MAJOR FACTORS AFFECTING UPTAKE

Solubility

•  Partition coefficients express relative solubility of anesthetic gas at equilibrium

•  Lower partition coefficients imply ↓ solubility, faster equilibration of partial pressure (alveolus ↔ blood ↔ brain), rapid induction (e.g., desflurane)

•  Higher partition coefficients imply ↑ solubility, slower equilibration as more molecules are dissolved in blood, prolonged induction (e.g., halothane)

•  Tissue: Blood partition coefficient = time for equilibrium of tissue with arterial blood

Cardiac Output

•  Increased cardiac output results in faster uptake but ↓ alveolar concentration (Fa) and therefore slower induction (more blood passing through lungs = anesthetic is carried away faster).

•  Effect is less pronounced for insoluble agents

•  Note: Slower induction with R → L cardiac shunt due to no uptake of agent in shunted blood → dilution of arterial concentration despite faster ↑ in alveolar concentration (Fa); least soluble agents are affected most

Alveolar-Venous Concentration Gradient

•  Depends on uptake by desired (brain) and undesired (fat, muscle) tissues

•  Tissue uptake is determined by partition coefficients and regional blood flow

•  Less tissue uptake means blood returns to alveolus with higher partial pressure, thus alveolar concentration (Fa) can ↑ faster

OTHER FACTORS INFLUENCING UPTAKE

Concentration Effect: Increasing the inspired concentration of a gas results in a disproportionate ↑ in the alveolar concentration (Fa); most clinically significant with N₂O, as can be used at ↑↑ inspired concentrations than volatile anesthetics

Second Gas Effect: Large-volume uptake of the first gas (classically N₂O) causes ↓ total gas volume in alveolus, thereby ↑ alveolar concentration/accelerating uptake of second gas (volatile agent)

Factors that Speed Rate of Induction (↑ Fa/Fi)

•  Use of agents with ↓ solubility (low partition coefficients)

•  Low cardiac output with minimal R → L shunt and preserved cerebral blood flow

•  Increased alveolar minute ventilation, ↑ inspired concentration of agent, ↑ fresh gas flow rate (replaces anesthetic taken up in bloodstream)

•  Pediatric pts → faster induction due to ↑ alveolar ventilation, ↓ FRC, ↑ % of blood flow to brain

ELIMINATION/RECOVERY

•  Reduction of anesthetic in brain tissue is via exhalation >> biotransformation > transcutaneous loss

•  Biotransformation via P-450 enzymes more important for halothane (20%) than sevoflurane (5%), isoflurane (0.2%), or desflurane (<0.1%)

•  Recovery expedited by high fresh gas flows, elimination of rebreathing, low absorption by the circuit, decreased solubility, high cerebral blood flow and ↑ minute ventilation

•  Context-sensitive elimination time: Longer duration of anesthetic is associated with longer time to recovery; over longer time more anesthetic is deposited in undesired tissues and must be “washed out”; effect more pronounced with ↑ solubility of agent (see Fig. 2A-2)

Figure 2A-2. Solubility and duration of use affect rate of recovery from inhaled anesthetics.

DIFFUSION HYPOXIA

•  High concentrations of relatively insoluble gasses (N₂O) diffuse out of the blood and enter the alveolus, displacing and reducing alveolar concentration of O₂ and CO₂

•  Dilution of alveolar O₂ can lead to hypoxia, dilution of CO₂ can ↓ ventilatory drive and worsen hypoxia

•  Administer high-flow 100% O₂ for 5 to 10 min after discontinuation of N₂O

MINIMUM ALVEOLAR CONCENTRATION (MAC)

•  Unitless value comparing potency of inhaled anesthetic agents

•  Reference point (1 MAC) = alveolar concentration at which 50% of patients will not move in response to a standardized surgical stimulus; analogous to ED₅₀

•  MAC values are roughly additive (i.e., 0.5 MAC of N₂O plus 0.5 MAC of sevoflurane ≈ 1.0 MAC)

•  MAC is greatest at 1 yr of age and reduced by 6% per decade of life

•  At MAC 1.3, 95% of patients will not move in response to surgical stimulus

•  MAC-BAR (1.5–2.0 MAC): Concentration which Blocks Adrenergic Response to nociceptive stimuli

•  MAC-Aware (estimated 0.4–0.5 MAC): Concentration at which 50% of patients will not be forming long-term memory

•  MAC-Awake (0.15–0.5 MAC): Concentration at which 50% of patients open eyes on command

CLINICAL CONSIDERATIONS OF INHALED ANESTHETICS

•  Volatile agents may trigger malignant hyperthermia (MH) (see Appendix C)

•  Agents in current use are nonflammable at clinical concentrations

•  All potentiate neuromuscular blockade, degree varies with combinations of drugs/agents; effect of volatiles > N₂O

•  Carbon monoxide formed in reaction of volatile agents with desiccated CO₂ absorbent, (desflurane > isoflurane >> halothane, sevoflurane); CO production ↑ with Baralyme, dry granules (classic example is Monday AM after O₂ flows left on), ↑ temperature, ↑ concentration of agent

•  Exothermic degradation reaction of sevoflurane in the presence of desiccated Baralyme linked to rare absorbent canister fires

SYSTEMIC EFFECTS OF INHALED AGENTS

•  Cardiovascular:

• All volatile agents are dose-dependent CV depressants, though mechanism of ↓ BP differs (see Table, Differential Physiologic Effects of Inhaled Anesthetics)

• Heart rate effects vary with MAC and inspired concentration rate of change

•  Pulmonary:

• All agents cause ↑ RR with ↓ TV, overall volatile agents cause ↓ in minute ventilation and ↑ resting PaCO₂

• All blunt ventilatory response to hypoxemia (even at 0.1 MAC), volatile agents ↓ response to hypercarbia

• Volatile agents are potent bronchodilators

• Minimal inhibition of hypoxic pulmonary vasoconstriction (HPV)

•  Neurologic:

• All agents ↑ cerebral blood flow causing ↑ ICP (especially halothane) and impair autoregulation of vascular tone (least with sevoflurane at <1 MAC)

• Volatile agents ↓ cerebral metabolic rate, N₂O may ↑

• Desflurane and isoflurane at <1 MAC can suppress status epilepticus while ↑ sevoflurane concentrations associated with epileptiform EEG ∆

• All agents ↓ SSEP/MEP signals

•  Hepatic: Halothane causes both hepatic artery vasoconstriction and ↓ portal vein flow (potential for hypoxic hepatic injury, ↑ LFTs), others preserve vascular supply better with ↑ in hepatic artery flow compensating for ↓ portal vein flow

•  Renal: All cause ↓ renal blood flow, ↓ GFR, ↓ urine output without lasting dysfunction; untreated hypotension can cause acute kidney injury

INHALATIONAL ANESTHETICS, SPECIFIC COMMENTS

Nitrous Oxide (N₂O)

•  Key features: MAC of 104% precludes use as solo agent for surgical anesthesia; used at 30–70% concentration as adjuvant to IV or potent inhaled anesthetics. Low solubility = rapid onset/offset of action. Nonpungent, has analgesic properties

•  Disadvantages: Rapidly diffuses into and expands air-containing cavities → avoid in air embolism, pneumothorax (75% N₂O doubles size in 10 min), bowel obstruction, pneumocephalus, middle ear and retinal procedures; monitor ETT cuffs and PAC balloons for expansion

•  Prolonged exposure → inhibits B₁₂-dependent enzymes responsible for myelin and nucleic acid synthesis; megaloblastic bone marrow ∆ possible with >12–24 hrs use; neurotoxicity with repeated exposures (abuse)

•  Increased homocystine levels possibly related to ↑ postoperative MI (ENIGMA trial; Anesth Analg. 2011 Feb;112(2):387–393)

•  Teratogenic in animal models, no evidence in humans at clinical doses

•  Not flammable, although does support combustion

•  May ↑ PONV risk

•  CV effects: Sympathomimetic, though direct myocardial depressant effect may prevail in hypovolemia, cardiac dx; ↑ PVR especially in patients with pre-existing pulmonary HTN

Isoflurane

•  Key features: Inexpensive; slower onset/offset of action, pungent. Versatile use

•  Disadvantages: Coronary vasodilator, potential for coronary “steal” effect (flow diverted away from vessels with fixed lesions) of uncertain clinical significance

Desflurane

•  Key features: Most rapid onset/offset of action among volatiles; very pungent

•  Disadvantages: High vapor pressure requires an electrically heated vaporizer (eliminates variation in delivery owing to ∆ in ambient temperature). Pungency may be irritant in patients prone to bronchospasm. Rapid increase or high MAC (>1.25) may cause transient but significant sympathetic stimulation

Sevoflurane

•  Key features: Least pungent (best choice for inhalational induction); fast onset/offset of action; causes ↓ tachycardia than desflurane or isoflurane; does not sensitize myocardium to catecholamines

•  Disadvantages: Controversial potential for nephrotoxicity due to metabolic production of fluoride ion and degradation to Compound A (nephrotoxic in animals). Compound A production ↑ with low flows, high concentrations of sevoflurane, desiccated barium lime absorbent; minimizing exposure recommended although studies have not shown nephrotoxicity in humans (if using flow rate of 1–2 L limit exposure to <2 MAC hrs; use >2 L for longer cases)

Halothane

•  Key features: Low pungency (ideal for gas induction), inexpensive, ↑ cerebral blood flow > other volatiles, especially potent bronchodilator

•  Disadvantages: Use ↓↓ due to rare but fulminant postoperative auto-immune hepatitis, CV depression and myocardial sensitization to catecholamines (↑ ventricular dysrhythmias)

Heliox (Helium–Oxygen Combination)

•  Non-anesthetic gas mixture, commonly 70–79% helium + 21–30% O₂

•  Lower density of gasses (up to 2/3 ↓ than air + O₂) promotes laminar flow, reduces turbulence in upper airway obstruction, asthma, COPD

•  Helps ↓ pressures needed to ventilate pts with small-diameter ETTs; ↓ work of spontaneous breathing