Mark D. Antoszyk, CRNA, BS

Director Anesthesia Services

Department of Anesthesiology Carolina’s Medical Center Northeast

Concord, North Carolina

Mark D. Antoszyk, CRNA, BS, is director of anesthesia services in the Department of Anesthesiology at Carolina’s Northeast Medical Center in Concord, North Carolina. Mark received his Bachelor of Science degree from La Roche College in Pittsburgh, Pennsylvania. He has worked in a variety of settings utilizing general and regional anesthesia techniques for cardiovascular, ear, nose and throat, neurosurgical, obstetrics, gynecology, ophthalmology, pediatric, plastic, reconstructive, orthopedic, and general surgery. Mark is a member of the American Association of Nurse Anesthetists and has served on the National Advisory Council for Novations. Mark is a certified instructor for cardiopulmonary resuscitation, pediatric advanced life support, advanced cardiac life support, and is also a licensed paramedic.

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Standards of Care in Perioperative Patient

Management: Anesthesiology Clinical

Case Challenge

Slide Booklet

Learning ObjectivesLearning Objectives

Discuss opportunities to provide improved perioperative pain control in anesthesia practice

Describe the advantages and disadvantages of short-acting opioids as part of a general anesthesia regimen

Identify opportunities to improve hemodynamic control and postoperative recovery time with opioid-based anesthesia

Good Anesthesia = Titration to EffectGood Anesthesia = Titration to Effect

Pharmacodynamic approach

– Titrating drugs to effect

Pharmaceutical approach

– Choosing “forgiving drug”

Pharmacokinetic approach

– Knowledge of concentration-effect relationship

Preanesthesia Considerations Prior to Using a Short-acting Opioid

PreanesthesiaPreanesthesia EvaluationEvaluation

Notable history and physical

Comorbidities

Concomitant medications

Type of surgery

Previous history of anesthesia

Allergies

Venous access

Airway

Rationale for & Comparison of Available Short-acting Opioids

OpioidOpioid Receptors and ResponseReceptors and Responseto Stimulationto Stimulation

ReceptorReceptor ResponseResponse

Mu‐1 Supraspinal analgesia

Mu‐2

Depression of ventilationCardiovascular effectsPhysical dependence

Euphoria

Delta Modulate Mu receptors

KappaSpinal analgesia

SedationMiosis

SigmaDysphoriaHypertonia

OpioidOpioid BenefitsBenefits

Analgesia

– Blunt neuroendocrine activation

Hemodynamic stability

– No direct myocardiac depression

– Blunt catecholamine response to noxious stimuli

Decreased need for hypnotic anesthetics

Development of Newer Development of Newer OpioidsOpioids

Goals for opioids have been to:

– Increase potency, safety, & therapeutic index

– Improve PK/PD effects titratability

– Improve overall patient satisfaction

Considerations?

– Superior intraoperative control

– Respiratory compromise (OSA)

– Emergence & recovery

– Decrease risk for preoperative adverse events

Glass PSA. J Clin Anesth. 1995;7:558-563.OSA, obstructive sleep apnea.

Structure of Synthetic Structure of Synthetic µµ--OpioidsOpioids

Fentanyl

N‐C‐CH2‐CH3

H

OCH2‐CH2‐N

Alfentanil

CH3‐CH2‐N N‐CH2‐CH2‐N

N‐C‐CH2‐CH3

CH2‐O‐CH3

N N

O

O

Sufentanil

CH2‐O‐CH3

N‐C‐CH2‐CH3

CH2‐CH2‐N O

S

N‐C‐CH2‐CH3

C‐O‐CH3

Remifentanil

CH3‐O‐C‐ CH2‐CH2‐N

O

O

•HCI

O

Bailey P, Egan T. In: White PF, ed. Textbook of IV Anesthesia. Baltimore, MD: Williams & Wilkins; 1997:213‐245.

Desirable CharacteristicsDesirable Characteristicsof of µµ--OpioidsOpioids

CharacteristicCharacteristic AlfentanilAlfentanil FentanylFentanyl RemifentanilRemifentanil SufentanilSufentanil

µ‐Opioid receptor selectivity X X X X

No histamine release X X X X

Rapid response to titration X

Rapid, predictable offset of opioid effects (5‐10 min) 

X

Elimination independent of renal or hepatic function

X

Onset and Offset Rates of Onset and Offset Rates of µµ--OpioidsOpioids

*The time required for drug concentrations in blood or at effect site to decrease by 50%. Based on a 3-hour infusion.†Increases with increasing infusion duration due to accumulation.

Data derived from manufacturers’ labeling and Egan TD, et al. Anesthesiology. 1993;79:881-892;Egan TD, et al. Anesthesiology. 1996;84:821-833; Scott JC, et al. Anesthesiology. 1991;74:34-42.

Pharmacokinetics Alfentanil Fentanyl Remifentanil Sufentanil

Onset: blood‐effect siteequilibration, mean

0.96 min 6.6 min 1.6 min 6.2 min

Organ‐independentelimination

No No Yes No

Nonspecific esterasemetabolism

No No Yes No

Offset: context‐sensitivehalf‐time, mean*

50‐55 min† >100 min† 3‐6 min 30 min†

Infusion FrontInfusion Front--end Kineticsend Kinetics

Egan TD (in Miller & Pardo), Elsevier; 2011.

Pro

por

tion

of S

tead

y-S

tate

Ce

(%)

Infusion Duration (min)

Morphine

Sufentanil

Fentanyl

Alfentanil

Remifentanil100

80

60

40

20

0

0 100 200 300 400 500 600

Quick to steady-state…

Infusion begins at time zero

Infusion BackInfusion Back--end Kineticsend Kinetics

Tim

e to

50%

Dec

rem

ent

in C

e(%

)

Infusion Duration (min)

Morphine

Sufentanil

Fentanyl

Alfentanil

Remifentanil

400

350

300

250

200

150

100

50

0

0 100 200 30 400 500 600

Rapid offset after infusion…

Egan TD (in Miller & Pardo), Elsevier; 2011.

Alfentanil

Remifentanil

Mean Concentration Over Time With Mean Concentration Over Time With ShortShort--acting IV acting IV OpioidsOpioids

Time (min)

Mean Concentration (ng/mL)

(n=5)0.5 mcg/kg/min

(n=6)0.05 mcg/kg/min

Discontinuation of infusion

0 60 120 180 240 300 360 420 4800.1

1

10

100

ContextContext--Sensitive HalfSensitive Half--timetime

Egan TD, et al. Anesthesiology. 1993;79:881‐892.

0 100 200 300 400 500 6000

25

50

75

100

Minutes Since Beginning of Continuous Infusion

Time to 50% Decrease in Blood Concentration (min)

FentanylAlfentanilSufentanilRemifentanil

Ideal Characteristics of ShortIdeal Characteristics of Short--term term OpioidsOpioids for Anesthesiafor Anesthesia

To provide precise control you need:

– Rapid onset of action

– Predictable control of hemodynamic response (HR)

– Rapid titration, providing rapid response to intraoperative stress

– Control of sympathomimetic response

– Predictable duration and offset of action

OpioidOpioid PharmacodynamicPharmacodynamic VariabilityVariability

Ausems ME, et al. Anesthesiology. 1986;65:362‐373.

Plasma Alfentanil (ng/mL)

100

50

0

0 200 400 600 800 1000

Intubation

Skin Incision

Skin Closure

Probability of No Response (%) (n=37)

Plasma Alfentanil (ng/mL)

100

50

0200 400 600

OpioidOpioid PharmacodynamicPharmacodynamic VariabilityVariability

Ausems ME, et al. Anesthesiology. 1988;68:851-861.

Probability of No Response to Surgical Incision (%)

Blood and Effect Site Concentrations of Blood and Effect Site Concentrations of RemifentanilRemifentanil After TitrationAfter Titration

0

1

2

3

4

5

Co

nc

entr

atio

n (

ng

/mL

)

Minutes Since Beginning Infusion

00

Infu

sio

n R

ate

(mc

g/k

g/m

in)

55 1010 1515 2020 2525 3030 3535 4040 4545 5050 5555 6060

0.10

0.15

0.00

0.05BloodEffect siteInfusion rate

Minto CF, et al. Anesthesiology. 1997;86:24-33.

Metabolism of Remifentanil

Metabolism by HydrolysisMetabolism by Hydrolysis(Facilitated by (Facilitated by EsterasesEsterases))

N‐C‐CH2‐CH3

C‐O‐CH3

Remifentanil

CH3‐O‐C‐CH2‐CH2‐N

O

O

O

C‐O‐CH3

Major Metabolite (>95%)

N‐C‐CH2‐CH3

H‐O‐C‐CH2‐CH2‐N

O

O

O

GR90291

N‐C‐CH2‐CH3

C‐O‐CH3

H‐N

O

O

GR94219

Nonspecific 

Esterases

What Are the CurrentRisks with Opioids?

OpioidOpioid RisksRisks

Respiratory depression

Bradycardia

Chest wall/laryngeal muscle rigidity

Postoperative nausea and vomiting (PONV)

Pruritus

Delayed emergence

Dependency

Where Do Short-acting OpioidsFit Best in Our Practice?

Why Choose a ShortWhy Choose a Short--lived lived OpioidOpioidIntraoperativelyIntraoperatively??

Minimize effects of drug accumulation

Predictable and rapid onset and offset

Rapid patient response to titration (up or down)

– Manage intraoperative hemodynamic changes from surgical manipulation or pain

Generally unaffected by gender or renal/hepatic function or by age or weight

Significant potential for reduced PONV

General Inhalational AnesthesiaGeneral Inhalational Anesthesiavsvs Total Intravenous Anesthesia (TIVA)Total Intravenous Anesthesia (TIVA)

How do we determine which technique is most appropriate for which patient?

What are the primary considerations for each?

What Anesthesia Technique You Use What Anesthesia Technique You Use Should Be Based on Your GoalsShould Be Based on Your Goals

“Balanced” anesthesia with opioid and volatile agent

– Safe

– Ubiquitous

– Practiced for decades

TIVA

– Safe

– Relative newcomer to the OR

• Outpatient > inpatient

• Need to consider patient satisfaction

OR, operating room.

Inhalation Inhalation vsvs TIVATIVA

Major issues:– Decreased PONV with propofol TIVA

• Significant for patient satisfaction

– Greater patient satisfaction with IV induction• Less PONV with IV induction and inhalational

maintenance than with inhalational induction and maintenance

– Emergence and exiting facility for outpatients essentially identical

Joshi GP. Anesthesiol Clin North Am. 2003;21(2):263‐272.

IV, intravenous.

Specific Case Considerations& Personal Experience

Surgery Induction Maintenance Emergence

Head and neck dissection

Propofol and a short‐acting opioid. 

Short‐acting muscle relaxant for

intubation only.

Continuous infusion with 100 µg/kg/min propofol plus a short‐acting opioid initially. 

Then titrate to needed  level.

IV acetaminophen  ~1 hr before emergence.

Assuming no expectation of 

tracheal or laryngeal edema, remove the ET after return of spontaneous respiration and patient arousal

Case Considerations Using TIVA: Head Case Considerations Using TIVA: Head and Neck Dissectionand Neck Dissection

ET, endotracheal tube.

Surgery Induction Maintenance Emergence

Tonsillectomy, female 7 years old

Inhalation of sevoflurane 8% 

exhaled and a nitrous oxide to oxygen mix

Following IV placement, switch to an IV opioid‐based maintenance 

regimen

Remove ET as patient awakens after spontaneous 

respiration has been established

Case Considerations Using TIVA: Case Considerations Using TIVA: TonsillectomyTonsillectomy

Maintenance Infusion RatesMaintenance 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 satisfactory

for spontaneous ventilation

Steven L. Schafer, MD Professor of Medicine, Stanford University

0

5

10

15

20

25

30

0 10 20 30 40 50 60Minutes

Rem

ifen

tan

ilco

nce

ntr

ati

on

(n

g/m

l) 1.0 g/kg/min 

0.5 g/kg/min 

Respiratory depression

Apnea

Rigidity0.25 g/kg/min 

0.1mg/kg/min 

ENTENT

Hemodynamic stability without vasodilators

Decreased bleeding, improved operative conditions during nasal/sinus surgery

Rapid awakening, rapid ability to protect airway, rapid recovery

Surgery Induction Maintenance Emergence

Open inguinal hernia repair, male 

45 years old, 

BMI = 38

Infusion of propofolplus short‐acting 

opioid.

Bolus muscle relaxant.

Following intubation, 100 µg/kg/min of 

propofol as the base along with a short‐

acting opioid.

Turn off the infusion during skin closure for quick wake up at time of dressing being 

placed.

Case Considerations Using TIVA: Open Case Considerations Using TIVA: Open Inguinal Hernia RepairInguinal Hernia Repair

BMI, body mass index.

MACMAC

Marked decrease in propofol use

– Much more cooperative for blocks

– Rapid recovery

Decreased need for GA for inadequate local/block

GA, general anesthesia.

Infusion Rates for MAC SedationInfusion Rates for MAC Sedation

0.2 µg/kg/min– Apnea likely

0.1 µg/kg/min– Respiratory depression

0.05 µg/kg/min– Little likelihood of

respiratory depression

0.025 µg/kg/min– Few problems expected

0

2

4

6

8

10

0 10 20 30 40 50 60Minutes

Rem

ifen

tan

ilco

nce

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

NeuroanesthesiaNeuroanesthesia

Hemodynamic stability without vasodilators

Improved ability to rapidly change anesthetic depth

Rapid recovery with early ability to assess neurologic function

Improved SSEP monitoring with TIVA

SSEP, somatosensory evoked potential.

Emergency CasesEmergency Cases

Rapid sequence induction

Awake fiber-optic intubation

Intensive care unit ET changes

Induction

– Midazolam, 2 mg

– Remifentanil, 0.1 µg/kg

– Propofol, bolus 2 mg

Maintenance

– Remifentanil, 0.1 µg/kg/min

– Propofol, 100 µg/kg/min

– At ~45 min, intraoperative spike in hemodynamic response from surgical stimulus, titrated remifentanil to 0.2 µg/kg/min and propofol to 140 µg/kg/min, then backed off

– Intraoperative medications

• At ~30 min, XXXXXXXX, 0.2 mg

• At ~30 min, ondansetron, 4 mg

• At ~45 min, ketorolac, 30 mg

Emergence

– ~30 min prior to end of surgery, bolus morphine (2 mg)

– Infusion stopped

– Bolus morphine, 2 mg, repeated again at the end of the surgery x4

1616--Year Old with Muscular Dystrophy: Year Old with Muscular Dystrophy: CholecystectomyCholecystectomy (1 hour, 50 min; BIS)(1 hour, 50 min; BIS)

Induction– Sevoflurane, 2.8%

– Midazolam, 0.5 mg

– Remifentanil, 0.1 µg/kg

– Propofol, bolus 40 µg

Maintenance

– Sevoflurane, 1.25%-1.45%

– Remifentanil, 0.15 µg/kg/min

Emergence

– ~1 hr to 30 minutes prior to the end of surgery

• Morphine, 0.8 mg

• Ondansetron, 1 mg

• Ketorolac, 4 mg

– Infusion stopped

1414--Month Old: Sigmoid Month Old: Sigmoid ColectomyColectomy with with Central Line (2 hours, 40 min)Central Line (2 hours, 40 min)

Postoperative AnalgesiaPostoperative Analgesia

Opioids prior to emergence (not comprehensive list)

– Morphine 0.1 to 0.2 mg/kg IV ~ 20 to 30 min

– Fentanyl 1 to 1.5 µ/kg IV ~ 5 min

Activate epidural

Infiltrate with long-acting local anesthetic

Major Nerve Block (often done before procedure)

Continue remifentanil 0.05 to 0.1 µg/kg/min

IV Acetaminophen 1000 mg (or 15 mg/kg)

• Ketorolac 30 mg IV ~ 30 min

A Debate on Techniques and Monitoring: Current Thoughts

Manual Controlled Infusion Manual Controlled Infusion vsvs Target Target Controlled Infusion (TCI)Controlled Infusion (TCI)

A contemporary debate

– Fifty ASA grade I or II patients, aged 18 to 65 years, scheduledfor elective orthopedic or body surface surgery lasting >30 min

– TCI: Commonly higher propofol doses administered within first 30 min of anesthesia (may delay recovery)

– TCI: Lower Bispectral Index Score (BIS) in first 15 min

Reflect on European vs small US experience

– TCI: Lower dosing; better on elderly; surgery specific

Breslin DS, et al. Anaesthesia. 2004:59:1059-1063.

ASA, American Society of Anesthesiologists.

Monitoring Strategies for Anesthesia Monitoring Strategies for Anesthesia Depth: Pros and ConsDepth: Pros and Cons

Attempts to quantify patient awareness with depth of anesthesia (to ensure zero recall)– Glasgow Coma Scale (GCS) test (not used in anesthesia

routinely)– Electroencephalogram (EEG) monitoring/computed analytics

• BIS

• Spectral Edge Frequency (SEF)

• State Entropy (SE) Index

• Patient State Analyzer – 4-channel EEG (PSA 4000)

– Auditory evoked potential (AEP) monitor

Anesthesiologists agree that none are the “gold standard” or are sufficiently sensitive to guarantee that patients will not awaken during surgery

Considerations forEmergence & Recovery

Emergence and Recovery: Emergence and Recovery: ConsiderationsConsiderations

Goal is to prepare for and have smooth transition to postoperative analgesia

Early planning important because some agents have rapid offset of action (within 5-10 minutes)

– Benefit of lack of cumulative effects, but may be disadvantage in postoperative setting when considering pain control

– Need to be prepared

Identify risk for pulmonary aspiration of gastric contents

PropofolPropofol Emergence DataEmergence Data

DIPRIVAN (propofol) injection, emulsion [APP Pharmaceuticals, LLC]. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee0c3437‐614d‐4631‐a061‐257f5f60c70b

Plasm

a PropofolConcentration

(mcg/m

L)

1.00

0.75

0.50

0.25

0.00

Minutes After End of Infusion

0 20 40 60 80

Target plasma concentration Recovery after:10‐day infusion10‐hour infusion1‐hour infusion

Awakening

ShortShort--acting acting OpioidOpioid Improves Time to Improves Time to Orientation Compared With NOrientation Compared With N22OO

Pro

po

rtio

n N

ot

Ori

ente

d

Time (min)

During ambulatory orthopedic surgery with a desflurane‐fentanylgeneral anesthetic

‐‐

Infusion of remifentanil0.085 µg/kg/min compared with66% N2O

1.0

0.8

0.6

0.4

0.2

0.00 5 10 15 20 25

Remifentanil

Nitrous oxide

Mathews DM, et al. Anesth Analg. 2008;106:101‐108.

Postoperative Management

Postoperative Analgesia Postoperative Analgesia Management OptionsManagement Options

Choice of analgesia should depend upon patient and type of surgery:

– Nonsteroidal agent administered IV or IM

– IV acetaminophen

– Major nerve block

– Local anesthetic wound infiltration

– Long-acting opioids administered 20 to 30 minutes before discontinuation of certain short-acting opioids

– Epidural administration of an opioid and/or local anesthetic

IM, intramuscular.

Considerations forSpecial Populations

Considerations for Special PopulationsConsiderations for Special Populations

Age

Comorbidities

Body mass effects

Practical Considerations& Summary

Practical Considerations:Practical Considerations:Rapid OnsetRapid Onset

ADVANTAGES

Rapid response to titration and bolus

Control of anesthetic depth

Hemodynamic stability

Predictable plasma & receptor level

DISADVANTAGES

Increased risk for:

– Bradycardia

– Hypotension

– Chest wall rigidity

– Apnea

Practical Considerations:Practical Considerations:Rapid OffsetRapid Offset

ADVANTAGES

Rapid response to titration

Predictable emergence

High-dose opioid technique without need for post-op ventilation

Ideal for TIVA

DISADVANTAGES

No residual analgesia

– Hemodynamic instability

SummarySummary

Newer opioids have the potential to improve therapeutic index, titratability, recovery, and overall patient experience & satisfaction

Short-acting opioids:

– Decrease drug accumulation

– Provide rapid onset, offset, and response to titration

– Unaffected by patient gender, age, or weight

Early planning is essential to ensure a smooth emergence & recovery, and proper postoperative analgesia

Understanding and anticipating the potential side effects of short-acting opioids allows the practitioner to potentially eliminate them from practice