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A Practical Approach to the use of Inhalational Anesthetics

James H. Philip, M.E.(E.), M.D. Anesthesiologist and

Director of Bioengineering, Department of Anesthesia, Brigham and Women's Hospital

Medical Liaison for Anesthesia, Department of Biomedical Engineering Partners HealthCare System Professor of Anaesthesia Harvard Medical School

For BWH employees, the CE number for this lecture is 322799 © 1995 - 2014, James H Philip, all rights reserved

A Practical Approach to the use of Inhalational Anesthetics

James H. Philip, M.E.(E.), M.D. Anesthesiologist and

Director of Bioengineering, Department of Anesthesia, Brigham and Women's Hospital

Medical Liaison for Anesthesia, Department of Biomedical Engineering Partners HealthCare System

Associate Professor of Anaesthesia Harvard Medical School

Conflicts of interest: Financial - None Non-financial - 1) Author of Gas Man® computer simulation of inhaled anesthetics, distributed by Educational

Charitable Organization, Med Man Simulations, Inc. (MMSI) 2) President without financial compensation of MMSI. www.medmansimulations.org

Anyone can download the program and textbook from from the web site, free.

General Anesthesia Techniques

TIVA = Total Intravenous Anesthesia IV drugs only

VIMA = Volatile Induction and Maintenance Anesthesia

Balanced = Inhaled and IV drugs Induction (beginning) = IV Maintenance = IV opioid + IV muscle relaxant + Inhaled sleep and amnesia drug

Components of General Anesthesia

1. Sleep – sedation -> unconsciousness 2. Amnesia - loss of recall 3. Analgesia - loss of pain sensation 4. Paralysis - muscles relaxed or soft 5. Autonomic block - no body response

End of IV Anesthesia

We usually want all effects to go away Except analgesia to block the perception and response to noxious stimuli that remain after the surgery is over, AKA postoperative pain

Prevent or treat postoperative pain with Opioids Non-opioid analgesics of many classes Local anesthesia, Regional anesthesia

Intravenous Anesthesia Drugs and Purpose

Sleep - Sedative/Hypnotic – e.g., propofol Amnesia - e.g., midazolam, propofol Analgesia – opioid plus adjunct Paralysis – Neuro-Muscular junction Blocker-NMB Autonomic block – Beta blocker, side effect of other

drugs

What causes end of IV Anesthesia? Plasma level falls Effect site follows plasma level with 3 – 5 min delay Sedative/Hypnotic drug redistributes fast Hypnotic drugs redistribute slowly; rarely reversed Pain drugs other than remifentanil redistribute slowly NMB drugs we reverse with antagonist physostigmine

and block side effects with glycopyrolate Sympathetic blockade follows sedative/hypnotic drug

Inhalation Anesthesia

One drug does most of everything 1. Sleep – sedation -> unconsciousness 2. Amnesia – no recall 3. Analgesia – no pain sensation 4. Paralysis - muscles relaxed or soft 5. Autonomic block - no sympathetic response

What causes end of Inhalation Anesthesia? Drug is exhaled and removed from blood Plasma level falls rapidly Effect site follows plasma level

3 – 5 min time constant Pain is prevented or treated the same as after IV

anesthesia I give drugs to cover post-op and not intra-op pain

Volatile Induction and Maintenance Anesthesia VIMA No Propofol No NMB

Volatile Induction and Maintenance Anesthesia VIMA No Propofol No NMB No use No waste if prepared properly

BWH Pharmacy robotically-filled Propofol syringes

Inhalation Anesthetic History - William TG Morton

1846 Ether for General Anesthesia demonstrated, published, patented

Ether was made and delivered at the point of use

Oct 16, 1846 Surgery @ MGH Oct 22, 1846 US Patent 4,848

Sep 30, 1846 Tooth extraction

History

1846 Morton found Ethyl Ether to be a vapor that anesthetizes 1950 Kety explained Kinetics from Vaporizer to Brain 1963 Eger normalized drug concentrations to

MAC = Minimum Alveolar Concentration to anesthetize 1 MAC is the ED50 for “no movement from incision”

1963 Eger established End-Tidal = Expired ~ Alveolar conc. Recent

understanding 1.3 MAC ~ ED95 0.7 MAC provides amnesia 0.33 MAC patients respond to command These levels are all in the Brain which is delayed from ET

Inhaled Anesthetic Choices Ether is long gone – Flammable and very slow wake up Halothane was used in pediatric anesthesia until ~ 2005 Nitrous Oxide (N2O) old, rarely used USA

environmental harm, MAC = 110% atm thus not potent Todays agents Name MAC (%atm) Isoflurane 1.1 Sevoflurane 2.1 Desflurane 6.0

2014 Inhaled Agents Isoflurane –

inexpensive, slow return to normal Sevoflurane –

tolerated for mask induction and LMA FDA limits FGF > 1 or 2 LPM. $5 – $10 / hr pretty fast return to normal

Desflurane – very fast return to normal expensive at high FGF FDA approved for very low FGF; cost < $3 / hour

Each delivered with an Anesthesia Delivery Systems

Anesthesia Delivery Systems GE Aisys Draeger Apollo

We could use a manual resuscitator for easy delivery

Gases breathed in, breathed out, thrown away

We could use a manual resuscitator for easy delivery

Gases breathed in, breathed out, thrown away But, much wasted drug and potential environmental harm.

Lets explore rebreathing of anesthetic agents.

CO2

Ab- sorb- ant

Fresh

Normal flow in the breathing circuit - Inspiration

Inspired

Exhaust

CO2

Ab- sorb- ant

Fresh

Normal flow in the breathing circuit - Expiration

1

2 Expired

This is “Circle-Absorber System”

Exhaust Expired

CO2

Ab- sorb- ant

Inspired Fresh

VE

Gas is sampled from circuit near patient to measure I and E

Sampled

Exhaust Expired

CO2

Ab- sorb- ant

200 mL/min

Inspired Fresh

VE

Gas Monitor screen

Agent wave – continuous display

Sevoflurane concentration

6 sec

CO2 wave, also. This shows patient is alive

Sevoflurane concentration

CO2 concentration 6 sec

Inspired and Expired (End-Tidal) timing

I E

Inspired and End-Tidal (ET) numeric display

I E

Graphic Trend of Agent – insp, exp

1 hour

I

E

Graphic Trend of Sevoflurane VIMA Two anesthetics in an 8 hour day

Graphic Trend of Agent

Desflurane 5 minutes

66/18/08 Robot-assisted myomectomy

JHP photo of JHP case 6/18/08

6 hr Robotic Myomectomy w Desflurane

GE Aisys 2007

6 hr Robot Hyx

JHP photo of JHP case 6/18/08

GE Aisys 2007

6 hr Robot Hyx

JHP photo of JHP case 6/18/08

41 mL / 6 hr = 7 mL/hr @$.50/mL =

$3.50 / hr = $21.00 / case

GE Aisys 2007

6 hr Robot Hyx

41 mL / 6 hr = 7 mL/hr @$.50/mL =

$3.50 / hr = $21.00 / case

276 L / 6 hr = 0.7 LPM

JHP photo of JHP case 6/18/08

02/27/07 BWH OR Boston 6 hour Robot-assisted, Radical hysterectomy, w lymph node dissection

6 hr Robotic Hysterectomy w Desflurane

JHP photo of JHP case 2/27/2007

02/27/07 BWH OR Boston 6 hour Robot-assisted, Radical hysterectomy, w lymph node dissection

Emergence - Observe 1 hr trend graph

2 3

JHP photo of JHP case 2/27/2007

Inhalation Agent Theory (Kety 1950)

Anesthetic Path from Vaporizer to Brain: Del (D) -> CKT (I) -> Alv (A, E) -> art (a) -> Brain (VRG)

MAC in brain 1 MAC: 50 % of patients don’t move with incision

100 % are amnestic We use the term Anesthetic Tension rather than Anesthetic Concentration because

Tension equalizes while Concentration equilibrates with a ratio of concentrations in the two compartments that equilibrate.

Thus, anesthetic tension shows the Del -> Brain process

6 sec

Inhalation Agent Practice – Gas Monitor

Anesthetic Path from Vaporizer to Brain: Del (D) -> CKT (I) -> Alv (A, E) -> art (a) -> Brain (VRG)

MAC in brain 1 MAC: 50 % of patients don’t move with incision

100 % are amnestic

6 sec

Set Vaporizer

Inspired Expired = End-Tidal

Vital signs Brain Monitor

Alveolar Tension Curve

We explore kinetics by viewing the

Alveolar response to an Inspired Step

Alveolar Tension Curve

The time course of alveolar tension = PA in response to a step change in

inspired tension = PI

=

PI PA

Path of Anesthetic Tension from Vaporizer to Brain

I Br VRG

A a D

Philip JH, Gas Man®, www.medmansimulations.org, 1984 - 2014

Flows facilitate or impede the passage

I Br A a D

Open (Non-Rebreathing) Circuit provides controlled Inspired Step

I Br A a I D

Good for theory, expensive for practice

0 1 2 0.0

1.0 A / I

3 minutes (time)

Axes and Labels

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired Step

Alveolar response to a step change in inspired agent

Inspired Tension

Alveolar Tension

exponential curve

0 1 2 0.0

1.0 A / I

3 minutes (time)

Pure Lung wash-in Without Uptake into Blood

0.63

0.5 min τ =

Alveolar Tension

Inspired Tension

Time constant, tau ( τ ) is the time required to achieve

63% of the final value*

0 1 2 0.0

1.0 A / I

3 minutes (time) * Derive in long course

Time Constant

0.63

0.5 min τ =

Alveolar Tension

Inspired Tension

Time constant, tau ( τ ) time required to fill the compartment

if there were no mixing

0 1 2 0.0

1.0 A / I

3 minutes (time) * Derive in long course

Time Constant

Alveolar Tension

Inspired Tension

0 1 2 0.0

1.0 A / I

3 minutes (time) * Derive in long course

Pure Lung wash-in Without Uptake into Blood

is the same for: Cardiac Output = zero ( CO = 0) or Zerothane, Drug with solubility = zero (λ = 0) Xe, which has a very low solubility ~ 0 This is mixing a new gas into a container with

old gas

Now, add uptake into blood

Uptake into blood produces an Alveolar Tension Plateau

The plateau is formed by the equilibrium between

ventilation in and cardiac output out

0 1 2 0.0

1.0 A / I

3 minutes (time)

Alveolar Tension

Inspired Tension

Pure Lung wash-in Without Uptake into Blood

Plateau

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Alveolar

Plateau is produced by Anesthetic Removal by Blood

Alveolar Tension Plateau

Tail

Plateau

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Alveolar

Delivery

Removal

Alveolar Tension Plateau

Tail

Plateau

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Alveolar

Delivery = VA

Removal = CO • λ

Alveolar Tension Plateau

Hal Enf

Iso

Sevo N O 2

Des

Xe or Zerothane

Infinithane 0 1 2

0.0

1.0 A / I

3 minutes (time)

Alveolar Plateaus

Several Drug Plateaus

Ether

Alveolar Plateau Heights

.38

.54

.66

Ht 1

.24

.06

Hal Enf

Iso

Sevo N O 2

Des

Zerothane

0 1 2 0.0

1.0 A / I

3 minutes (time)

Plateau Heights

Ether

Alveolar Plateau Heights and solubilities

.38

.54

.66

Ht 1

.24

.00

Hal Enf

Iso

Sevo N O 2

Des

Zerothane

0 1 2 0.0

1.0 A / I

3 minutes (time)

1.3 2.4

λ

.67

.42

0

Inf.

Height and Solubility

Ether .06 12.1

Venous Return brings anesthetic back to alveoli

I Br A a V

Tail of the Alveolar Tension Curve

Tail

Plateau

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Alveolar

Plateau produced by Removal by Blood

Venous Return converts Plateau

0 1 2 0.0

1.0 A / I

3 minutes (time)

Plateau

Tail Alveolar

Inspired

Alveolar

Venous Return converts Plateau into Tail

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Arterial ~ Alveolar (ignore shunt)

Arterial = Alveolar

0 1 2 0.0

1.0 A / I

3 minutes (time)

Inspired

Tail

VRG = Brain, etc.

VRG follows arterial blood with τ = 3 – 5 min

τ = time constant, time for 63% response

Real drugs and real curves Next,

Des

Sev

Iso

Hal

30 0 Minutes of administration 30 0

P I

P A

1.0

Yasuda & Eger, 1991

Real drugs and real curves

A / I

Des

Sev

Iso

Hal

30 0 Minutes of administration 30 0

1.0 Zero A / I

Plateau height is determined by λ

Des Sev

Iso

Hal

λ

1.3

.67

.42

0

2.4

inf.

.38

.54

.66

1

.24

.00

Ht

Inf

Blood / Gas Solubility Dominates Inhalation Kinetics Determines how closely Expired Tension

approaches Inspired Tension in the first few minutes after you

change inspired

Wake Up !

0

.2

.4

.6

.8

Des

Sev

Iso

Hal

P A

0

0.62

0.34

0.76 Knee

Initial Fall = 0.5 min

0.46

0.00

E = all tissues

0.12

0.29

0.44

0.17

Tail

30 Minutes of emergence

10 20

Emergence from a long 1 MAC anesthetic MAC

1

P MAC

Yasuda & Eger, 1991. Analysis by JHP.

0

.2

.4

.6

.8

Des

Sev

Iso

Hal

P A

0

Initial Fall = 0.5 min

0.00

E = all tissues

0.12

0.29

0.44

0.17

Tail

30 Minutes of emergence

10 20

Emergence from a long 1 MAC anesthetic MAC

1

P MAC

Yasuda & Eger, 1991. Analysis by JHP.

Eger EI, Shafer SL. Tutorial: Context-Sensitive Decrement Times for Inhaled Anesthetics. Anesth Analg 2005 101: 688-696

Eger published this, Sept 2005 80% 88%

90% 92%

95%

The time required to reduce drug level further is termed the Context-sensitive decrement time. These times differentiate these drugs even more

Clinical Care – precise control of anesthetic depth Every time I make a change, up or down, the same thing happens - Initial change, plateau Good clinicians use the shape of this curve to contour the course of inspired, expired, and brain tension to produce the anesthetic they desire It is the tail of the curve that lets the patient drift too deep or too light after the plateau turns into a knee and ongoing tail

IV vs Inhaled agent kinetics

Context-Sensitive Half Time: Opioids and Hypnotics

50 min

Remifentanil

Shafer SL. Varvel JR: Pharmacokinetics. Pharmacodynamics, and rational opioid selection. Anesthesiol. 74:53-63,1991

Context-Sensitive Half Time: Opioids and Hypnotics

H Z D S

and Inhalants

Remifentanil

50 min

Shafer SL. Varvel JR: Pharmacokinetics. Pharmacodynamics, and rational opioid selection. Anesthesiol. 74:53-63,1991

Philip, Gas Man 2008

Computer simulation can explain what we observe

during clinical anesthesia and can help us to plan and create

effective clinical techniques

Simulation Example - Desflurane

FGF Comparison High FGF

5 L/min O2 Progressively increase vaporizer setting

Low FGF 1 L O2 /min Air + O2 Set vaporizer to 18% Watch, wait, Readjust when circumstances merit

Both techniques are after IV induction and secure airway

$7.80 for $0.75 in body

$2.90 for $0.75 in body

Economic advantage of low solubility If expired is close to inspired, then when we lower FGF the expired gas that the patient breaths contains enough anesthetic to not lower the inspired concentration much. Thus, low solubility promotes low FGF Low FGF promotes cost saving

Calculating cost of anesthesia

Fresh Gas Flow, Vaporizer Setting, cost per mL of anesthetic liquid, liquid/vapor volume ratio, and anesthetic administration duration together determine cost of anesthetic administered.

Cost = product of all these

Sevoflurane VIMA1 with VCI2 1 VIMA = Volatile induction and Maintenance Anesthesia

2 VCI = Vital Capacity (single, deep breath) Induction This requires that you supply very high (~ 8%) inspired concentration throughout each inspiration for the first few breaths. Gas Man shows how and why this works.

Philip BK, Lombard LL, Roaf ER, Drager LR, Calalang I, Philip JH. Comparison of Vital Capacity Induction with Sevoflurane to Intravenous Induction with Propofol for Adult Ambulatory Anesthesia. Anes Analg 1999; 89:623-627.

Agent Monitor Graph

Gas Man

Graph

Superimpose

Inhaled anesthetics have a special place in anesthesia care

Sometimes they can be used by themselves with nothing else

As long as we keep FGF low they are very inexpensive

$0

$10

$20

$30

0 1 2 3 4 5 6

Hourly Cost US

FGF L/min

Isoflurane

Desflurane

Sevoflurane

Gas Man 2008 Analysis

Thank you Jphilip@partners.org

For BWH employees, the CE number for this lecture is 322799

End