General Anesthesia

The inhalational anesthetics share the clinical goal of producing reversible unconsciousness but differ substantially in their pharmacokinetic properties, organ system effects, and toxicity profiles. Understanding these differences drives agent selection for specific clinical situations.

The primary molecular mechanism of volatile halogenated agents is potentiation of the gamma-aminobutyric acid type A receptor, a ligand-gated chloride channel that mediates inhibitory neurotransmission throughout the central nervous system. By enhancing chloride conductance and hyperpolarizing neurons, volatile agents suppress cortical and subcortical circuits responsible for consciousness. Nitrous oxide acts through a different primary mechanism — antagonism of N-methyl-D-aspartate glutamate receptors — which explains both its analgesic properties and its distinct clinical profile compared to the halogenated agents.

Anesthetic potency correlates with lipid solubility (the Meyer-Overton correlation), reflected in the oil:gas partition coefficient: more lipid-soluble agents are more potent and have lower minimum alveolar concentration values. This empirical relationship is now understood to reflect binding at lipophilic sites on membrane proteins rather than bulk membrane dissolution.

Nitrous oxide is unique among inhalational anesthetics: it is a gas at room temperature (stored as a liquid under pressure), it has analgesic properties that the volatile halogenated agents lack, and its minimum alveolar concentration of approximately 104% means it cannot produce surgical anesthesia alone at atmospheric pressure. It is always used as part of a combined anesthetic, where it reduces the required concentration of the co-administered volatile agent (minimum alveolar concentration additivity).

The primary anesthetic mechanism of nitrous oxide is N-methyl-D-aspartate receptor antagonism, shared with ketamine. This is distinct from the gamma-aminobutyric acid type A potentiation of the volatile halogenated agents. Nitrous oxide's N-methyl-D-aspartate antagonism also underlies its significant analgesic properties, making it useful for procedural analgesia at sub-anesthetic concentrations (50% inspired mixture).

Nitrous oxide has mild sympathomimetic cardiovascular effects, maintaining or slightly increasing heart rate, blood pressure, and cardiac output. This is in contrast to the myocardial depression of volatile agents, making nitrous oxide a useful adjunct in patients with limited cardiovascular reserve. In patients with severely depleted catecholamine stores, however, the direct myocardial depressant effect may be unmasked.

Nitrous oxide diffuses into air-filled body cavities approximately 34 times faster than nitrogen leaves them, causing progressive expansion of any closed gas-containing space. This produces several important contraindications.

Nitrous oxide irreversibly oxidizes the cobalt ion of vitamin B12, inactivating methionine synthase. This enzyme is required for the conversion of homocysteine to methionine and for normal thymidylate (deoxyribonucleotide) synthesis. Acute inhibition impairs deoxyribonucleic acid synthesis. With single exposures this is transient and subclinical, but repeated or prolonged exposures can produce megaloblastic anemia and subacute combined degeneration of the spinal cord — a syndrome identical to that of nutritional vitamin B12 deficiency. Nitrous oxide must be avoided in patients with pre-existing vitamin B12 deficiency and used cautiously with drugs that also inhibit folate metabolism.

Nitrous oxide increases the incidence of postoperative nausea and vomiting in a duration-dependent manner and is a component of postoperative nausea and vomiting risk reduction strategies in high-risk patients. It is not a triggering agent for malignant hyperthermia — a critical distinction from the volatile halogenated agents. Diffusional hypoxia at emergence is covered in Module 1.

Isoflurane has a blood:gas partition coefficient of approximately 1.4 — intermediate between halothane and sevoflurane — producing a moderately rapid induction and emergence. It undergoes approximately 0.2% hepatic metabolism, producing inorganic fluoride and trifluoroacetic acid at levels insufficient to cause clinically significant organ toxicity. This near-metabolic inertness was a major safety advantage over halothane when isoflurane was introduced.

Isoflurane is a peripheral vasodilator. It reduces systemic vascular resistance and blood pressure, and unlike halothane (which directly suppresses the sinoatrial node and causes bradycardia), isoflurane triggers a baroreceptor-mediated reflex tachycardia. Cardiac output is relatively preserved. Myocardial contractility is only minimally depressed at clinical doses, making isoflurane substantially less cardiotoxic than halothane. Isoflurane does not sensitize the myocardium to catecholamine-induced arrhythmias.

Isoflurane reduces cerebral metabolic rate and at doses of 1.5 to 2 minimum alveolar concentration produces burst suppression on electroencephalography — a property sometimes exploited during neurosurgical procedures requiring temporary vascular occlusion. It causes less cerebral vasodilation and less intracranial pressure elevation than halothane, and the rise in intracranial pressure is more readily blunted by hyperventilation, giving isoflurane a more favorable neurosurgical profile.

Sevoflurane has largely replaced halothane in high-resource settings as the preferred agent for inhalational induction, particularly in pediatric patients. Its combination of low blood solubility (blood:gas partition coefficient approximately 0.65), a pleasant non-pungent odor, potent bronchodilation, and hemodynamic stability at induction doses makes it ideal for mask induction without intravenous access.

The minimum alveolar concentration of sevoflurane is approximately 2.0% in oxygen. Approximately 3 to 5% of the absorbed dose undergoes hepatic metabolism — higher than isoflurane or desflurane — generating inorganic fluoride and hexafluoroisopropanol. Despite serum fluoride levels that can transiently rise above thresholds historically associated with nephrotoxicity from other agents, clinically significant renal dysfunction from sevoflurane has not been convincingly demonstrated in clinical practice.

Sevoflurane degrades in contact with carbon dioxide absorbents (soda lime) at low fresh gas flow rates to produce compound A, a vinyl ether that causes dose-dependent nephrotoxicity in rats. Human nephrotoxicity from compound A has not been demonstrated in clinical studies, and regulatory agencies in most countries permit low-flow sevoflurane anesthesia. Nevertheless, caution is advised in patients with pre-existing renal impairment undergoing prolonged procedures at very low fresh gas flows.

Sevoflurane causes dose-dependent reductions in blood pressure and systemic vascular resistance similar to isoflurane. It does not sensitize the myocardium to catecholamine-induced arrhythmias and does not cause the sympathetic activation on rapid concentration increase seen with desflurane, making it more suitable for inhalational induction. Sevoflurane is the preferred volatile agent in patients with asthma or reactive airways disease, largely replacing halothane for this indication in high-resource settings.

A clinically important adverse effect of sevoflurane is emergence agitation — also called emergence delirium — occurring particularly in young children (peak incidence ages 2 to 5). It presents as inconsolable crying, thrashing, disorientation, and failure to recognize caregivers in the immediate post-anesthetic period, typically resolving within 15 to 30 minutes. The mechanism is incompletely understood but is related to the rapid offset of sevoflurane sedation before full cortical reintegration occurs.

Effective prevention strategies include midazolam premedication, a small dose of propofol at emergence, fentanyl before awakening, adequate multimodal analgesia, and dexmedetomidine near the end of the procedure. Emergence agitation is distinct from postoperative delirium in elderly adults, which involves different pathophysiology and a more prolonged course.