Inhaled anesthetics Tom Archer, md, mba



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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



Kataloq: obstetrics

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