Inhaled anesthetics

Tom Archer, MD, MBA

UCSD Anesthesia

Inhaled anesthetics are weird.

Inhaled anesthetics
are not normal medicines

Anesthesia has a monopoly on

powerful and dangerous
inhaled drugs.

Inhaled anesthetics
Powerful poisons.
Toxic to heart and breathing.
Need to change dose rapidly.
Unique route of administration.

Inhaled anesthetics

How the heck do we know what dose the

heart and brain are seeing?

Brain is highly perfused

Blood perfusion

For all modern inhaled agents,

brain equilibrates with arterial
blood within 5-10 minutes.

Small brain
sponge

Large brain
blood flow

Size of brain sponge =

Brain / blood
partition coefficient

Brain has 19 balls halothane / ml

Blood has 10 balls halothane / ml

No net diffusion
when partial
pressures are equal.

Halothane brain / blood partition coefficient = 1.9

Brain has 11 balls N2O / ml

Blood has 10 balls N2O / ml

No net diffusion
when partial
pressures are equal.

N2O brain / blood partition coefficient = 1.1

Brain rapidly equilibrates with

arterial blood
Time constant (2-4 minutes) is brain /
blood partition coefficient divided by brain
blood flow.
Blood / brain partition coefficients vary
relatively little between anesthetic agents
After one time constant, brain partial
pressure is at 63% of arterial partial
pressure.

Brain / blood partition coefficients

(and time constants) vary by a
factor of only 1.7

Isoflurane 1.6
Enflurane 1.5
Halothane 1.9
Desflurane 1.3
Sevoflurane 1.7
N2O 1.1

Time constant =
BBPC / brain blood
flow.

OK, so brain quickly = arterial.

But, how can we measure the
arterial partial pressure?

Arterial blood has same partial pressure of agent as alveolus.

PP inhaled = 2A

Equilibration is complete
across AC membrane.

PP alveolar = A

=
PP < A

Pulmonary
artery

PP = A

Pulmonary
capillary

Pulmonary
vein =
arterial
blood

So, how can we know alveolar

partial pressure?

Alveolar = end tidal

Brain = arterial =
alveolar = end tidal

So end-tidal agent here gives us arterial agent partial pressure

Desflurane 4.5%

The alveolus is boss.

The alveolus is
boss of the brain.
End-tidal gives us alveolar.
End-tidal gives us brain.

End tidal gives us brain

(with 5-10 minute time lag)

Brain agent
Follows alveolar agent within 5-10 minutes.
Speed of equilibration inversely proportional
to brain / blood partition coefficient.
BBPCs do not vary much between agents.

End tidal gives us brain

(with 5-10 minute time lag)

What, then, determines alveolar

concentration of agent?
Unfortunately, many things.

Alveolar partial pressure is a balance between

input and output of agent from alveolus.
Increased input of agent to
alveoli:

FI = 16 mm Hg

High vaporizer %, alveolar

ventilation and FGF.
FA = 8
mm Hg

Venous (PA) agent

= 4 mm Hg

FA / FI = 8/16 = 0.5

Arterial (PV) agent

= 8 mm Hg

Increased output of agent from alveoli:

Low venous agent, high solubility, high CO

Movement of agent from

alveoli into blood is uptake.
FI = 16 mm Hg

FA = 8
mm Hg

Venous (PA) agent

= 4 mm Hg

Arterial (PV) agent

= 8 mm Hg

High output of
agent from
alveolus (uptake)

Low venous agent

High blood solubility
Alveolar
High CO
agent partial
pressure

High input of agent

to alveolus

High vaporizer %
High alveolar
ventilation
High FGF

FA / FI
Ratio of alveolar agent to inhaled agent.
The higher the blood / gas partition coefficient
(solubility), the greater the uptake from the
alveolus and
The slower the rise of FA to met FI.
Minute ventilation, CO, FGF, and venous agent
PP also affect rise of FA to meet FI.

High blood-gas partition coefficient =

slow rate of rise of FA to meet FI.
N2O, low blood / gas

Halothane, high blood / gas

When venous agent = alveolar agent,

uptake stops and FA / FI = 1.0
FI = 16 mm Hg

FA = 16
mm Hg

Venous (PA) agent

= 16 mm Hg

FA / FI = 16/16 = 1.0

Arterial (PV) agent

= 16 mm Hg

Venous agent = arterial agent

when tissues are saturated.
Movement of agent from blood
into tissues is distribution.

Uptake stops when distribution

stops, and FA = FI.
N2O, low blood / gas

Halothane, high blood / gas

More of this punishment later

Gas vs. Vapor

Vapor: gaseous form of a substance that is
primarily liquid at room temperature.
N2O and Xe are gases at room temperature
(and normal pressure) and should be called
gases.
If youre talking about sevoflurane, et al., say,
Lets turn on some vapor.

Benefits of inhaled anesthetics

Presumed unconsciousness
Amnesia
Immobility (spinal cord)
Muscle relaxation (not N2O).
Suppression of reflex response to painful
stimulus (tachycardia, hypertension, etc.)

Only N2O is an analgesic.

Volatile agents reduce blood pressure

BP = CO X SVR
Halothane reduces CO, maintains SVR
Sevoflurane, desflurane and isoflurane reduce
SVR, maintain CO.
Using N2O + volatile agent attenuates BP drop
at constant MAC.

Volatile agents have

varying effects on HR
Halothane and sevoflurane have minimal
effects on HR.
Isoflurane and desflurane can cause
sympathetic stimulation and can increase HR
and CO, with a low SVR.
One can confuse hyperdynamic effect of iso
and des with light anesthesia.

Volatile agents
depress ventilation
TV and minute ventilation fall.
RR rises.
Inefficient ventilation d/t increased ratio of
dead space to tidal volume.
Expiratory muscle effort increases
promotes atelectasis

Volatile agents
depress ventilation

Decrease ventilatory response to both

CO2 and hypoxia.
N2O + volatile agent attenuates ventilatory
depression by volatiles at constant MAC.

Airway irritation
N2O, sevoflurane and halothane are well
tolerated for inhalation induction.
Desflurane and isoflurane are pungent they
make people cough and can cause
bronchospasm.
Des and iso are better tolerated with opioids
on board.

Cerebral blood flow and

oxygen consumption
N2O increases cerebral O2 consumption
modestly and increases CBF.
Volatiles decrease cerebral O2
consumption but increase CBF
(uncoupling).
Use only very low volatile agent (if any)
with increased ICP.

Volatile agents and NMBs

Volatile agents potentiate NMBs a very
useful property.
Distinguish between relaxation and
relaxant.
We can get increased relaxation with
propofol, deeper volatile, hyperventilation,
or NMB.

N2O diffuses into gas spaces

faster than N2 diffuses out.
N2O will rapidly expand PNX, VAE
N2O will slowly expand bowel gas
N2O will increase middle ear pressure and
expand gas bubbles in head or eye.

Possible mechanisms of
anesthesia
Opening of inhibitory ion channels (Cl- or K+)
Closing of excitatory ion channels (Na+)
Hyperpolarization of nerve cell membrane
Diminished propensity to action potential
Multiple sites of action

Example: GABA receptor opens an inhibitory Cl- channel.

Benzodiazepines, barbiturates and ETOH
turn up the gain (modulate) the GABA receptors function.

 Summation: graded potentials (EPSPs and

IPSPs) are summed to either depolarize or
hyperpolarize a postsynaptic neuron.

Fig.48.14
Copyright2002PearsonEducation,Inc.,publishingasBenjaminCummings

Meyer-Overton Rule

Oil / gas partition coefficient X MAC = k.

This holds over a 100,000 - fold range of
MACs!

Oil / gas partition coefficient X MAC = a constant, over a range of 100,000.

Anesthetic potency is proportional to solubility in olive oil!
Is general anesthesia site a lipid? Probably its a protein.
This all implies that anesthesia is produced when a certain number of molecules
occupy a region of nerve cell membrane.

www.anes.upmc.edu/.../articles/focus.html

Anesthetic potency correlates very tightly

with potency to inhibit firefly luciferase, a
protein

www.nature.com
/.../n1s/fig_tab/0706441f3.html

Meyer-Overton Rule

O / G x MAC = k.
Amazing!

Now, back to
the dose question

MAC
Minimum alveolar concentration of
anesthetic needed to suppress movement
to incision in 50% of patients.
Assumes time for equilibration between
alveolus and brain (5-10 minutes).
Primary site of immobilizing action is spinal
cord.

MAC
MAC is a partial pressure, it is NOT a %.
Huh? Come again?
MAC is a partial pressure, not a %
MAC is expressed as a %, but this assumes sea
level pressure.

Can you survive breathing 21%

oxygen?

Can you survive breathing 21%

oxygen?
Not if youre at the top of Mount Everest!

MAC

So MAC, just like survival while breathing

oxygen, is a matter of partial pressure, not %.

MAC
In Denver (the Mile High City), the % MAC
of sevoflurane will be higher than in Houston,
but the partial pressure MAC will be the same
(2.2% X 760 = 16.7 mm Hg)
If barometric pressure is 600 mm Hg, %MAC
of sevoflurane = 2.8% (16.7 / 600 = 2.8%)

MAC
Question: What is the % MAC for sevoflurane
33 feet under water?
Answer: 1.1%, since barometric pressure is 2
atmospheres or 1520 mm Hg.
16.7 mm Hg / 1520 mm Hg = 1.1%

Partial pressure
Does not mean concentration.
Huh?
Does not mean concentration.

For a given partial pressure, a

more soluble agent will dissolve
more molecules in solution.

Blood has 8 balls / ml desflurane

Gaseous desflurane has 20 balls / ml

No net diffusion
when partial
pressures are equal.

Desflurane blood / gas partition coefficient = 0.42

Blood has 50 balls of halothane / ml

Gas has 20 balls of halothane / ml

No net diffusion
when partial
pressures are equal.

Halothane blood / gas partition coefficient = 2.5

MAC
Standard deviation of MAC is about 10%,
therefore, 95% of patients should hold still
at 1.2 MAC.

MACs are additive, e.g., 50% N2O + 1%

sevoflurane should be 1 MAC.

But, what determines the alveolar

partial pressure of agent?

Time lag between turning vaporizer

on and brain going to sleep.
Vaporizer
4% sevoflurane
PP= 30 mm Hg at
sea level

Circle
system
(hoses)
PP = 24 mm Hg

Inhaled FI
PP = 16 mm Hg

Alveoli FA
PP = 8 mm Hg

Arterial Blood
PP = 8 mm Hg

Brain
PP = 5 mm Hg

Alveolar partial pressure is a balance

between input and output.
Increased input of agent to
alveoli: High vaporizer %,
alveolar ventilation and
FGF.

FI = 16 mm Hg

FA = 8
mm Hg

Venous (PA) agent

= 4 mm Hg

FA / FI = 8/16 = 0.5

Arterial (PV) agent

= 8 mm Hg

Increased output of agent from alveoli:

Low venous agent, high solubility, high CO

Output of agent from alveolus into

blood (uptake) is proportional to
blood / gas partition coefficient
Input
Inhaled FI
PP = 16 mm Hg

Alveoli FA
PP = 8 mm Hg

Output (uptake) is low

Sevoflurane b/g = 0.7
Blood and tissues
PP = 6 mm Hg

Low Blood / Gas Partition Coefficient (Low Solubility of Gas in Blood)

Causes Quick-On and Quick-Off Effects of Desflurane and
Sevoflurane
Agent Relatively Insoluble in Water (Blood and Tissue)Little Uptake by Tissues,
Rapid Rise of Fa- Fi. Examples: N2O, desflurane, sevoflurane,

Blood

Alveolar Gas

Partial pressures
equilibrate rapidly

Desflurane
Desflurane

Output of agent from alveolus into

blood (uptake) is proportional to
blood / gas partition coefficient
Input
Inhaled FI
PP = 16 mm Hg

Alveoli FA
PP = 4 mm Hg

Output (uptake) is large

Halothane b/g = 2.5
Blood and tissues
PP = 2 mm Hg

High Blood / Gas Partition Coefficient (High Solubility of Gas in Blood)

Causes Slow-On and Slow-Off Effects of Isoflurane, Halothane and
Diethyl Ether.
Agent Highly Soluble in Water (Blood and Tissues)Much Uptake by Tissues, Slow Rise of Fa - Fi.
Examples: Isoflurane or Halothane or Ether.

Blood

Alveolar Gas

Partial pressures equilibrate

slowly

Halothane

Halothane

High B/G solubility means high uptake,

means slow rate of rise of FA to meet FI.
N2O, low blood / gas

Halothane, high blood / gas

Blood / gas partition coefficients

vary by a factor of 6

Isoflurane 1.5
Enflurane 1.9
Halothane 2.5
Desflurane 0.42
Sevoflurane 0.69
N2O 0.46

Hence, rates of rise of FA / FI will vary

dramatically between agents.

FA / FI for N2O and desflurane

FA / FI for N2O and isoflurane

This stuff really works!

Are we done yet?

No.
Why does brain closely follow arterial?

Time constants

Time constant

How many minutes will it take for a tissue

bed partial pressure to reach 63% of the
arterial partial pressure?

Time constant

Time constant = Brain / blood partition

coefficient divided by tissue blood flow.
Time constant = Size of sponge / flow of
water to the sponge

Size of brain
sponge

Brain blood
flow

Brain sponge size for halothane

Halothane brain / blood partition coefficient = 1.9

Brain sponge size for N2O

N2O brain / blood partition coefficient = 1.1

Brain / blood partition coefficients

vary only by a factor of 1.7

Isoflurane 1.6
Enflurane 1.5
Halothane 1.9
Desflurane 1.3
Sevoflurane 1.7
N2O 1.1

Blood / gas partition coefficients

vary by a factor of 6

Isoflurane 1.5
Enflurane 1.9
Halothane 2.5
Desflurane 0.42
Sevoflurane 0.69
N2O 0.46

Time constants
Brain takes about 3 time constants to be in
equilibrium with arterial blood.
Narrow range of brain / blood partition coefficients
means that time constants will vary little between
agents
Time constant for N2O / Des = 2 min
Time constant for halo / iso / sevo = 3-4 minutes

Time constants
Brain will be at alveolar / arterial partial
pressure after 6 minutes for N2O or
desflurane (3 time constants).
Brain will be at alveolar / arterial partial
pressure after 9 minutes for isoflurane,
halothane or sevoflurane (3 time
constants).

Halothane vs. N2O

Halothanes rate of rise of FA / FI is much
slower than N2Os, because of
halothanes much higher blood / gas
solubility coefficient.

Halothane vs. desflurane

But time constant for halothane is only 1.7
x that of N2O.
So once alveolar
halothane is adequate,
brain will go to sleep
quite fast, just as with
N2O.

Blood / gas vs. Brain / blood

Blood / gas partition coefficients vary
between anesthetic agents more than
brain / blood partition coefficients.
Therefore, brain partial pressure follows
alveolar partial pressure relatively fast for
all agents.

Blood / gas vs. Brain / blood

The key to getting the patient asleep is
raising the alveolar partial pressure of
agent.

For a highly soluble agent, where FA

follows FI slowly, we need to use
overpressure.

Overpressure
Temporarily raising the inspired
concentration to rapidly raise the alveolar
concentration.
For example: halothane 4-5% inspired for
a few minutes to raise alveolar tension,
despite the fact that this dose in the
brain or heart is lethal.

Overpressure

For soluble agents such as halothane or ether,

vaporizer output concentration will differ
immensely from brain concentration.

Alveolar (end-tidal) agent

concentration is key.

Nowadays we measure end tidal agent

concentrations, and hence, have a pretty
good handle on brain concentration,
despite all of these complexities.

Summary
Brain / blood = time constant
Oil / gas = potency
Blood / gas = FA / FI rate of rise

Summary

Alveolus is boss of brain (5-10 min).

End tidal = alveolar = arterial = brain.

The End