Propofol - Is it safe in the GI suite.ppt

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

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), and Guilford Pharmaceuticals (Aquavan)

• I’m 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

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.

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.• We’ve trained for years, yet we’ve 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.

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.

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. 2001;76:995-1010

• That’s at least 295 colonoscopies / year / anesthesiologist

– In addition to the 714 surgical procedures / year / anesthesiologist

Observation 1

• It is not in the patient’s interest that they receive anesthesiologist delivered propofol.

• We simply can’t provide the service

• They will die of colon cancer waiting for their colonoscopy

•Nonstarter

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

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

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

Is Propofol Safe?

• What are the relevant PK characteristics of propofol?

Propofol Pharmacokinetics

Schnider et al, Anesthesiology 1998;88:1170-82

““ Diprifusor” Diprifusor” Target Controlled Drug DeliveryTarget Controlled Drug Delivery

““ Diprifusor” Diprifusor” Target Controlled Drug DeliveryTarget Controlled Drug Delivery

Extended PK/PD Concept: The “Effect Site”

I

V 2k 12 V 1

k 13 V 3

Rapidly Equilibrating Compartment

k 21Central

Compartmentk 31

Slowly EquilibratingCompartment

k 10

Effect Site

V e

Drug Administration

k 1e

k e0

Fentanyl TCI

Fen

tany

l Con

cent

rati

on

(ng/

ml)

Time (minutes)

awaken patient

skin closure

maintenance

titrating

incision

waiting

prep

induction

0 10 20 30 40 50 600

2

4

6

8

10

Plasma

Fentanyl TCIPlasma Target

Fen

tany

l Con

cent

rati

on

(ng/

ml)

Time (minutes)

awaken patient

skin closure

maintenance

titrating

incision

waiting

prep

induction

0 10 20 30 40 50 600

2

4

6

8

10

Effect Site

Plasma

Fentanyl TCIEffect Site Target

Fe

nta

nyl C

once

ntr

atio

n

(ng

/ml)

Time (minutes)

awaken patient

skin closuretitrating

incision

induction

0 10 20 30 40 50 600

2

4

6

8

10

30

40

Effect Site

Plasma

Minutes0 10 20 30 40 50 60

Pro

pofo

l (m

cg/m

l)

0

2

4

6

Skin Closure

Titrating

Incision

Waiting forSurgeon

Prep

Induction

Awaken

Maintenance

Propofol: Plasma Control

Propofol: Effect Site Control

Minutes0 10 20 30 40 50 60

Pro

po

fol (

mcg

/ml)

0

2

4

6

Skin Closure

Titrating

Incision

Waiting forSurgeon

Prep

Induction

Awaken

Maintenance

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

Is Propofol Safe?

• What studies have examined propofol safety?

Propofol is Coming to a GI Suite Near You

www.drnaps.org

Dr. NAPS

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

Dr. NAPS

www.drnaps.org

• 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

Dr. NAPS

www.drnaps.org

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

Dr. NAPS “Safety Net”

www.drnaps.org

• Rescue Drugs– Atropine – Ephedrine– Oxygen

• Standard monitoring • Capnography • Nurse ventilation confirmation • Nurse - patient interface

• Airway rescue– Nurse– gastroenterologist– respiratory technician– emergency room physician– Anesthesiologist

Propofol Sedation during Endoscopic Procedures:Safe and Effective Administration by Registered

Nurses Supervised by Endoscopists

• Tohda et al

• Endoscopy. 2006;38:360-7 (April)

• Private hospital in Japan

• Propofol protocol developed by anesthesiologists prior to study

• 27,500 endoscopy patients



Upper Endoscopy Colonoscopy TotalAge (years) Mean (SD) 45 ± 7 49 ± 9 46 ± 8 Range 14 - 92 16 - 89 14 - 92

Sex Male 56% 60% 57% Female 44% 40% 43%

Number 19600 7900 27500

Total propofol dosage (mg) Mean 72 ± 10 94 ± 13 Range 20 - 150 40 - 190

Summary of 27,500 Patients



n % n % n %Emergency Interventions 0 0 0 0 0 0Oxygen administered 1130 5.77 577 7.31 1707 6.21Intravenous Saline 157 0.8 512 6.48 669 2.43Spo2 < 90% 1275 6.51 567 7.18 1842 6.7Spo2 < 85% 121 0.62 20 0.25 141 0.51Prolonged 12 0.06 0 0 12 0.04Systolic BP < 90 mm Hg 235 1.2 276 3.49 511 1.86HR < 50 BPM 143 0.73 325 4.11 468 1.7

Total(n = 27500)

Summary of 27,500 PatientsUpper Endoscopy

(n = 19600)Colonoscopy

(n = 7900)

Sedation with Propofol for Routine ERCP in High-RiskOctogenarians: A Randomized, Controlled Study

• Riphaus et al

• Am J Gastroenterol. 2005 Sep;100:1957-63

• 150 consecutive patients ≥ 80 years old

• 91% ASA ≥ III

• Propofol alone vs. Midazolam/meperidine

Sedation with Propofol for Routine ERCP in High-RiskOctogenarians: A Randomized, Controlled Study

Midazolam/Meperidine Propofol Group (n = 75) Group (n = 75)

Onset of effective sedation (min) 5 ± 3 (3–9) 3 ± 2 (2–7)Patient cooperation (rated by endoscopist) 7.3 ± 1.5 (3–10) 8.7 ± 1.7 (5–10)Patient cooperation (rated by observer) 7.0 ± 1.4 (2–10) 8.5 ± 1.0 (5–10)Recovery time (min) 31 ± 8 (25–42) 22 ± 7 (15–37)Postanaesthesia recovery score(30 min after ERCP) 6.1 ± 1.1 (5–8) 8.3 ± 1.2 (6–10)Patient tolerance (rated by the patient 4 h after procedure) 7.6 ± 1.8 (6–10) 8.5 ± 1.9 (6–10) Midazolam (mg) 6.3 2.9 (2.5-12)Meperidine 50 25 (25-75)Propofol 322 208 (40-900)Maximum decrease in SpO2 6% 3% 3% 2%SpO2 drop below 90% 7 8Heart rate < 50 4 3Mean systolic BP drop 12% 5% 7% 4%Systolic < 90 mmHg 4 6

Parameters of Sedation Efficacy

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

• Weston et al.

• Am J Gastroenterol. 2003,Nov;98:2440-7

• 20 outpatients with known chronic liver disease

• Patients undergoing variceal screening

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

Midazolam/Meperidine Propofol Group (n = 10) Group (n = 10)

Time to achieve full sedation 7.3 (2.8) 3.6 (1.2) Time to exit procedure room after completion of procedure 10.4 (3) 9.5 (2.8) Time to reach OAAS 5 29 (10.5) 15 (3.6) Time to drink fluids 37.7 (9.2) 27.5 (9.5) Time to full recovery 51.6 (18.4) 34.9 (10.3) Time to discharge 71.0 (22.3) 54.2 (10.4) Midazolam (mg) 5.3 0.9 (3-6)Meperidine 71.3 17.7 (50-100)Propofol 203 44 (150-280)Maximum decrease in SpO2 n.d. n.d.SpO2 drop below 90% n.d. n.d.Mean systolic BP drop n.d. n.d.Systolic < 90 mmHg n.d. n.d.

Parameters of Sedation Efficacy

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 I’m aware of showing a significant risk of propofol sedation in the hands of a properly trained nurse

Let’s get political!

• What do societies say?

• Whose interests do they represent?

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.

“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 <1 or >70; or

• pregnancy; or

• history of drug or alcohol abuse; or

• uncooperative or acutely agitated patients (e.g., delirium, organic brain disease, senile dementia); or

“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.

2004 Joint Recommendation

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

Endoscopy

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.


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.


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.


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.


PROCEDURES

• The routine assistance of an anesthesiologist/anesthetist 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.


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.


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.

Propofol and Endoscopy

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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)

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

What do Anesthesiologists Say?

• “Only anesthesiologists can use propofol because that’s 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 won’t be able to change the label, because only the company that owns the label has the authority to change it.

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

“Aquavan”

• Developed as a non-stinging propofol prodrug.

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

“Aquavan”Water soluble propofol prodrug

Fechner et al, Anesthesiology 2003; 99:303

“Aquavan”

Fechner et al, Anesthesiology 2003; 99:303

Propofol Sedation Delivery System

The Automated Responsiveness Measure for Procedural Sedation

• Invented by Randy Hickle, MD

• Potential as a feedback system for sedation delivery

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

First Loss of ARMvs. Transition to Deep Sedation

0

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Subject

Pro

pofo

l Eff

ect S

ite

(g/

ml) Loss of ARM

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.

Sedation is about relieving stress…

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Propofol - Is it safe in the GI suite.ppt