Propofol in the GI Suite: Is it safe

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Propofol in the GI Suite Is it safe?
Steven L. Shafer, M.D. Professor of Anesthesia,
Stanford University Adjunct Professor of
Pharmaceutical Sciences, UCSFEditor in Chief,
Anesthesia Analgesia
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),
  and Guilford Pharmaceuticals (Aquavan)
• Im the Chair of the Anesthesia Advisory Panel
  for Ethicon Endo-Surgery, and have been involved
  with the development of their Sedation Delivery
  System for 5 years

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Is Propofol Safe in the GI Suite

• I will assume that if propofol is safe if it is
  administered by an anesthesiologist.
• If not, then you are at the wrong lecture
• The question is whether propofol is safe in the
  GI suite if it is NOT administered by an
  anesthesiologist.
• This implies propofol administration by a nurse.

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Yikes!

• This is very controversial because
• It affects our income.
• If nurses can give propofol safely in the GI
  suite, then why not in the OR?
• It affects our pride.
• Weve trained for years, yet weve still had
  nightmare cases of sedation where it took all our
  skill to manage the patient.
• We fear for the wellbeing of the patient.
• If the patient was your mom, would you want a
  nurse or an anesthesiologist to give the propofol.

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Key Question

• We will start by addressing the key question
  what is best for the patient?
• After that, we will consider some of the
  political, economic, and regulatory baggage that
  accompanies the issue.

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Colonoscopy Recommendations for Risk-Free
Individuals

• Colonoscopy screening at ages 50, 60, 70, and 80
• Based on 2005 census data, works out to 9.3
  million colonoscopies / year
• Approximately 35,000 anesthesiologists in the
  United States
• Schubert, Mayo Clin Proc. 200176995-1010
• Thats at least 295 colonoscopies / year /
  anesthesiologist
• In addition to the 714 surgical procedures / year
  / anesthesiologist

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Observation 1

• It is not in the patients interest that they
  receive anesthesiologist delivered propofol.
• We simply cant provide the service
• They will die of colon cancer waiting for their
  colonoscopy
• Nonstarter

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Is Current Practice Safe?

• Current practice consists of a midazolam and an
  opioid, typically meperidine or fentanyl
• Must first consider the clinical pharmacology of
  midazolam

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Midazolam Risks
The Introduction of Versed
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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
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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

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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
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Midazolam Sedation for Endoscopy
Adapted from Bell, J Clin Pharmacol 1987
Feb23(2)241-3
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Midazolam-Opioid Interactions(young volunteers)
Adapted from Kissen et al, Anesth Analg 7265-69,
1990
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Benzodiazepine EEG Effects
Midazolam
V/sec)
Flumazenil
m
EEG Amplitude within 11.5-30 Hz (
Bretazenil
Ro 19-4603
m
Blood concentration (
g/ml)
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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)
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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
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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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Observation 2

• Midazolam is not intrinsically safe
• Midazolam for sedation has caused a large number
  of deaths
• Like propofol, midazolam shows profound synergy
  with opioids at inducing ventilatory depression

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Is Propofol Safe?

• What are the relevant PK characteristics of
  propofol?

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Propofol Pharmacokinetics
Schnider et al, Anesthesiology 1998881170-82
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Diprifusor Target Controlled Drug Delivery
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Extended PK/PD Concept The Effect Site
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Fentanyl TCI
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Fentanyl TCIPlasma Target
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Fentanyl TCIEffect Site Target
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Propofol Plasma Control
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Propofol Effect Site Control
6
Induction
Incision
4
Prep
Titrating
Propofol (mcg/ml)
Skin Closure
2
Waiting for
Surgeon
Maintenance
Awaken
0
0
10
20
30
40
50
60
Minutes
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50 Effect Site Decrement Time
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Is Propofol Safe?

• What studies have examined propofol safety?

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

• 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

www.drnaps.org
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Dr. NAPS

• 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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Dr. NAPS

• Claims gt 27,000 patients without an adverse event.

www.drnaps.org
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Dr. NAPS Safety Net

• Rescue Drugs
• Atropine
• Ephedrine
• Oxygen

• Standard monitoring
• Capnography
• Nurse ventilation confirmation
• Nurse - patient interface
• Airway rescue
• Nurse
• gastroenterologist
• respiratory technician
• emergency room physician
• Anesthesiologist

www.drnaps.org
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Propofol Sedation during Endoscopic
ProceduresSafe and Effective Administration by
RegisteredNurses Supervised by Endoscopists

• Tohda et al
• Endoscopy. 200638360-7 (April)
• Private hospital in Japan
• Propofol protocol developed by anesthesiologists
  prior to study
• 27,500 endoscopy patients

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Propofol Sedation during Endoscopic
ProceduresSafe and Effective Administration by
RegisteredNurses Supervised by Endoscopists
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Propofol Sedation during Endoscopic
ProceduresSafe and Effective Administration by
RegisteredNurses Supervised by Endoscopists
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Sedation with Propofol for Routine ERCP in
High-RiskOctogenarians A Randomized, Controlled
Study

• Riphaus et al
• Am J Gastroenterol. 2005 Sep1001957-63
• 150 consecutive patients 80 years old
• 91 ASA III
• Propofol alone vs. Midazolam/meperidine

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Sedation with Propofol for Routine ERCP in
High-RiskOctogenarians A Randomized, Controlled
Study
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Nurse-Administered Propofol Versus Midazolamand
Meperidine for Upper Endoscopy in Cirrhotic
Patients

• Weston et al.
• Am J Gastroenterol. 2003,Nov982440-7
• 20 outpatients with known chronic liver disease
• Patients undergoing variceal screening

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Nurse-Administered Propofol Versus Midazolamand
Meperidine for Upper Endoscopy in Cirrhotic
Patients
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Observation 3

• Propofol has now been studied numerous times for
  GI sedation, given by a nurse
• The available data suggest it is safe when used
  for moderate sedation
• I have not cherry picked the articles to make a
  point there are no published studies that Im
  aware of showing a significant risk of propofol
  sedation in the hands of a properly trained nurse

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Lets get political!

• What do societies say?
• Whose interests do they represent?

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Blue Cross Policy

• September 22, 2005
• "The routine assistance of an Anesthesiologist or
  CRNA for average risk patients undergoing
  standard upper and/or lower gastrointestinal
  endoscopic procedures is considered not medically
  necessary."
• It is considered medically necessary in some
  settings.

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anesthesia services including monitored
anesthesia care (MAC) is considered medically
necessary during gastrointestinal endoscopic
procedures in any of the following situations"

• prolonged or therapeutic procedure requiring deep
  sedation or
• history of or anticipated intolerance to standard
  sedatives or
• increased risk for complication due to severe
  comorbidity (American Society of
  Anesthesiologists (ASA)) class III physical
  status or greater or
• patient of extreme age lt1 or gt70 or
• pregnancy or
• history of drug or alcohol abuse or
• uncooperative or acutely agitated patients (e.g.,
  delirium, organic brain disease, senile
  dementia) or

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anesthesia services including monitored
anesthesia care (MAC) is considered medically
necessary during gastrointestinal endoscopic
procedures in any of the following situations"

• increased risk for airway obstruction due to
  anatomic variant including any of the following
• history of previous problems with anesthesia or
  sedation or
• history of stridor or sleep apnea or
• dyamorphic facial features such as Pierre-Robin
  syndrome or trisomy-21 or
• presence of oral abnormalities including but not
  limited to a small oral opening (less than 3cm in
  an adult), high arched palate, macroglossia,
  tonsillar hypertrophy, or a non-visible uvula or
  
• neck abnormalities including but not limited to
  short neck, obesity involving the neck and facial
  structures, limited neck extension, decreased
  hyoid-mental distance (less than 3cm in an
  adult), neck mass, cervical spine disease or
  trauma, tracheal deviation, or advanced
  rheumatoid arthritis or
• jaw abnormalities including but not limited to
  micrognathia, retrognathia, trismus, or
  significant malocclusion.

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2004 Joint Recommendation

• Issued by
• The American College of Gastroenterology
• American Gastroenterological Association
• American Society for Gastrointestinal Endoscopy

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• In general, diagnostic and uncomplicated
  therapeutic endoscopy and colonoscopy are
  successfully performed with moderate (conscious)
  sedation.
• Compared to standard doses of benzodiazepines and
  narcotics, propofol may provide faster onset and
  deeper sedation.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• More rapid cognitive and functional recovery can
  be expected with the use of propofol as a single
  agent.
• Clinically important benefits over standard
  sedatives have not been consistently demonstrated
  in average-risk patients undergoing standard
  routine upper and lower endoscopy. Further
  randomized clinical trials are needed in this
  setting.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• Propofol may have more clinically significant
  advantages when used for prolonged and
  therapeutic procedures, including, but not
  limited to, ERCP and EUS.
• There are data to support the use of propofol by
  adequately trained non-anesthesiologists. Large
  case series indicate that with adequate training
  physician-supervised nurse administration of
  propofol can be done safely and effectively. The
  regulations governing the administration of
  propofol by nursing personnel vary from state to
  state.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• Patients receiving propofol should receive care
  consistent with deep sedation. Personnel should
  be capable of rescuing the patient from general
  anesthesia and/or severe respiratory depression.
• A designated individual, other than the
  endoscopist, should be present to monitor the
  patient throughout the procedure and should be
  able to recognize and assist in the management of
  complications.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• The routine assistance of an anesthesiologist/anes
  thetist for average risk patients undergoing
  standard upper and lower endoscopic procedures is
  not warranted.
• Physician-nurse teams administering propofol
  should possess the training and skills necessary
  to rescue patients from severe respiratory
  depression.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• Complex procedures and procedures in high-risk
  patients may justify the use of an
  anesthesiologist/anesthetist to provide conscious
  and/or deep sedation. In such cases this provider
  may bill separately for their professional
  services.
• The use of agents to achieve sedation for
  endoscopy must conform to the policies of the
  individual institution.

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RECOMMENDATIONS ON THE ADMINISTRATION OF SEDATION
FOR THE PERFORMANCE OF ENDOSCOPIC PROCEDURES

• Reimbursement for conscious sedation is included
  within the codes covering endoscopic procedures.
• Billing separately for conscious sedation has
  been targeted by the OIG as a possible fraud and
  abuse violation, and is not recommended.

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Propofol and Endoscopy
Peer Reviewed Manuscripts in Medline
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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
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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

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What do Anesthesiologists Say?

• Only anesthesiologists can use propofol because
  thats what it says on the package insert.
• Hard to defend based on available evidence.
• Unclear if anesthesiologists are looking out for
  their patients or their turf.
• Major push by GI doctors to change that, given
  the lack of a safety signal when propofol is used
  by nurses under careful guidelines.
• They wont be able to change the label, because
  only the company that owns the label has the
  authority to change it.

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Technologies to Make Propofol Sedation Safer

• Are they needed, or is propofol safe enough
  already?
• Aquavan
• Propofol prodrug
• Ethicon Sedation Delivery System
• Integrated propofol monitoring and delivery
• I have significant COI, so interpret my comments
  skeptically

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Aquavan

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

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AquavanWater soluble propofol prodrug
Fechner et al, Anesthesiology 2003 99303
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Aquavan
Fechner et al, Anesthesiology 2003 99303
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Propofol Sedation Delivery System
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The Automated Responsiveness Measure for
Procedural Sedation

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

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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
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First Loss of ARMvs. Transition to Deep Sedation
5
Loss of ARM
4.5
Transition to Deep Sedation
g/ml)
4
3.5
3
2.5
Propofol Effect Site (
2
1.5
1
0.5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Subject
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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.
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Sedation is about relieving stress
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