Transcript Inhaled anesthetics

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
•
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•
•
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.
FI = 16 mm Hg
Increased input of agent to
alveoli:
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 you’re talking about sevoflurane, et al., say,
“Let’s 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 receptor’s function.
• Summation: graded potentials (EPSPs and
IPSPs) are summed to either depolarize or
hyperpolarize a postsynaptic neuron.
Fig. 48.14
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
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 it’s 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.htm
l
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 you’re 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.
FI = 16 mm Hg
Increased input of agent to
alveoli: 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
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.
Alveolar Gas
Blood
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 desflurane
1.20
1.00
FA / FI
0.80
Fe/Fi N2O
0.60
Fe/Fi Des
0.40
0.20
0.00
0
2
4
6
8
10
Minutes
12
14
16
18
FA / FI for N2O and isoflurane
FA / FI for N2O and isoflurane
1.2
1
FA / FI
0.8
Fe/Fi N2O
0.6
Fe/Fi Iso
0.4
0.2
0
0
2
4
6
8
Minutes
10
12
14
16
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
• Halothane’s rate of rise of FA / FI is much
slower than N2O’s, because of halothane’s
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