Tom Archer, MD, MBA UCSD Anesthesia 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

Brain / blood partition coefficient 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 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 PP = A Pulmonary artery Pulmonary vein = arterial blood Pulmonary capillary

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 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 / FI = 8/16 = 0.5 FA = 8 mm Hg Venous (PA) agent = 4 mm Hg 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 input of agent to alveolus High output of agent from alveolus (uptake) High vaporizer % High alveolar ventilation High FGF Low venous agent High blood solubility High CO Alveolar agent partial pressure

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 / FI = 16/16 = 1.0 FA = 16 mm Hg Venous (PA) agent = 16 mm Hg 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 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.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 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?

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. Circle system (“hoses”) 4% sevoflurane PP= 30 mm Hg at sea level PP = 24 mm Hg Inhaled “FI” Alveoli “FA” PP = 16 mm Hg PP = 8 mm Hg Arterial Blood Brain PP = 8 mm Hg 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 / FI = 8/16 = 0.5 FA = 8 mm Hg Venous (PA) agent = 4 mm Hg 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

Rapid Rise of Fa- Fi. Examples: N2O, desflurane, sevoflurane, Low Blood / Gas Partition Coefficient (Low Solubility of Gas in Blood) Causes “Quick-On and Quick-Off” Effects of Desflurane and Sevoflurane Blood Alveolar Gas Agent Relatively Insoluble in Water (Blood and Tissue)—Little Uptake by Tissues, Rapid Rise of Fa- Fi. Examples: N2O, desflurane, sevoflurane, 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. Blood Alveolar Gas Agent Highly Soluble in Water (Blood and Tissues)—Much Uptake by Tissues, Slow Rise of Fa - Fi. Examples: Isoflurane or Halothane or Ether. 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 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