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CSA - Sedatives for Procedures Use SHIFT ENTER to open the ... CSA - Sedatives for Procedures Use SHIFT ENTER to open the ... Presentation Transcript

  • 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
  • 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
        • GABA A
            • Ligand gated ion channel
            • Cl - channel
            • Site of action of benzodiazepines, barbiturates, and propofol
            • Not the site of action of inhaled anesthetics
        • GABA B
            • Slow inhibitory post-synaptic potentials, regulates K + and Ca ++ conductance
            • Not a binding site of anesthetic drugs
        • GABA C
            • Also a Cl - channel
            • Not a binding site of anesthetic drugs
    View slide
  • GABA A 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
    View slide
  • Continuum of Depth of Sedation Definition 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 May be impaired Usually maintained Usually maintained Unaffected Cardiovascular Function Frequently inadequate May be inadequate Adequate Unaffected Spontaneous Ventilation Intervention often required Intervention may be required No intervention required Unaffected Airway Unarousable, even with painful stimulus Purposeful* response following repeated or painful stimulation Purposeful* response to verbal or tactile stimulation Normal response to verbal stimulation Responsiveness General Anesthesia Deep Sedation / Analgesia Moderate Sedation / Analgesia (“Conscious Sedation”) Minimal Sedation (“Anxiolysis”)
  • 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 Source: NDC; Verispan, Guilford Pharmaceuticals 12 million 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) Minor Surgery 12 million Cardiac catheterization, Angiography, TEE, Angioplasty, Cardioversion, Pacemaker Cardiology 24 million Colonoscopy, other gastrointestinal endoscopies Gastroenterology Estimated No. of Procedures (US, 2003) Procedures Clinical Settings
  • Worldwide Market Size Total: 175-233 million procedures Source: Population Reference Bureau; NDC 26-35 million 89-118 million 60-80 million Estimated number of procedures 127.5 million 427 million 289 million 2003 population Japan Europe US
  • Sedative-Hypnotic Use: Worldwide Propofol and Midazolam Sales
  • 50% Effect Site Decrement Time
  • 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
  • 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
  • Increasing Interest in propofol by GI Community
  • 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 ®
  • Onset Elimination Half-Life Duration Equipotent Doses Diazepam "slow" 40 hr "long" 10 mg Midazolam "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 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
  • Midazolam Sedation for Endoscopy Adapted from Bell, J Clin Pharmacol 1987 Feb;23(2):241-3
  • Midazolam-Opioid Interactions (young volunteers) Adapted from Kissen et al, Anesth Analg 72:65-69, 1990
  • Benzodiazepine EEG Effects EEG Amplitude within 11.5-30 Hz (  V/sec) Blood concentration (  g/ml) Midazolam Bretazenil Flumazenil Ro 19-4603
  • EEG Effects of Midazolam Adapted from Bührer, CPT 48:555-567, 1990
  • Revised Midazolam Comparative Pharmacology Plasma-Effect Site Equilibration Half-Life range (average) Potency range (mean) Diazepam 1-2.4 min (1.6 min) 406-1256 ng/ml (958 ng/ml) Midazolam 1.6-6.8 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 (SaO 2 <90%)
        • 100% missed by clinical observation
      • Over half of the patients were at risk
    * Gastrointestinal Endoscopy 55:826-831, 2002
  • Propofol for MAC Sedation
    • Acknowledgements
        • Paul White
        • David Goodale
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  • Propofol PK and age Schnider et al, Anesthesiology 88:1170-1182, 1998
  • The elderly brain is more sensitive to propofol Probability 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 Probability 75 50 25
  • After a propofol bolus, everyone falls asleep quickly Minutes 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 Minutes Age 0 2 4 6 8 10 12 20 30 40 50 60 70 Schnider et al, Anesthesiology 1999 (in press)
  • Propofol dosing and age Rate 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 Infusion rate (  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
  • Desired Sedation Target Minimal Sedation Moderate Sedation Deep Sedation General Anesthesia Sedation Depth (Propofol Concentration) No response to pain No response to verbal/touch
  • Continuum of Depth of Sedation Definition 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 May be impaired Usually maintained Usually maintained Unaffected Cardiovascular Function Frequently inadequate May be inadequate Adequate Unaffected Spontaneous Ventilation Intervention often required Intervention may be required No intervention required Unaffected Airway Unarousable, even with painful stimulus Purposeful* response following repeated or painful stimulation Purposeful* response to verbal or tactile stimulation Normal response to verbal stimulation Responsiveness General Anesthesia Deep Sedation / Analgesia Moderate Sedation / Analgesia (“Conscious Sedation”) Minimal Sedation (“Anxiolysis”)
  • Study Design Doufas et al. Anesthesiology. 2004 101:1112-21.
  • ART Data Doufas et al. Anesthesiology. 2004 101:1112-21.
  • ART data with probability curves Doufas et al. Anesthesiology. 2004 101:1112-21.
  • First Loss of ARM vs. Transition 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.
  • Desired Sedation Target Minimal Sedation Moderate Sedation Deep Sedation General Anesthesia Loss of ARM Sedation Depth (Propofol Concentration) No response to pain No response to verbal/touch
  • Novel GABAergic Hypnotic: THRX-918661 Beattie et al, SIVA UK, May 2003 Pig EEG study:
  • THRX-918661 vs propofol in Rats Beattie et al, SIVA UK, May 2003
  • THRX-918661 vs. propofol in Rats THRX- 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…