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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
Schnider et al, Anesthesiology 1999 (in press)
But the elderly sleep longer
Min
utes
Age
0
2
4
6
8
10
12
20 30 40 50 60 70
Schnider et al, Anesthesiology 1999 (in press)
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
Doufas et al. Anesthesiology. 2004 101:1112-21.
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
Doufas et al. Anesthesiology. 2004 101:1112-21.
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
Doufas et al. Anesthesiology. 2004 101:1112-21.
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
Beattie et al, SIVA UK, May 2003
THRX-918661 vs. propofol in RatsTHRX- 918661
10mg/kg i.v.
30mg/kg i.v.
Propofol
3mg/kg i.v.
10mg/kg i.v.
Beattie et al, SIVA UK, May 2003
“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…