Inhalational anesthestics

Historical Facts

Several accounts of various forms of anesthesia in the BCE era using everything from cannabis and other herbs to carotid compression.

Modern anesthesia

• 1842 – Dr. Crawford Long had been using ether for fun with its exhilarating effects on what were known as ether frolics.
  • Dr. Long used ether to anesthetize a friend to excise some neck tumors (not reported until 1849)
• 1845 – Dentist Horace Wells successfully uses nitrous oxide for dental extractions; however, public demonstration fails.
• 1846 – First public demonstration of ether at MGH in what is now called the ether dome by Dr. Morton.
  • Dr. Warren (famous surgeon) was skeptical of Dr. Morton’s offer to keep the patient from pain after Dr. Well’s failed demonstration with nitrous. Dr. Warren called it “Humbug”.
  • Dr. Morton stayed up all night with Dr. Gould (instrument maker) to construct a device to deliver ether that was more sophisticated than a rag. They arrived for the schedule vascular tumor removal on Mr. Abbot 15 minutes late. Dr. Warren remarked “Well, Sir, your patient is ready”. After inducing anesthesia Dr. Morton fired back “Sir, your patient is ready!”.
  • After the surgery Dr. Warren commented, “Gentlemen, this is no humbug”

Pharmacokinetics

Pharmacokinetics of inhalational agents divided into four phases

• Uptake
• Metabolism (minimal)
• Distribution (to CNS = site of action)
• Elimination

Goal: to produce partial pressure of gas in the alveolus that will equilibrate with CNS to render anesthesia

• PARTIAL PRESSURE yields effect, not concentration
• At higher altitudes where P_atm < 760 mmHg, the same concentration of inhalation agent will exert a lower partial pressure within alveolus and therefore a REDUCED anesthetic effect

At equilibrium the following applies P_CNS=P_{arterial blood}=P_alveoli

FI (inspired concentration)

Determined by fresh gas flows, volume of breathing system, and absorption by machine/circuit • ↑ fresh gas flow, ↓ circuit, and ↓ circuit absorption allow actual Fi to be close to delivered Fi

FA (alveolar concentration)

Determined by uptake, alveolar ventilation, and concentration/second gas effects • PA (alveolar partial pressure) is determined by input (delivery) minus uptake (loss)

Uptake:

Uptake is defined as gas taken up by the pulmonary circulation.

• Affected by blood solubility, alveolar blood flow (i.e. cardiac output), alveolar-to-venous partial pressure difference
  • ↓ blood solubility, ↓ CO, ↓ alveolar-venous partial pressure difference → ↓ uptake
  • ↓ uptake → ↑ FA/FI → faster induction
• Highly soluble gases = more gas required to saturate blood before it is taken up by CNS
• High CO = equivalent to a larger tank; have to fill the tank before taken up by CNS
• Rate of rise in FA/FI ratio is a marker of anesthetic uptake by the blood.
  • More uptake means slower rise of FA/FI
  • Gases with the lowest solubilities in blood (eg. Desflurane) will have fastest rise in FA/FI

• Alveolar Blood Flow:
  • In the absence of any shunt, alveolar blood flow = cardiac output
  • Poorly soluble gases are less affected by CO (so little is taken up into blood)
  • Low cardiac output states predispose patients to overdose of inhalational agents as Fa/Fi will be faster (esp. for soluble gases)
• Shunt States
  • Right to Left Shunt (intracardiac or transpulmonary, i.e. mainstem intubation)
    • increases alveolar partial pressure, decreases arteriolar partial pressure; dilution from nonventilated alveoli → slows onset of induction
    • will have more significant delay in onset of poorly soluble agents
    • IV anesthetics = faster onset (if bypassing lungs, quicker to CNS)
  • Left to Right Shunt
    • Little effect on speed of induction for IV or inhalation anesthetics
• Concentration effect:
  • ↑ FI not only ↑ FA , but also ↑ rate at which FA approaches FI (see following graph)
• Second Gas Effect:
  • concentration effect of one gas augments another gas (questionably clinically relevant with nitrous both during induction and emergence)
  • rapid intake of nitrous into blood → ↑ relative concentration of second gas

Anesthetic Gas Properties

	Blood:Gas Partition Coefficient	Partial Pressure	MAC
Nitrous Oxide	0.47	-39000	104%
Desflurane	0.42	681	6%
Sevoflurane	0.69	160	2.15%
Isoflurane	1.40	240	1.2%
Halothane	2.3%	243	0.75%
Enflurane	1.8	175	1.68%

Example: Blood:gas partition coefficient of nitrous = 0.47 = at steady state 1ml of blood contains 0.47 as much nitrous oxide as does 1 ml of alveolar gas. In other words, at steady state if your fraction inspired gas is 50% N2O then 1ml of blood will contain 0.47x0.5 ml’s of N2O or 0.235 ml (Jaffe)

Fat:blood partition coefficient is >1. Therefore, things that increase fat in the blood (e.g. postprandial lipidemia will increase the overall blood:gas partition coefficient → slows induction

ITE tips

• Factors that increase the rate of rise of FA/FI
  • Relatively low blood:gas partition coefficient (solubility) for the anesthetic
  • Low cardiac output (affects soluble gasses more)
  • High minute ventilation
  • Low (Parterial – Pvenous), meaning less blood uptake
• Increase in cardiac output would decrease rate of rise in FA/FI for relatively soluble inhaled anesthetics, (*but would NOT produce much effect for insoluble agents.)
• Shunts on the other hand, typically affect insoluble agents more than soluble agents
• Which of the following is true about Fa/Fi when cardiac output is doubled?
  • A. increasing cardiac output has no significant effect on anesthetic uptake.
  • B. Fa/Fi ratio rises faster for soluble agents than insoluble agents.
  • C. Fa/Fi ratio rises slower for soluble agents than insoluble agents.
  • D. the rate of rise is the same for insoluble and soluble agents.

Pharmacodynamics

• No clear mechanism
• Direct binding to amphiphilic cavities in proteins, but unclear how this produces anesthesia
• Likely enhancement of inhibitory channels and attenuation of excitatory channels
  • GABA, NMDA, glycine receptor subunits have all been shown to be affected
• Potency of anesthetic has been roughly linked to lipid solubility

Shared Properties

System	Property
Neuro	CMRO2 ↓; cerebral vascular resistance ↓ → CBF ↑ → ICP ↑ except N2O: CMRO2 ↑ and CBF ↑ Sevo/Des/Iso 0.5 MAC: CMRO2 ↓ counteracts cerebral vasodilatation on CBF → CBF ↔ 1 MAC: CMRO2 ↓ maximal, so vasodilatory effects more prominent → CBF ↑
CV	Dose-related ↓ SVR → ↓ MAP (but CO maintained) Halothane cause decreases in myocardial contractility
Pulm	↓ Vt, ↑ RR → preserved minute ventilation Dose-dependent ↓ of ventilatory response to hypercapnia and hypoxemia ↑ bronchodilation
Renal	↓ renal blood flow and ↓ GFR
MSK	↑ muscle relaxation (except N2O)

Nitrous Oxide

• Low potency (MAC 104% - can never reach 1 MAC!)
• Low solubility in blood facilitates rapid uptake and elimination
• Commonly administered as an anesthetic adjuvant
• Does not produce skeletal muscle relaxation
• Can potentially contribute to PONV (but can be controlled with antiemetics)
• Can diffuse into air filled cavities and cause expansion of air filled structures (pneumothorax, bowel, middle ear, ET tube balloons, pulmonary blebs, etc.)
• Nitrous oxide can enter cavities faster than nitrous can leave
  • Often contraindicated in these settings
• Myocardial depression may be unmasked in CAD or severe hypotension • Can cause pulmonary hypertension if used for prolonged period
• NMDA antagonist → may have analgesic effects
• Prolonged exposure can result in bone marrow depression and peripheral neuropathies • NOT a trigger for MH (unlike volatile agents)
• Should periodically let air out of the ETT cuff if using nitrous to avoid tracheal injury

Isoflurane

• Highly pungent
• Least expensive among clinically used volatile anesthetics
• Second most potent of the clinically used inhalational agents (MAC 1.2%)
• Has been implicated for causing “coronary steal” – Dilation of “normal” coronary arteries causing blood to be diverted away from maximally dilated, stenotic vessels to vessels with more adequate perfusion
• Causes vasodilation
  • Decreases BP
  • Increases CBF (usually seen at 1.6 MAC) •
    • Minimal compared to halothane
  • Increases ICP (usually at above 1 MAC; short lived)
    • Minimal compared to halothane
• At 2 MAC produces electrically silent EEG

Sevoflurane

• Half as potent as isoflurane (MAC 2%)
• Rapid uptake and elimination
• Sweet smelling, non-pungent
  • Popular for inhalational induction
• Can form CO in desiccated CO2 absorbent
  • Can cause fires
• Forms Compound A in CO2 absorbent (nephrotoxic in rats, however no human clinical evidence of nephrotoxicity)
  • Guidelines recommended to keep fresh gas flows >2 L/min to prevent rebreathing of Compound A (not formation of it)
  • Occurs in alkali such as barium hydroxide lime or soda lime but NOT calcium hydroxide

Desflurane

• Lowest blood:gas solubility coefficient (lower than N2O)
• Low potency (MAC 6.6%)
• High vapor pressure (669 mmHg) is close to atmospheric pressure therefore boils at sea level
  • Must be stored in a heated, pressurized vaporizer so pressure stays constant (the vaporizer is set to 2 atm) and Desflurane vaporizers are set to deliver a constant volume of anesthetic.
  • **Remember that the anesthetic affect (MAC) correlates to the partial pressure, NOT the concentration.
• Very pungent
• Can cause breath-holding, bronchospasm, laryngospasm, coughing, salivation when administered to an awake patient via face mask
• Can form CO in desiccated CO2 absorbent (more so than other volatiles)
• Can cause an increased sympathetic response (tachycardia, hypertension) when inspired concentration is increased rapidly

Delivery of Volatile Anesthetics

• Modern anesthetic machines use vaporizers that take a reservoir of liquid anesthetic and create saturated vapor in equilibrium with the liquid.
  • A portion of the fresh gas flow or carrier gas then passes through the vaporizer chamber and becomes saturated with anesthetic gas, which then is carried to the patient as a mix of fresh gas and anesthetic gas.
  • Liquid anesthetic evaporates in chamber up to its saturated vapor pressure (SVP).
    • SVP: partial pressure at a given temp where the liquid and vapor are in equilibrium.
    • Partial pressure of the anesthetic gas in the carrier gas is equal to the SVP of the anesthetic
    • SVP/P_T = V_A/(V_C+V_A)
      • P_T = total pressure (usually atmospheric pressure)
      • V_A = agent vapor volume
      • V_C = carrier gas volume Delivery of Volatile Anesthetics
• Using the SVP and total pressure, you can calculate the volume of anesthetic delivered in a volume of fresh gas to determine how much anesthetic you are delivering to a patient.
  • Rearrange previous equation to: V_A = (SVP x V_C)/ (P_T - SVP)
• Once V_A or volume of anesthetic is calculated, the total % concentration delivered can then be determined.
  • % Volatile anesthetic = V_A / (FGF + V_A) x 100
    • It is worth knowing SVP of Sevoflurane and Isoflurane for your basic exam, as you may be asked to calculate anesthetic gas output.

ITE tips

There is a shortcut for calculating vaporizer output!

• If you can remember the PP fraction for each gas (which is calculated from the gas SVP divided atmospheric pressure), you can just multiply that fraction by the fresh gas flow to get the anesthetic volume … see fractions below.

Agent	SVP	PP/(ATM-PP)
Sevo	160	~1/4
Enflurane	175	~1/3
Isoflurane	238	~1/2
Halothane	241	~1/2
Desflurane	669	N/A

So… if fresh gas flow is 3L/ min and of that 200 mL/min goes through the sevo vaporizer, you can estimate that ~ 1/4th of that 200 mL flow will be sevo (about 50 mL), and the volume concentration will then be (50/3000 + 50) x100 = 1.6% sevo

Anesthesia in Denver?

• For Sevo and Iso:
• Remember modern vaporizer output is a function of partial pressure of the anesthetic in proportion to atmospheric pressure … so dropping atmospheric pressure will increase the output of your vaporizer in order to keep the partial pressure of your anesthetic gas the same.
  • In terms of volume : altitude has significant effect on vaporizer output.
    • There must be increased volume when atmospheric pressure is reduced.
  • But in terms of partial pressure, altitude has little effect on modern vaporizers
  • Remember partial pressure of an anesthetic gas in the alveoli is what determines MAC, (and there fore how anesthetized your patient is).
  • Therefore in Denver to give 1 MAC of Sevo you still turn the dial to 2% because the vaporizer compensates with more output.
• But also remember…
  • Desflurane uses a DIFFERENT heated vaporizer system that delivers anesthetic at a fixed percent concentration and NOT at a fixed partial pressure (like sevo and iso vaporizers do!).
  • At higher altitudes the partial pressure of Des is reduced due to lower barometric pressure. So: Des required dial setting = desired % x (760 mmHg/ current atmospheric pressure)
  • To deliver 1 MAC of Des at 380 ATM, you must turn the dial to 12%.