Remifentanil Update

1
Remifentanil Update

• Steven L. Shafer, M.D.Professor of Anesthesia,
  Stanford UniversityAdjunct Professor of
  Biopharmaceutical Sciences, UCSF

2
Remifentanil Key Concepts

• Remifentanil is an OPIOID
• Pure m agonist
• little binding at k, s, and d receptors
• The effects of remifentanil are identicalwith
  other commonly used opioids
• fentanyl
• alfentanil
• sufentanil

3
Classical Opioid Pharmacology

• Analgesia
• modest to profound with no ceiling effect
• Sedation
• modest to profound, but has a ceiling effect
• unconsciousness cannot be assured
• Reduces MAC
• with a ceiling effect
• Synergy with hypnotics
• modest at causing sedation
• profound at suppressing movement response to
  noxious stimulation

4
Classical Opioid Pharmacology

• High dose remifentanil anesthesia will be
  associated with hemodynamic stability
• High dose remifentanil will attenuate the stress
  response

5
Classical Opioid Pharmacology

• Urinary retention
• Ileus
• Addiction potential

• Ventilatory depression
• Muscle Rigidity
• Nausea, Vomiting
• Pruritis

6
Remifentanil Key Concepts

• Remifentanil is an ESTER, similar to
• succinylcholine
• esmolol
• Remifentanil is metabolized by nonspecificesteras
  es in blood and tissue (mostly gut)
• Most remifentanil metabolism occurs in tissue

7
Esterases

• Responsible for metabolizing many
  neurotransmitters
• Nearly fully developed at time of birth
• Ubiquitous in all body tissues

8
Remifentanil Metabolism

• Extremely rapid
• Not influenced by
• Hepatic disease
• Renal disease
• Pseudocholinesterase deficiency
• Administration of neostigmine
• Very young age
• Modest decrease in elderly patients

9
The remifentanil Unit Disposition Function

• Expected plasma concentration
• following bolus of 1 unit
• Age range 20-85 yrs
• Very rapid decrease
• Less variability than with other anesthetic drugs

Minto et al, Anesthesiology 8610-23, 1997
10
Rapid decrease after infusion
Glass et al, Anesth Analg 771031
-
1040, 1993
11
Rapid recovery from ventilatory depression
Glass et al, Anesth Analg 771031-1040, 1993
12
Remifentanil vs. other opioids
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
remifentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
13
Three Compartment Modelplus an Effect Site
14
Remifentanil vs. other opioids
sufentanil
100
80
fentanyl
Percent of peak effect site opioid concentration
60
alfentanil
40
20
remifentanil
0
0
2
4
6
8
10
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
15
Remifentanil vs. other opioids

• Recovery from remifentanil is unlike that seen
  with any other opioid
• The time to a given decrease in effect site
  concentration is constant over time
• no accumulation

60
fentanyl
40
20 decrease
alfentanil
20
sufentanil
0
remifentanil
120
fentanyl
90
alfentanil
Minutes required for a given percent decrease in
effect site concentration
60
50 decrease
sufentanil
30
remifentanil
0
300
fentanyl
240
alfentanil
180
80 decrease
120
sufentanil
60
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
16
20 effect sitedecrement curves
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
17
50 effect sitedecrement curves
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
18
80 effect sitedecrement curves
300
fentanyl
240
alfentanil
180
Minutes required
120
sufentanil
60
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
19
Special Populations

• Gender
• No Gender differences in PK or PD
• Minto et al, Anesthesiology 8610-23, 1997

20
Special Populations

• Infants
• Very rapid clearance, even in newborns
• Half-life of 3-6 minutes
• 5 mg/kg caused hypotension about 20 of patients
• Ross et al, Anesth Analg 2001 931393-401
• Not associated with increased post-op apnea
• Galinkin et al, Anesth Analg 2001 931387-92

21
V1 and Clearance decrease with age
15

• V1 decreases about 20 from age 20 to 80
• Common finding for anesthetic drugs
• Clearance decreases about 30 from age 20 to 80
• Mechanism unknown

10
V1 (liters)
5
0
5
4
3
Clearance (l/min)
2
1
0
20
40
60
80
100
Age (years)
Minto et al, Anesthesiology 8610-23, 1997
22
C50 decreases with age

• C50 is a measure ofbrain sensitivity
• Decreased C50 means increased sensitivity
• Decreased C50 with age also reported for
• fentanyl
• alfentanil
• sufentanil

30
20
C50 (ng/ml)
10
0
20
40
60
80
100
Age (years)
Minto et al, Anesthesiology 8610-23, 1997
23
t 1/2 ke0 increases with age

• t 1/2 ke0 is the time required for the brainto
  equilibrate withthe plasma
• an increase in t 1/2 ke0would be expected
  toresult in a slower onsetof drug effect

5
4
3
t ½ ke0 (min)
2
1
0
20
40
60
80
100
Age (years)
Minto et al, Anesthesiology 8610-23, 1997
24
Bolus doses should be reduced by 50 in the
elderly

• The reduction in bolus dose is because of the 50
  increase in sensitivity in the elderly
• Adjusting the bolus for age is at least as
  important as adjusting it for body weight

400
300
LBM
Bolus (mg)
200
75kg
100
35kg
0
20
40
60
80
Age (years)
Minto et al, Anesthesiology 8624-33, 1997
25
Infusion rates should be reduced by 2/3s in the
elderly

• The infusion rate is decreased because of
  increased sensitivity and decreased clearance
• Adjusting the infusion rate for age is more
  important than adjusting it for weight

60
50
40
LBM
Infusion Rate (mg/min)
30
75kg
20
10
35kg
0
20
40
60
80
Age (years)
Minto et al, Anesthesiology 8624-33, 1997
26
Age does not affect average time to emergence
15
80 yrs
80
20 yrs
10
Minutes required for agiven decrease ineffect
site concentration
80 yrs
5
50
20 yrs
80 yrs
20
20 yrs
0
0
300
600
Infusion duration (minutes)
Minto et al, Anesthesiology 8624-33, 1997
27
Age affects variability in time to emergence
Minto et al, Anesthesiology 8624-33, 1997
28
Age does not affect theability to titrate
remifentanil
100
Targeted effect
Predicted effect - 20 yrs
80
Predicted effect - 80 yrs
60
Percentage of maximum EEG effect
40
20
0
0
30
60
90
Time (minutes)
Minto et al, Anesthesiology 8624-33, 1997
29
Hemodynamics in Elderly

• Blood pressure may decrease 10-40 percent in
  elderly (gt70 yrs).
• Easily treated with ephedrine.
• May be associated with ST changes if patient has
  coronary artery disease.

150
100
MAP (percent of baseline)
50
ST Elevation
0
0
5
10
Minutes (relative to start of infusion)
Minto et al, Anesthesiology 81, A11
30
Hemodynamics in Elderly

• Blood pressure may rebound 20-40 on emergence.
• Typically well tolerated.
• Response may be increased if CO2 is elevated.

150
100
MAP (percent of baseline)
50
0
0
5
10
15
20
25
Minutes (post infusion)
Minto et al, Anesthesiology 81, A11
31
Hemodynamics in Elderly
ST elevation

• Heart rate is usually stable but may increase
  abruptly on emergence.
• May be associated with ST changes if patient has
  coronary artery disease

SVT
150
100
Heart Rate
50
0
-5
0
5
10
15
20
25
30
35
Minutes (from start of infusion)
Minto et al, Anesthesiology 81, A11
32
Ambulatory Anesthesia

• 34 published studies
• Types of Surgery
• ENT
• Arthroscopy
• Oral / Dental surgery
• Laproscopic surgery
• GYN
• Adrenalectomy
• Cholecystectomy

• Urologic
• Pediatric
• TA
• Strabismus
• MAC
• Colonoscopy

33
Ambulatory Anesthesia

• Positive outcomes
• More stable intraoperative hemodynamics
• Faster emergence in OR
• Faster recovery in PACU
• Faster discharge
• Reduced N/V when combined with propofol
• Faster recovery when combined with desflurane
• Able to intubate without relaxants
• Remifentanil 3-4 mg/kg propofol 2-2.5 mg/kg
• Earlier studies used infusion rates of 0.25 1.0
  mg/kg, later studies used 0.1 to 0.25 mg/kg.

34
Ambulatory Anesthesia

• Negative outcomes
• Increased post-op pain (no additional opioid
  given)
• Increased cost by 17/patient (one study)
• More bradycardia than alfentanil (one study)
• Sevo/fentanyl faster recovery than propofol/remi
  (one study)

35
General OR

• Thoracotomy
• 3 papers
• Works well combined with epidural
• Arthroscopy
• 7 papers
• Usually combined with propofol or sevoflurane
• Associated with rapid recovery
• Adds 5 to cost of anesthetic
• Vascular surgery
• Faster recovery with remifentanil / desflurane
  than fentanyl desflurane in carotid surgery

36
Neurosurgery

• 38 papers
• Works exceptionally well for
• Awake craniotomies
• Intraoperative awakening
• Brain mapping
• Described with good results for
• Pediatric VP shunt placement
• Pediatric craniosynostosis repair
• Adult craniotomies
• Significantly smoother intraoperative course,
  faster emergence

37
Cardiac surgery

• Myles PS, et al, Remifentanil, fentanyl, and
  cardiac surgery a double-blinded, randomized,
  controlled trial of costs and outcomes. Anesth
  Analg 2002 95805-12 (October)
• 3 groups
• Remifentanil 0.83 mg/kg/min
• Fentanyl 12 mg/kg bolus
• Fentanyl 24 mg/kg bolus

38
Cardiac surgery

• Conclusions
• Remifentanil, when compared with fentanyl (total
  doses of approximately 15 and 28 mg/kg)
• blunts the hypertensive responses associated with
  cardiac surgery,
• is associated with more hypotension,
• reduces cortisol excretion when compared with
  fentanyl 15 mg/kg.
• No affect on hospitalization cost
• Larger-dose opioids (remifentanil 0.85 mg/kg/min
  or fentanyl 28 mg/kg) were associated with a
  decreased rate of myocardial infarction after
  cardiac surgery.

39

• Dosing Guidelines

40
Setting up drug infusions

• Check out your infusion pump as thoroughly as you
  check out your anesthesia machine.
• Is your drug dilution correct?
• Is the syringe adequately held?
• Is the syringe plunger properly held in the
  clamp?
• Are your infusion units correct?
• Is the weight correct (for calculator pumps)?
• Has the dead space been taken out of the line?
• Have the batteries been checked?
• Think of the check out as though you were going
  to infuse sodium nitroprusside.

41
Setting up drug infusions

• Infuse as close to the IV catheter site as
  possible.
• Typical IV tubing contains 3-5 mls of dead space
  between injection ports and catheter.

42
Induction
43
Bolus Dose Equivalents

• Remifentanil 70 mg (1 mg/kg)
• Fentanyl 225 mg (3.2 mg/kg)
• Alfentanil 1000 mg (15 mg/kg)
• Sufentanil 25 mg (0.35 mg/kg)
• Remifentanil 35 mg (0.5 mg/kg)
• Fentanyl 100 mg (1.5 mg/kg)
• Alfentanil 500 mg (7 mg/kg)
• Sufentanil 12 mg (0.2 mg/kg)

44
Bolus vs 1 minute infusion
6

• True bolus peaks about a minute earlier than a
  bolus given over 1 minute
• Both will be associated with a rapid onset of
  drug effect
• Side effects will be similar with both

Apnea
True Bolus
4
One minute infusion
Remifentanil concentration (ng/ml)
Ventilatory Depression
2
0
0
2
4
6
8
10
Minutes
45
25
1.0 mg/kg/min
20
15
Remifentanil concentration (ng/ml)
0.5 mg/kg/min
10
Rigidity
Apnea
5
Ventilatory Depression
1.0 mg/kg
0
0
2
4
6
8
10
Minutes
46
Induction Bolus vs Infusion
25

• Concentrations rapidly rise during infusions.
• With infusions, expect apnea and rigidity within
  2-3 minutes.
• Especially at a rate of 1.0 mg/kg/min

m
1.0
g/kg/min
20
15
Remifentanil concentration (ng/ml)
m
0.5
g/kg/min
10
Rigidity
Apnea
5
Ventilatory Depression
m
1
g/kg bolus
0
0
2
4
6
8
10
Minutes
47
Induction TechniqueRemifentanil 1.0 mg/kg bolus
25

• Hypnotic and relaxant just before remifentanil
  bolus.
• Intubate 60-90 seconds after remifentanil bolus.
• Suitable for rapid sequence.

20
15
Remifentanil concentration (ng/ml)
Intubate

10
Rigidity
Relaxant
Apnea

5
Hypnotic

Ventilatory Depression
1.0
m
g/kg
0
-2
0
2
4
6
8
10
Minutes
48
Induction TechniqueRemifentanil 1.0 mg/kg/min
25

• Hypnotic and relaxant 30-90 seconds prior to
  starting remifentanil infusion.
• Intubate 90-120 seconds after starting
  remifentanil infusion.
• Decrease infusion rate after intubation.

1.0
m
g/kg/min
20
15
Remifentanil concentration (ng/ml)
Intubate

10
Rigidity
Relaxant

Apnea
5
Hypnotic

Ventilatory Depression
0
-2
0
2
4
6
8
10
Minutes
49
Induction TechniqueRemifentanil 0.5 mg/kg/min

• Start remifentanil infusion.
• Give hypnotic 30-90 seconds after starting
  infusion, followed by relaxant.
• Slower, gentler technique.

25
20
15
Remifentanil concentration (ng/ml)
0.5
m
g/kg/min
Intubate
10

Rigidity
Relaxant

Apnea
5
Hypnotic

Ventilatory Depression
0
-2
0
2
4
6
8
10
Minutes
50
Maintenance
General Anesthesia and Continuing Into the
PACU or Intensive Care Setting
Continuous IV
Infusion Dose
Supplemental IV
Phase
Infusion of ULTIVA
Range of ULTIVA
Bolus Dose of
(mcg/kg/min)
(mcg/kg/min)
ULTIVA (mcg/kg)
Induction of Anesthesia
(through Inbutation)
0.5-1
Maintenance of anesthesia with
Nitrous oxide (66)
0.4
0.1-2
1
Isoflurane (0.4-1.5 MAC)
0.25
0.05-2
1
Propofol (100-200 mcg/kg/min)
0.25
0.05-2
1
Not recommended
Continuation as an analgesic into
the immediate postoperative period
0.1
0.025-0.2
An initial dose of 1 mcg/kg may be administered
over 30 to 60 seconds if endotracheal
intubation is to occur less than 8 minutes after
the start of the infusion of ULTIVA
Under the direct supervision of an anesthesia
practitioner
51
ULTIVA Dosing Guide

• Maintenance of anesthesia calls for typical doses
  of hypnotic
• Remifentanil 0.05-2.0 mg/kg/min infusion
• Additional bolus dosesof 1 mg/kg for light
  anesthesia
• 0.5 mg/kg if breathing spontaneously

52
Maintenance Infusion Rates
30
m
1.0
g/kg/min
25
20
m
0.5
g/kg/min
Remifentanil concentration (ng/ml)
15
10
Rigidity
m
0.25
g/kg/min
Apnea
5
0.1
m
g/kg/min
Respiratory depression
0
30
40
50
60
0
10
20
Minutes
53
Maintenance Infusion Rates

• 1.0 mg/kg/min
• Profound analgesia
• 0.5 mg/kg/min
• Paralysis required
• 0.25 mg/kg/min
• Ventilation required
• gt 50 MAC reduction
• 0.1 mg/kg/min
• Works well with nitrous
• May be satisfactoryfor spontaneous ventilation

30
m
1.0
g/kg/min
25
20
Remifentanil concentration (ng/ml)
m
0.5
g/kg/min
15
10
Rigidity
m
0.25
g/kg/min
5
Apnea
m
0.1
g/kg/min
Respiratory depression
0
0
10
20
30
40
50
60
Minutes
54
MAC Reduction
Lang et al, Anesthesiology 85, 721-728, 1996
55
Propofol/Alfentanil Interaction
400

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

Intubation
300
Maintenance
200
Alfentanil Concentration (ng/ml)
Emergence
100
0
0
2
4
6
8
10
Propofol Concentration (mg/ml)
56
Propofol Anesthesia and Rational Opioid Selection
Determination of Optimal EC50-EC95
Propofol-Opioid Concentrations that Assure
Adequate Anesthesia and a Rapid Return on
Consciousness
Jaap Vuyk, M.D., Ph.D., Martijn J. Mertens, M.D.,
Erik Olofsen, M.Sc., Anton G.L. Burm, M.Sc,
Ph.D. James G. Bovill, M.D., Ph.D., F.F.A.R.C.S.I.
Anesthesiology 1997 871549-62
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10 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
66
60 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
67
300 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
68
600 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
69
Optimal Maintenance Propofol / Opioid
Concentrations
Sufentanil (ng/ml)
70
Propofol/Opioid Recovery
40
35
30
25
Fentanyl
Minutes for Recovery
20
Alfentanil
15
Sufentanil
10
5
Remifentanil
0
0
120
240
360
480
600
Infusion Duration (minutes)
71
Propofol/Remifentanil TIVA

• Remifentanil
• 0.25 mg/kg/min
• Propofol
• 80 mg/kg/min
• Requires controlled ventilation
• If combined with N2O, can be run at 0.1 to 0.2
  mg/kg/min.

Shafer SL, ASA Refresher Course, Chapter 19, 1996

• Little tolerance for interruption of
  remifentanil or propofol infusion

72
Transition to postoperative analgesia

• Local Anesthesia
• Methadone 5-10 mg
• 45-60 minutes before the end of anesthesia
• Morphine 5-10 mg
• 15-30 minutes before the end of anesthesia
• Fentanyl 50-100 mg
• 5-10 minutes before the end of anesthesia
• Continue remifentanil infusion.
• 7 incidence of severe ventilatory depression
• Bowdle et al, Anesth Analg 831292-7, 1996
• Probably reflects difficulty with infusion
  techniques

73
MAC Dosing Guidelines
74
Infusion rates for MAC sedation
10
Rigidity
8
6
0.2
m
g/kg/min
Remifentanil concentration (ng/ml)
Apnea
4
0.1
m
g/kg/min
Respiratory depression
2
0.05
m
g/kg/min
Analgesia
0.025
m
g/kg/min
0
0
10
20
30
40
50
60
Minutes
75
Infusion rates for MAC sedation

• 0.2 mg/kg/min
• Apnea likely
• 0.1 mg/kg/min
• Respiratory depression
• 0.05 mg/kg/min
• Little likelihood of respiratory depression
• 0.025 mg/kg/min
• Few problems expected
• Modestly analgesic

10
Rigidity
8
6
0.2
m
g/kg/min
Apnea
Remifentanil concentration (ng/ml)
4
0.1
m
g/kg/min
Respiratory depression
2
0.05
m
g/kg/min
Analgesia
0.025
m
g/kg/min
0
0
10
20
30
40
50
60
Minutes
76
Recommendation forMAC Sedation

• Initial bolus of 0.5 mg/kg or less
• Infusion at 0.025-0.1 mg/kg/min
• Careful attention to infusion system
• Little latitude for unexpected boluses

• Reduce by 50 - 70 in the elderly
• Dont titrate to sedation
• I virtually never use remi for sedation other
  than neurosurgery more hassle than its worth.

77
Unique Benefits

• Anesthesia maintained with high-dose remifentanil
  is associated with rapid recovery.
• Within 5-10 minutes of turning off an infusion
  there is virtually no residual remifentanil drug
  effect.
• The offset of opioid drug effect following
  turning off a remifentanil infusion resembles the
  offset associated with giving titrated doses of
  naloxone to a patient who has received fentanyl,
  alfentanil, or sufentanil.
• Even after cardiac type doses of remifentanil,
  patients will be awake within 10-15 minutes of
  turning off an infusion

78
Unique Benefits

• High-dose opioid techniques with little risk of
  post-operative ventilatory depression.
• Can do cardiac anesthetics on outpatients
• Every patient can have profound analgesia at
  critical junctures (e.g. intubation, incision)

79
Unique Benefits

• Remifentanil can be used as the analgesic
  component of a sedation case with the ability to
  rapidly recover from an overdose by simply
  turning the infusion off.
• If a patient is overdosed, the effect is quickly
  reversed by turning off the infusion.
• Sedation is not a good endpoint for remifentanil
  titration.
• Titrating to sedative endpoints has been
  associated with increased side effects
• ventilatory depression, muscle rigidity, and
  nausea

80
Unique Benefits

• Changes in remifentanil drug effect rapidly
  follow changes in the remifentanil infusion rate.
  
• Titration of remifentanil is more precise than
  with the presently available opioids

81
Unique Benefits

• The relationship between remifentanil infusion
  rate and concentration will be consistent from
  patient to patient, and will be independent of
  disease state.
• No influence from
• Liver disease
• Renal disease
• Genetic disorders
• Metabolism is intact in neonates
• The most pharmacokinetically predictable drug in
  anesthesia

82
Potential Risks

• The rapid onset of remifentanil may be associated
  with life-threatening rigidity.
• Usually associated with
• Large bolus doses
• Rapid infusions
• Easily treated with muscle relaxants
• If an infusion is used for induction, muscle
  relaxants should be administered at first signs
  of rigidity or loss of response.

83
Potential Risks

• The analgesic effects are evanescent.
• Post-operative analgesic needs must be
  anticipated.
• Combine with local anesthesia
• Administer a long-action opioid prior to
  emergence from anesthesia
• Methadone 5-15 mg 60 minutes before emergence
• Morphine 5-10 mg 15-30 minutes before emergence
• Fentanyl 50-100 mg 5-10 minutes before emergence
• Titrate fentanyl as remifentanil is wearing off
• Continue remifentanil infusion (not recommended!)

84
Potential Risks

• The rapid onset and offset of remifentanil drug
  effect have made post-operative titration
  difficult.
• Aggressive titration can lead to oscillations
  between
• Rigidity and apnea
• Untreated pain
• Gently adjust infusion rate within therapeutic
  range
• 0.025-0.1 mg/kg/min

85
Potential Risks

• If a remifentanil infusion is interrupted during
  surgery, the interruption must be quickly
  discovered and corrected before the patient
  awakens in pain.
• Have an alternative plan ready
• Propofol bolus
• Fentanyl bolus
• Turn on / turn up inhalational anesthetic
• Have next syringe made up and ready to go.
• Spending 2 minutes changing syringe might be too
  long during light anesthetics

86
Potential Risks

• Cannot be administered epidurally or
  intrathecally.
• Contains glycine.

87
Conclusions

• Benefits
• Rapid onset
• Rapid offset, rapid recovery
• Reduced intraoperative stress by maintaining high
  opioid concentrations
• Highly predictable
• Risks
• Must have post-op analgesic plan
• Very modest increase in cost
• A 2 mg ampule is 18
• An ampule of generic vecuronium is 12
• Fentanyl is free
• Requires setting up and titrating an infusion