Inhaled anesthetics Tom Archer, md, mba

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?

For all modern inhaled agents, brain equilibrates with arterial blood within 5-10 minutes.

Size of brain sponge =

• Brain / blood

• partition coefficient

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

OK, so brain quickly = arterial. But, how can we measure the arterial partial pressure?

So, how can we know alveolar partial pressure?

Alveolar = end tidal

Brain = arterial = alveolar = end tidal

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.

Movement of agent from alveoli into blood is “uptake.”

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.

When venous agent = alveolar agent, uptake stops and FA / FI = 1.0

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.

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.

• Summation: graded potentials (EPSPs and IPSPs) are summed to either depolarize or hyperpolarize a postsynaptic neuron.

Meyer-Overton Rule

• Oil / gas partition coefficient X MAC = k.

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

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?

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.

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.

Alveolar partial pressure is a balance between input and output.

Output of agent from alveolus into blood (“uptake”) is proportional to blood / gas partition coefficient

Low Blood / Gas Partition Coefficient (Low Solubility of Gas in Blood) Causes “Quick-On and Quick-Off” Effects of Desflurane and Sevoflurane

Output of agent from alveolus into blood (“uptake”) is proportional to blood / gas partition coefficient

High Blood / Gas Partition Coefficient (High Solubility of Gas in Blood) Causes “Slow-On and Slow-Off” Effects of Isoflurane, Halothane and Diethyl Ether.

High B/G solubility means high uptake, means slow rate of rise of FA to meet FI.

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

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.

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