the use of ultra-short opiods in anesthesia

The Use of Ultra-Short

Opioids in Anesthesia

Mark D. Antoszyk, CRNA, BS

Pharmacokinetics of Remifentanil: Overview

Rapid offset of opioid effects (within 5-10 min)

Rapid blood-effect site equilibration half-time

(approximately 1.6 min) leading to rapid onset of action

Rapid response to titration

Nonspecific esterase metabolism

Elimination unaffected by sex, weight,

or renal/hepatic function

Egan TD, et al. Anesthesiology. 1996;84:821-833.

ULTIVA® (remifentanil hydrochloride) for injection [package insert].

Remifentanil MetabolismHydrolyzed by nonspecific esterases in the blood and

tissues: organ-independent elimination

Rapid clearance without accumulation regardless of dosage level or duration of infusion

Metabolism not altered in patients with pseudocholinesterase deficiency

Clearance is not altered by concomitant thiopental, isoflurane, propofol, or temazepam during anesthesia

In vitro studies of hydrolysis not inhibited by atracurium, mivacurium, esmolol, echothiophate, neostigmine, physostigmine, or midazolam


Context-sensitive Half-time of -Opioid Agonists

Adapted with permission from Egan TD, et al. Anesthesiology. 1993;79:881-892.

Duration of Infusion (min)

100

75

50

25

0

0 100 200 300 400 500 600

Sim

ula

tion o

f T

ime to 5

0%

Decre

ase

in B

lood C

oncentr

ation (

min

)

Fentanyl

Alfentanil

Sufentanil

Remifentanil

Study A104.

Dosing Guidelines

Remifentanil Dosing Guidelines for

General Anesthesia

*An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.

Reduce starting dosage up to 50% in elderly (>65 y) patients.


Anesthesia Phase

(Adults)

Induction (through intubation)

Maintenance with

Nitrous oxide (66%)

Isoflurane (0.4-1.5 MAC)

Propofol (100-200 mcg/kg/min)

Continuous

IV Infusion

(mcg/kg/min)

Infusion Dose

Range

(mcg/kg/min)

Supplemental

IV Bolus Dose

(mcg/kg)

0.5-1*

0.4

0.25

0.25

0.1-2

0.05-2

0.05-2

1

1

1

Bolus Dose Equivalents

• Remifentanil 70 g (1 g/kg) • Fentanyl 225 g (3.2 g/kg)

• Alfentanil 1000 g (15 g/kg)

• Sufentanil 25 g (0.35 g/kg)

• Remifentanil 35 g (0.5 g/kg) • Fentanyl 100 g (1.5 g/kg)

• Alfentanil 500 g (7 g/kg)

• Sufentanil 12 g (0.2 g/kg)

Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

Bolus vs 1 minute infusion

• 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

0

2

4

6

0 2 4 6 8 10Minutes

Rem

ifen

tanil

conce

ntr

atio

n (

ng/m

l)

One minute infusion

True Bolus

Apnea

Ventilatory Depression


Induction: Bolus vs Infusion

• Concentrations

rapidly rise during

infusions.

• With infusions,

expect apnea and

rigidity within 2-3

minutes.

• Especially at a rate

of 1.0 g/kg/min0

5

10

15

20

25

0 2 4 6 8 10Minutes

Rem

ifen

tanil

conce

ntr

atio

n (

ng/m

l)

1.0 g/kg/min

1 g/kg bolus

Apnea

Ventilatory Depression

Rigidity

0.5 g/kg/min


Maintenance Infusion Rates

• 1.0 g/kg/min• Profound analgesia

• 0.5 g/kg/min• Paralysis required

• 0.25 g/kg/min• Ventilation required

• > 50% MAC reduction

• 0.1 g/kg/min• Works well with nitrous

• May be satisfactoryfor spontaneous ventilation

0

5

10

15

20

25

30

0 10 20 30 40 50 60Minutes

Rem

ifen

tanil

conce

ntr

atio

n (

ng/m

l)

1.0 g/kg/min

0.5 g/kg/min

Respiratory depression

Apnea

Rigidity

0.25 g/kg/min

0.1 g/kg/min


Remifentanil Adverse Events: General Anesthesia*

Nausea

Vomiting

Adverse Event†R

(n=921)A/F

(n=466)R

(n=281)M

(n=98)R

(n=929)A/F

(n=466)

Hypotension

Muscle Rigidity

Bradycardia

Shivering

Fever

Respiratory

Depression

<1%

19%

<1%

11%‡

7%

<1%

<1%

<1%

0%

6%

<1%

8%

5%

0%

0%

0%

22%

0%

8%

2%

1%

5%

<1%

7%

15%

0%

5%

0%

3%

9%

0%

4%

36%

2%

16%

<1%

1%

5%

5%

2%

43%

2%

20%

<1%

1%

2%

2%

4%

Induction/

Maintenance

Postoperative

Analgesia

After

Discontinuation

*Not all doses of remifentanil were equipotent to the comparator opioid. Administration of remifentanil in excess of the recommended doses (ie, >1 and up to 20 mcg/kg resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%).R = remifentanil; A/F = alfentanil/fentanyl; M = morphine. †Adverse events that occurred in 5% of patients in general anesthesia studies. ‡Incidence of chest wall rigidity (5%) is included in muscle rigidity.ULTIVA® (remifentanil hydrochloride) for injection [package insert].

Mac Dosing

Remifentanil Dosing Guidelines for MAC*

Method

(Adults) Timing

Remifentanil

Alone

Remifentanil +

Midazolam (2 mg)

Single IV

dose

90 sec before

local anesthetic

1 mcg/kg over

30-60 sec

0.5 mcg/kg over

30-60 sec

Continuous

IV infusionBegin 5 min

before local

anesthetic

0.1 mcg/kg/min 0.05 mcg/kg/min

After local

anesthetic0.05 mcg/kg/min

(range: 0.025-

0.2 mcg/kg/min)

0.025 mcg/kg/min

(range: 0.025-

0.2 mcg/kg/min)

*It is strongly recommended that supplemental oxygen be supplied to the patient

whenever remifentanil is administered as an analgesic component of monitored

anesthesia care.


Infusion rates for MAC sedation

• 0.2 g/kg/min• Apnea likely

• 0.1 g/kg/min• Respiratory depression

• 0.05 g/kg/min• Little likelihood of

respiratory depression

• 0.025 g/kg/min• Few problems expected

• Modestly analgesic0

2

4

6

8

10

0 10 20 30 40 50 60

Minutes

Rem

ifen

tanil

conce

ntr

atio

n (

ng

/ml)

0.1 g/kg/min

0.025 g/kg/min

Respiratory depression

Apnea

Rigidity

0.05 g/kg/min

0.2 g/kg/min

Analgesia


Remifentanil Adverse Events: MAC

Nausea

Vomiting

Pruritus

Headache

Sweating

Shivering

Dizziness

Adverse Event*

44%

Remifentanil(n=159)

Remifentanil + Midazolam† (2 mg)

(n=103)

Propofol(n=63)

22%

18%

18%

6%

5%

5%

18%

5%

16%

12%

0%

<1%

5%

32%

21%

0%

10%

2%

2%

2%

*Adverse events that occurred in 5% of patients. Administration of remifentanil in excess of the recommended infusion rate (ie, starting doses >0.1 mcg/kg/min) resulted in higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%).†With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.


Hypotension

Bradycardia

Pain at IV site

4% 0% 10%

4% 0% 11%

1% 0% 17%

Special Populations

Special Populations

• Infants• Very rapid clearance, even in newborns

• Half-life of 3-6 minutes

• 5 g/kg caused hypotension about 20% of patients• Ross et al, Anesth Analg 2001 93:1393-401

• Not associated with increased post-op apnea• Galinkin et al, Anesth Analg 2001 93:1387-92

Pharmacokinetics of Remifentanil in

Pediatric Patients


Clearance

(mL/min/kg)

VDss

(mL/kg)Age

Neonate (<2 months)

Adolescent (13-16 y)

90.5±36.8

Mean (± SD)

57.2±21.1

452±144

223±30.6

Half-life same in neonates and adolescents

Clearance maintained at or above normal adult values

in patients aged 5 days to 17 years

Remifentanil Dosing Guidelines for

Special Patient Populations

Adjust dosing in

Elderly (>65 y): reduce initial dose by 50%

Obese (>30% above ideal body weight [IBW]): dose

to IBW

No dosage adjustment for

Children (1-12 y)*

Renal/hepatic dysfunction

Pseudocholinesterase deficiency

*Remifentanil has not been studied in pediatric patients for use in the

immediate postoperative period or for use as a component of MAC.


Age Effects on Remifentanil Pharmacokinetics

*EC50 = concentration required for 50% of maximum response; Ke0 = blood-brain

equilibration.

Data on file, Abbott Laboratories.

Parameter*

Age Group, y

Cl (mL/min/kg)

Vss (mL/kg)

EC50 (ng/mL)

Ke0 (per min)

30 50 75

39

312

17.3

1.0

35 (10%)

245 (21%)

13.5 (22%)

0.71 (29%)

29 (26%)

162 (48%)

8.7 (50%)

0.29 (71%)

Measure (% Change Relative

to 30-Year-Old Patient)

C50 decreases with age

• C50 is a measure of

brain sensitivity

• Decreased C50 means

increased sensitivity

• Decreased C50 with age

also reported for:• fentanyl

• alfentanil

• sufentanil

Age (years)

20 40 60 80 100

0

10

20

30

C5

0(n

g/m

l)

Minto et al, Anesthesiology 86:10-23, 1997

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 0

100

200

300

400

20 40 60 80Age (years)

LBM

75kg

35kgB

olu

s (

g)


Infusion rates should be reduced by

2/3’s 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

20 40 60 80

0

10

20

30

40

50

60

Age (years)

LBM

75kg

35kgIn

fusi

on

Rat

e (

g/m

in)


Pharmacokinetics of Remifentanil in

Patients With Hepatic Impairment*

*Values shown are geometric mean (95% confidence interval); †low-dose infusion = 0.0125

mcg/kg/min for 1 hour followed by 0.025 mcg/kg/min for 3 hours; ‡high-dose infusion = 0.025

mcg/kg/min for 1 hour followed by 0.05 mcg/kg/min for 3 hours.

Adapted with permission from Dershwitz M, et al. Anesthesiology. 1996;84:812-820.

Clearance

(mL/min/kg)

Vd

(mL/kg)Treatment Group

T1/2

(min)

Hepatic

impairment (n=5)

Control (n=5)

33.3 (23.0-48.3) 272 (162-456)

33.0 (28.5-38.1) 205 (178-235)

5.7 (4.0-8.1)

4.3 (4.1-4.5)

High-dose group‡

Low-dose group†

Hepatic

impairment (n=5)

Control (n=5)

39.1 (33.2-46.0) 264 (196-356) 4.7 (3.7-5.9)

31.5 (23.8-41.6) 208 (112-384) 4.6 (2.8-7.4)

Study A211.

Pharmacokinetics of Remifentanil

in Patients With Renal Failure (<30 mL/min/1.73 m2)*

*Values shown are geometric mean (95% confidence interval); †low-dose infusion = 0.0125

mcg/kg/min for 1 hour followed by 0.025 mcg/kg/min for 3 hours; ‡high-dose infusion = 0.025

mcg/kg/min for 1 hour followed by 0.05 mcg/kg/min for 3 hours.

Adapted with permission from Hoke JF, et al. Anesthesiology. 1997;87:533-541.

Clearance

(mL/min/kg)

Vd

(mL/kg)Treatment Group

T1/2

(min)

Control (n=8) 33.2 (26.5-41.7) 191 (151-241) 4.0 (3.3-4.8)

Renal failure (n=9) 35.6 (31.7-40.0) 229 (211-249) 4.5 (3.9-5.1)

High-dose group‡

Low-dose group†

Renal failure (n=6) 35.1 (25.2-49.0) 282 (194-411) 5.6 (3.3-9.3)

Study A210.

Pharmacokinetics of Remifentanil in Obese

Patients

Open-label, single-dose, parallel, group study

12 obese (>80% IBW) and 12 lean (within 20% of IBW) patients undergoing elective, noncardiac, nonintracranial surgery

Patients received a 1-minute infusion of remifentanil (7.5 to 10 mcg/kg/min)

Results

Absolute volumes and clearances are similar in lean and obese patients

Dosing remifentanil based on total body weight results in excessively high remifentanil levels

Egan TD, et al. Anesthesiology. 1998;89:562-573. Study A227.

Remifentanil: Safety Profile

Failure to adequately clear the IV tubing or

remove residual remifentanil HCl has been

associated with the appearance of respiratory

depression, apnea, and muscle rigidity upon the

administration of additional fluids or

medications through the same IV tubing

Remifentanil: Safety Profile (Cont’d)

Continuous infusions of remifentanil should be

administered only by an infusion device

In monitored anesthesia care, when patients

are breathing spontaneously, single boluses of

remifentanil should be administered over 30 to

60 seconds and should not be administered

simultaneously with a continuous infusion

IV bolus administration of remifentanil should

only be used during the maintenance of general

anesthesia

Remifentanil: Safety Profile (Cont’d)

Rapid clearance and lack of accumulation

result in rapid offset of analgesic effects

following discontinuation of remifentanil;

therefore, when postoperative pain is

anticipated, adequate postoperative analgesia

should be established before discontinuation

Remifentanil produces adverse events

characteristic of -opioids, such as respiratory

depression, bradycardia, hypotension, and

skeletal muscle rigidity

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.


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.

Positive Outcome Anesthesia with

Remifentanil

• Positive outcomes• More stable intraoperative hemodynamics

• Faster emergence in OR

• Faster recovery in PACU

• Faster discharge

• Reduced N/V when combined with propofol

• Decrease MAC of Inhalation Agents

• Able to intubate without relaxants

• Remifentanil 3-4 g/kg + propofol 2-2.5 mg/kg

• Earlier studies used infusion rates of 0.25 – 1.0 g/kg, later studies

used 0.1 to 0.25 g/kg.

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 5-10 minutes of turning off an infusion

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)

Potential Risks

Contains Glycine

• Contraindicated for use in epidurals and spinals

Rapid onset of Remifentanil

• Could lead to life threatening rigidity

• Usually seen with large bolus and rapid infusion

• Treatable with muscle relaxants and turning off infusion

Postoperative analgesics must be anticipated

Potential Risks

Interruptions in Remifentanil must be corrected quickly

• Have a second syringe prepared

• Have an alternative medication

• Be aware that within 3-5 minutes the patient will develop

pain

Titrate with caution

• Aggressive titration could lead to rigidity, apnea, or pain

Potential Risks

• Cannot be administered epidurally or

intrathecally.

• Contains glycine.

Unique Postoperative Analgesia Management

Within 5-10 min after remifentanil discontinuation,

no residual opioid activity will be present*

When postoperative pain is anticipated, ending an infusion of

remifentanil should be preceded by the establishment of adequate

postoperative analgesia*

Choices could include any 1 or a combination of the following,

depending on patient type or surgery

Nonsteroidal agents

Local anesthetic wound infiltration

Long-acting opioids

Epidural administration of an opioid and/or local anesthetic

*ULTIVA® (remifentanil hydrochloride) for injection [package insert].

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 g • 5-10 minutes before the end of anesthesia

• Continue remifentanil infusion.• 7% incidence of severe ventilatory depression

Bowdle et al, Anesth Analg 83:1292-7, 1996

Probably reflects difficulty with infusion techniques

Remifentanil SummaryPrecise control and rapid response

Rapid onset of action

Rapid titration provides rapid, precise control

of intraoperative stress responses

Predictable duration and offset of action

Rapid, predictable recovery (within 5-

10 minutes) due to organ-independent

elimination and noncumulative properties


Remifentanil Summary (Cont’d)

Suitable for use in

Ambulatory and office-based procedures

Inpatient procedures

Patients who have renal or hepatic

impairment or are obese

Repeated or prolonged administration is not

associated with recurrent respiratory

depression (occurring >30 minutes after

discontinuation)


the use of ultra-short opiods in anesthesia

Documents

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injection package insert

bolus dosemcgkg0

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stanford universitybolus

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use of ultrashort opioids