Procedural Sedation

1
Procedural Sedation
Steven L. Shafer, M.D. Professor of
Anesthesia Stanford University School of
Medicine Adjunct Professor of Pharmaceutical
Science University of California at San Francisco
2
Disclosure

• Sedation is a labeled indication for all of the
  approved drugs I will be discussing.
• Ive consulted with Roche (midazolam),
  AstraZeneca (propofol), Theravance (THRX-918661),
  Ethicon Endo-Surgery (Sedation Delivery System),
  and Guilford Pharmaceuticals (Aquavan)

3
?-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

4
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

5
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)
Reflex withdrawal from a painful stimulus is
NOT considered a purposeful response
6
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

7
Clinical Settings Where Sedation is Used
Source NDC Verispan, Guilford Pharmaceuticals
8
Worldwide Market Size
Total 175-233 million procedures
Source Population Reference Bureau NDC
9
Sedative-Hypnotic Use Worldwide Propofol and
Midazolam Sales
10
50 Effect Site Decrement Time
11
Sedation and AmnesiaPropofol 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 87749-64

12
Sedation and AmnesiaPropofol 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 911056-61

13
Increasing Interest in propofolby GI Community
14
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

15
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

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Propofol is Coming to a GI Suite Near You
www.drnaps.org
17
Propofol is Coming to a GI Suite Near You

• 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

www.drnaps.org
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Midazolam Risks
The Introduction of Versed
19
Midazolam and Diazepam Clinical Pharmacology
(as originally introduced into clinical practice)
Elimination
Equipotent
Onset
Half-Life
Duration
Doses
Diazepam
"slow"
40 hr
"long"
10 mg
Midazolam
"fast"
4 hr
"short"
5 mg
20
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

21
FDAS REGULATION OF THE NEW DRUG
VERSED
HEARINGS
BEFORE A
SUBCOMMITTEE OF THE
COMMITTEE ON
GOVERNMENT OPERATIONS
HOUSE OF REPRESENTATIVES
ONE HUNDREDTH CONGRESS
SECOND SESSION
MAY 5 AND 10, 1988
22
Midazolam Sedation for Endoscopy
Adapted from Bell, J Clin Pharmacol 1987
Feb23(2)241-3
23
Midazolam-Opioid Interactions(young volunteers)
Adapted from Kissen et al, Anesth Analg 7265-69,
1990
24
Benzodiazepine EEG Effects
Midazolam
V/sec)
Flumazenil
m
EEG Amplitude within 11.5-30 Hz (
Bretazenil
Ro 19-4603
m
Blood concentration (
g/ml)
25
EEG Effects of Midazolam
Adapted from Bührer, CPT 48555-567, 1990
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Revised Midazolam Comparative Pharmacology
Plasma-Effect Site
Equilibration Half-Life
Potency
range (average)
range (mean)
1-2.4 min
406-1256 ng/ml
Diazepam
(1.6 min)
(958 ng/ml)
1.6-6.8 min
94-385 ng/ml
Midazolam
(4.8 min)
(190 ng/ml)
27
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
28
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
• gt 30 seconds (mean 60 seconds)
• 50 of episodes led to desaturation (SaO2lt90)
• 100 missed by clinical observation
• Over half of the patients were at risk

Gastrointestinal Endoscopy 55826-831, 2002
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Propofol for MAC Sedation

• Acknowledgements
• Paul White
• David Goodale

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Propofol PK and age
Schnider et al, Anesthesiology 881170-1182, 1998
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The elderly brain is more sensitive to
propofolProbability of unconsciousness after a 1
hour infusion
Unconscious
1.0
0.8
75
50
25
0.6
Probability
0.4
0.2
Conscious
0.0
0
2
4
6
8
Plasma propofol concentration (mg/ml)
Schnider et al, Anesthesiology 1999 (in press)
38
After a propofol bolus, everyone falls asleep
quickly
2.0
1.5
Minutes
1.0
0.5
0.0
20
30
40
50
60
70
Age
Schnider et al, Anesthesiology 1999 (in press)
39
But the elderly sleep longer
12
10
8
Minutes
6
4
2
0
20
30
40
50
60
70
Age
Schnider et al, Anesthesiology 1999 (in press)
40
Propofol dosing and ageRate to maintain
adequate anesthesia
350
300
g/kg/min)
m
250
25 years old
(
rate
50 years old
200
75 years old
Infusion
150
100
0
10
20
30
40
50
60
Time in minutes
Based on data in Schnider et al, Anesthesiology
881170-1182, 1998
41
The Automated Responsiveness Measure for
Procedural Sedation

• Invented by Randy Hickle, MD
• Potential as a feedback system for sedation
  delivery

42
Desired Sedation Target
General Anesthesia
No responseto pain
Deep Sedation
Sedation Depth(Propofol Concentration)
No responseto verbal/touch
Moderate Sedation
Minimal Sedation
43
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)
Reflex withdrawal from a painful stimulus is
NOT considered a purposeful response
44
Study Design
Doufas et al. Anesthesiology. 2004 1011112-21.
45
ART Data
Doufas et al. Anesthesiology. 2004 1011112-21.
46
ART data with probabilitycurves
Doufas et al. Anesthesiology. 2004 1011112-21.
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First Loss of ARMvs. Transition to Deep Sedation
48
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 1011112-21.
49
Desired Sedation Target
General Anesthesia
No responseto pain
Deep Sedation
Sedation Depth(Propofol Concentration)
No responseto verbal/touch
Moderate Sedation
Loss of ARM
Minimal Sedation
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Novel GABAergic HypnoticTHRX-918661
Pig EEG study
Beattie et al, SIVA UK, May 2003
51
THRX-918661 vs propofol in Rats
Beattie et al, SIVA UK, May 2003
52
THRX-918661 vs. propofol in Rats
THRX- 918661
Propofol
3mg/kg i.v.
10mg/kg i.v.
10mg/kg i.v.
30mg/kg i.v.
Beattie et al, SIVA UK, May 2003
53
AquavanWater soluble propofol prodrug
Fechner et al, Anesthesiology 2003 99303
54
Aquavan
Fechner et al, Anesthesiology 2003 99303
55
Aquavan

• Developed as a non-stinging propofol prodrug.
• Causes transient (lt 1 min) burning in the
  genitals and anus.

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Sedation is about relieving stress