Inhalational anesthetic
Inhalational anesthetics are volatile or gaseous agents administered via inhalation to induce and maintain general anesthesia, primarily during surgical procedures, by depressing central nervous system activity to produce unconsciousness, amnesia, analgesia, and muscle relaxation.[1] These agents include nitrous oxide, a non-halogenated gas, and halogenated compounds such as halothane, enflurane, isoflurane, desflurane, and sevoflurane, which are delivered through specialized anesthesia machines using face masks, laryngeal masks, or endotracheal tubes.[1] Their potency is quantified by the minimum alveolar concentration (MAC), defined as the lowest concentration in the alveoli that prevents movement in 50% of patients in response to a surgical incision, with values ranging from 104% for nitrous oxide to 1.2% for isoflurane.[1] The mechanism of action for inhalational anesthetics remains incompletely understood but involves enhancement of inhibitory neurotransmission, such as augmentation of gamma-aminobutyric acid (GABA) receptor activity and inhibition of excitatory pathways like N-methyl-D-aspartate (NMDA) receptors, leading to widespread neuronal depression.[1] Clinically, these agents are favored for their rapid onset and offset due to their low blood-gas solubility coefficients, allowing precise control of anesthetic depth through adjustments in inspired concentration, and they are often combined with intravenous agents for balanced anesthesia.[1] Nitrous oxide, in particular, provides adjunctive analgesia and is commonly used in dentistry, labor, and ambulatory settings, while volatile halogenated agents excel in maintaining anesthesia for longer procedures exceeding 30 minutes.[2][1] Monitoring during administration is critical and includes continuous assessment of end-tidal anesthetic concentration, carbon dioxide, oxygen saturation, and depth via tools like the bispectral index (BIS) to ensure safety and efficacy, adhering to standards from the American Society of Anesthesiologists.[1] Advantages include rapid recovery, hemodynamic stability in most cases, and bronchodilation properties useful for patients with reactive airways, though concerns such as environmental persistence of halogenated agents and occupational exposure risks—linked to reproductive effects—necessitate scavenging systems and ventilation controls in clinical environments.[1][2]Overview
Definition and general uses
Inhalational anesthetics are volatile or gaseous compounds administered via inhalation to induce and maintain general anesthesia, characterized by a reversible depression of the central nervous system that results in unconsciousness, amnesia, analgesia, and muscle relaxation.[1] These agents are primarily delivered through a face mask or endotracheal tube, allowing them to be absorbed directly into the bloodstream via the alveoli of the lungs.[1] The general uses of inhalational anesthetics center on surgical procedures, where they facilitate induction and maintenance of anesthesia to ensure patient immobility and unawareness during operations.[1] They are also employed for procedural sedation in non-surgical settings and, to a lesser extent, in veterinary medicine for animal surgeries and in dentistry for pain and anxiety management, particularly with agents like nitrous oxide.[3][4][5] A key property of inhalational anesthetics is their rapid onset and offset, enabled by efficient exchange in the alveoli, which allows for quick adjustments in depth of anesthesia by varying the inspired concentration.[1] The progression of anesthesia with these agents traditionally follows four stages: Stage 1 (analgesia), where patients remain conscious but experience pain relief with regular breathing; Stage 2 (excitement), marked by delirium, uncontrolled movements, and potential laryngospasm; Stage 3 (surgical anesthesia), featuring respiratory depression and suitable conditions for surgery; and Stage 4 (overdose), involving respiratory arrest and risk of death if not addressed.[6] Compared to intravenous anesthetics, which rely on bolus injections or infusions for dosing, inhalational agents offer precise control through real-time monitoring and adjustment of alveolar concentrations, facilitating smoother titration during procedures.[1][7]Historical context and evolution
The history of inhalational anesthetics began in the late 18th century with exploratory experiments on gases that could alter consciousness and relieve pain. In 1799, British chemist Humphry Davy conducted self-experiments at the Pneumatic Institution in Bristol, inhaling nitrous oxide (N₂O) and documenting its euphoric, analgesic, and intoxicating effects in his publication Researches, Chemical and Philosophical: Chiefly Concerning Nitrous Oxide, or Dephlogisticated Nitrous Air, and Its Respiration.[8] Davy suggested its potential for surgical pain relief, though it was not immediately adopted clinically. Building on this, American dentist Horace Wells observed the pain-insensitivity of a participant under nitrous oxide at a public demonstration in Hartford, Connecticut, in December 1844. Wells then self-administered nitrous oxide for his own dental extraction and began using it for patients, marking the first clinical application in dentistry, albeit with inconsistent results due to impure gas supplies.[9] The mid-19th century saw transformative breakthroughs that established inhalational anesthesia as a cornerstone of surgery. On October 16, 1846, dentist William T.G. Morton publicly demonstrated the use of diethyl ether (sulfuric ether) at Massachusetts General Hospital in Boston, successfully anesthetizing patient Edward Gilbert Abbott for a neck tumor excision without apparent pain—an event known as "Ether Day" that revolutionized operative procedures worldwide.[10] Just a year later, in November 1847, Scottish obstetrician James Young Simpson introduced chloroform as an alternative inhalational agent during a self-experiment with colleagues in Edinburgh; he soon applied it to labor analgesia, popularizing its use despite early concerns over toxicity and overdose risks.[11] These developments shifted anesthesia from rudimentary opiates and physical restraint to reliable gaseous methods, enabling longer and more complex surgeries. In the 20th century, advancements focused on improving safety, potency, and delivery amid growing concerns over flammability and side effects of early agents like ether and cyclopropane. Cyclopropane, a potent but highly flammable hydrocarbon, was synthesized and tested as an anesthetic by chemists George H. Lucas and V.E. Henderson at the University of Toronto in 1929, with clinical introduction by Ralph M. Waters at the University of Wisconsin in 1934; it offered rapid induction but was abandoned by the 1960s due to explosion hazards in oxygen-enriched environments.[12] A pivotal shift occurred in 1956 with the introduction of halothane, a non-flammable halogenated hydrocarbon developed by Imperial Chemical Industries, which provided smoother anesthesia with fewer irritant effects and marked the transition from flammable to safer volatile agents, dramatically reducing operating room fire risks.[13] Regulatory oversight further refined the field through U.S. Food and Drug Administration (FDA) approvals of modern halogenated ethers. Isoflurane received FDA approval in 1979 for induction and maintenance of general anesthesia, offering hemodynamic stability over predecessors like halothane.[14][15] Desflurane followed in 1992, noted for its low blood-gas solubility enabling faster recovery.[16] Sevoflurane was approved in 1995, prized for its non-pungent odor suitable for inhalational induction, particularly in pediatrics.[17] These milestones reflected iterative refinements prioritizing patient safety and clinical efficacy.Classification and Agents
Gaseous agents
Gaseous inhalational anesthetics are non-liquefied gases administered via inhalation to induce or maintain anesthesia, with nitrous oxide (N2O) serving as the primary agent still in widespread clinical use today.[18] Unlike volatile liquids that require vaporization, N2O is delivered directly as a gas, often mixed with oxygen. Its pharmacological profile includes weak anesthetic potency, reflected in a minimum alveolar concentration (MAC) of 105%, meaning it cannot produce surgical anesthesia alone at atmospheric pressure and is typically used in concentrations up to 70%.[18] The low blood-gas partition coefficient of 0.47 facilitates rapid onset and recovery due to minimal solubility in blood, allowing quick equilibration between inspired and alveolar concentrations.[18] In clinical practice, N2O functions primarily as an adjunct to other anesthetics, administered at 30-70% concentrations to provide analgesia and mild hypnosis while reducing the required doses of more potent volatile agents.[18] This combination helps minimize the environmental and physiological impacts of higher-potency drugs. It is particularly valued for self-administration in settings like labor analgesia and dentistry, where patients can control inhalation via masks for procedural sedation without deep unconsciousness.[3] N2O's minimal effects on respiration and hemodynamics make it suitable for ambulatory and emergency procedures.[18] Despite its utility, N2O has notable limitations. Upon discontinuation, it can cause diffusion hypoxia by diffusing from blood to alveoli faster than nitrogen, temporarily diluting inspired oxygen and risking hypoxemia, which is mitigated by administering 100% oxygen post-use.[1] Common side effects include nausea and vomiting, affecting patient tolerability during administration.[19] Prolonged exposure inactivates vitamin B12 by oxidizing its cobalt atom, inhibiting methionine synthase and potentially leading to megaloblastic anemia or neuropathy in susceptible individuals.[18] Environmentally, N2O contributes to global warming with a 100-year global warming potential (GWP) of 273 relative to carbon dioxide (IPCC AR6), prompting efforts to limit its use where alternatives exist.[20]Volatile liquid agents
Volatile liquid agents are the mainstay of modern inhalational anesthesia, consisting of halogenated ethers that are liquid at room temperature and require vaporizers for delivery. The three primary agents in clinical use—isoflurane, sevoflurane, and desflurane—offer varying degrees of potency, solubility, and suitability for different procedures due to their distinct chemical structures and physical properties. These agents are fluorinated to enhance stability and reduce hepatotoxicity compared to earlier compounds, enabling safe administration via inhalation for induction and maintenance of general anesthesia.[1] Isoflurane, introduced in the 1980s, is a chlorinated and fluorinated ether with a pungent odor that can irritate airways during induction. Its minimum alveolar concentration (MAC)—the alveolar concentration preventing purposeful movement in 50% of patients to a surgical stimulus—is 1.17% in young adults, indicating high potency. Isoflurane's oil-gas partition coefficient of 97 reflects moderate lipid solubility, contributing to its balanced uptake and distribution, while its blood-gas partition coefficient of 1.4 influences the rate of induction and recovery. The boiling point is 48.5°C, necessitating a temperature-compensated vaporizer for precise delivery. Clinically, isoflurane is favored for its hemodynamic stability, preserving cardiac output better than some alternatives during maintenance.[21][22][1] Sevoflurane, a fully fluorinated ether, features a non-pungent, sweet odor that minimizes airway irritation, making it ideal for mask induction. Its MAC is 1.8% in adults, lower than desflurane but higher than isoflurane, with an oil-gas partition coefficient of 60 and blood-gas coefficient of 0.69, allowing faster equilibration than isoflurane. The boiling point is 58.6°C, and it is administered via standard vaporizers. Sevoflurane's low solubility facilitates rapid changes in anesthetic depth, and it is particularly advantageous for pediatric induction due to pleasant aroma and reduced coughing or laryngospasm.[21][22][1][23] Desflurane, another fully fluorinated ether, has the lowest solubility among these agents, with a blood-gas partition coefficient of 0.42 and oil-gas coefficient of 18, enabling the quickest induction and emergence. Its MAC is 6.0%, reflecting lower potency that requires higher concentrations for equivalent effect. With a low boiling point of 23.5°C, desflurane vaporizes readily but demands a specialized, heated vaporizer to maintain consistent output. Despite a pungent odor similar to isoflurane, its clinical profile excels in outpatient surgery, where rapid recovery—often 50% faster than with sevoflurane—reduces postanesthesia care time.[21][22][24][25]| Agent | MAC (%) | Boiling Point (°C) | Blood:Gas Coefficient | Oil:Gas Coefficient | Odor Characteristics |
|---|---|---|---|---|---|
| Isoflurane | 1.17 | 48.5 | 1.4 | 97 | Pungent |
| Sevoflurane | 1.8 | 58.6 | 0.69 | 60 | Sweet, non-pungent |
| Desflurane | 6.0 | 23.5 | 0.42 | 18 | Pungent |