (years)0 20 40 60 80 100

Seda

tive

Dos

e (m

g)

0

5

10

15

Midazolam-Opioid Interactions(young volunteers)

Adapted from Kissen et al, Anesth Analg 72:65-69, 1990

0

5

10

15

20

0 500 1000 1500

[fentanyl - (g)]

Mid

azol

am E

D50

(mg)

[0] [135] [270] [400]

Alfentanil (g)

Benzodiazepine EEG EffectsE

EG

Am

plitu

de w

ithin

11.

5-30

Hz

( V/s

ec)

Blood concentration (g/ml)

Midazolam

Bretazenil

Flumazenil

Ro 19-4603

EEG Effects of Midazolam

0

50

100

150

200

0 30 60 90 120

Time (min)

EE

G E

ffec

t (m

V)

30 mg

50

15

Adapted from Bührer, CPT 48:555-567, 1990

Revised Midazolam Comparative Pharmacology

Plasma-Effect Site Equilibration Half-Life

range (average)Potency

range (mean)

Diazepam1-2.4 min (1.6 min)

406-1256 ng/ml(958 ng/ml)

Midazolam1.6-6.8 min (4.8 min)

94-385 ng/ml(190 ng/ml)

1991 Sedation Risks with Midazolam• Arrowsmith et al, FDA*

– 21,011 procedures– Complications with midazolam and diazepam– “Serious cardiorespiratory complications”: 54/10,000– Death: 3/10,000

*Results from the American Society for Gastrointestinal Endoscopy/U.S. Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointestinal Endoscopy, 1991

Current Sedation Risks with Midazolam• Vargo et al, Cleveland Clinic*

– 49 patients undergoing upper endoscopy– 57% of patients experienced 54 episodes of apnea

as identified by capnometry• > 30 seconds (mean = 60 seconds)• 50% of episodes led to desaturation (SaO2<90%)• 100% missed by clinical observation

– Over half of the patients were at risk

* Gastrointestinal Endoscopy 55:826-831, 2002

Propofol for MAC SedationPropofol for MAC Sedation

• Acknowledgements• Paul White

• David Goodale

At or DeeperP

rob

ab

ility

of B

ein

g A

t or

De

epe

r T

han

Effect Site Propofol Concentration (g/ml)

Sedation Therapeutic Window

Level 4 Level 3 Level 2

A G

ive

n L

eve

l of S

ed

atio

nThan Level:

2

3

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| | |||||||||||||| | | | || | | | | | | | | || | ||| | | | | | ||| | ||||||| ||| | ||| | |||| ||||| |||| | | | | ||| | || | | | | || | | || || || | | || ||||||||| | ||| || |||||||||||||||||||| |||||||||| ||||| ||||||||||||||||||||||||||||||||||| ||||| |||||||||| ||||||||||||||||||| ||||||||| ||||||||| ||||||| || ||||||| |||||||| |||| |||| ||||||| | || | || | | | || | | || | | | | | |||||| | || | ||| | ||| |||||| | || || || |||| | || | | | || || | |||| | || | | |

0 1 2 3

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 100%

50%

100%

150%

200%

250%

300%

350%

2'

2'

5'

5'

Simulated Propofol Concentration

Effect Site Plasma

at E

nd o

f Inf

usi

on

Per

cen

t of E

ffect

Site

Co

ncen

tra

tion

Minutes Since Beginning of Infusion

Pea

k E

ffec

t S

ite C

once

ntra

tion

Duration of Loading Infusion

0 2 4 6 8 10

0%

100%

200%

300%

400%

0.2

0.4

0.6

0.8

1.0

1.2

0.2

0.4

0.6

0.8

1.0

1.2

40 60 80 100

2040

60

80

Indu

ctio

n D

ose

(mg/

kg)

Induction Dose (m

g/kg)

Weight (kg)

Age in years

1.0 g/ml

Propofol Induction Dose Window

0.5 g/ml

25

50

75

100

25

50

75

100

0 60 120 180 240

4060

80100

Mai

nten

ance

Rat

e (m

cg/k

g)M

aintenance Rate (m

cg/kg)

Time (minutes)

Weight (kg)

1.0 g/ml

0.5 g/ml

Propofol Maintenance Dose Window

Infu

sion

Rat

e R

ange

( g

/kg/

min

)Infusion Rate Range to Maintain

Infusion Duration (minutes)

80 Year Old 20 Year Old

Age:

Sedation Therapeutic Window

0 20 40 60 80 100 1200

20

40

60

80

0.5 g/ml

1.0 g/ml

(70 kg man)

Propofol PK and age

60 120 180 240 300 3600

1

2

3

4

5

Prop

ofol

( g

/ml)

25 years old

50 years old75 years old

Infusion

Time in minutesSchnider et al, Anesthesiology 88:1170-1182, 1998

The elderly brain is more sensitive to propofolProbability of unconsciousness after a 1 hour infusion

Schnider et al, Anesthesiology 1999 (in press)

0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

Plasma propofol concentration (g/ml)

Unconscious

Conscious

Pro

babi

lity

75 50 25

After a propofol bolus, everyone falls asleep quickly

Min

utes

Age

0.0

0.5

1.0

1.5

2.0

20 30 40 50 60 70


But the elderly sleep longer

Min

utes

Age

0

2

4

6

8

10

12

20 30 40 50 60 70


Propofol dosing and ageRate to maintain “adequate anesthesia”

Based on data in Schnider et al, Anesthesiology 88:1170-1182, 1998

0 10 20 30 40 50 60

100

150

200

250

300

350

Time in minutes

Infu

sion

rat

e (

g/kg

/min

)

25 years old

50 years old

75 years old

The Automated Responsiveness Measure for Procedural Sedation

• Invented by Randy Hickle, MD

• Potential as a feedback system for sedation delivery

Minimal Sedation

Moderate Sedation

Deep Sedation

General Anesthesia

Desired Sedation TargetS

edat

ion

Dep

th(P

ropo

fol C

once

ntra

tion

)

No responseto pain

No responseto verbal/touch

Continuum of Depth of SedationDefinition of General Anesthesia and Levels of

Sedation / Analgesia(Developed by the American Society of Anesthesiologists)

(Approved by ASA House of Delegates on October 13, 1999)

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 following repeated or painful stimulation

Unarousable, even with painful stimulus

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

* Reflex withdrawal from a painful stimulus is NOT considered a purposeful response

Study Design

0

5

10

15

20

25

0 50 100 150 200 250

Time (minutes)

Pre

dict

ed E

ffec

t Sit

e P

ropo

fol

Con

cent

rati

on (g

/ml)

0

20

40

60

80

100

BIS

0.9 0.30.10.70.5

Doufas et al. Anesthesiology. 2004 101:1112-21.

ART Data

Post Hoc Bayesian Predicted Effect Site Propofol Concentration (g/ml)

0 1 2 3 4 5 6

ResponseNo Response


Post Hoc Bayesian Predicted Effect Site Propofol Concentration (g/ml)

0 1 2 3 4 5 6

Response

No Response

ResponseNo Response

ART data withprobabilitycurves


First Loss of ARMvs. Transition to Deep Sedation

00.5

11.5

22.5

3

3.54

4.55

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Subject

Prop

ofol

Eff

ect S

ite

(g/

ml)

Loss of ARTTransition to Deep Sedation

ARM Summary

• First loss of ARM consistently precedes deep sedation

• Alerts clinician to sedation level• Automatically reduces dose if patient remains non-

responsive– Override required for increasing dose

• ARM provides basis to individualize dosing• Assessment of drug effect for non-anesthesiologist• Reduces risk of transition to general anesthesia


Minimal Sedation

Moderate Sedation

Deep Sedation

General Anesthesia

Loss of ARM

Desired Sedation TargetS

edat

ion

Dep

th(P

ropo

fol C

once

ntra

tion

)

No responseto pain

No responseto verbal/touch

Novel GABAergic Hypnotic:THRX-918661

0 5 10 15 20 25 30 35 40 45 50 55 600

0 5 10 15 20 25 30 35 40 45 50 55 600

20

40

60

80

100

THRX-918661 (1.5mg/kg/min)Diprivan (0.5mg/kg/min)

Infusion

Time (mins)

BIS

val

ue

•20 minute infusion(n=4)

Beattie et al, SIVA UK, May 2003

Pig EEG study:

THRX-918661 vs propofol in Rats

0

10

20

30

40

50

60

70

Diprivan (20mins)Diprivan (3hrs)Diprivan (5hrs)THRX-918661 (20mins)THRX-918661 (3hrs)THRX-918661 (5hrs)D

urat

ion

(min

s) o

f los

sof

the

right

ing

refle

x

0

30

60

90

120

Dur

atio

n (m

ins)

for

tota

l rec

over

y


THRX-918661 vs. propofol in RatsTHRX- 918661

10mg/kg i.v.

30mg/kg i.v.

Propofol

3mg/kg i.v.

10mg/kg i.v.


“Aquavan”Water soluble propofol prodrug

Fechner et al, Anesthesiology 2003; 99:303

“Aquavan”

Fechner et al, Anesthesiology 2003; 99:303

“Aquavan”

• Developed as a non-stinging propofol prodrug.

• Causes transient (< 1 min) burning in the genitals and anus.

Sedation is about relieving stress…

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