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