Inhaled Anesthetics
History
Let’s start with a history lesson. Nitrous oxide was first created in 1772 by Joseph Priestly - an English author, chemist, and minister. In 1799, nitrous oxide was used as analgesia for a dental procedure for the first time by Sir Humphrey David. It was used in America (Hartford, CT) for the first time by a dentist named Horace Wells in the year 1842. He used it on himself and discovered its hypnotic and analgesic effects. He arranged a demonstration at Mass General Hospital to show a painless dental surgery. This demonstration was unfortunately unsuccessful and he was discredited of the discovery as a result. Chloroform was discovered by James Simpson, a Scottish obstetrician, as an anesthetic agent. This became popular in England for a short time. The practice was eventually discontinued due to several unexplained intraoperative deaths in healthy patients and high cases of hepatotoxicity.
Soon after the use of Nitrous Oxide came the discovery of diethyl ethers. Crawford Long was the first to administer diethyl ether to a patient, however William Mortan is more recognized as the discoverer of its use. Mortan noticed that as people used ether for inebriation (“ether frolics”), they had similar experiences to patients under nitrous oxide - hypnosis and analgesia. On October 16, 1846 (“Ether Day”), Mortan successfully demonstrated that diethyl ether could be administered as an anesthetic for his dental procedure at MGH. Modern day inhaled anesthetics are “halogenated” by fluorine, a compound that provides greater stability and lesser toxicity. The first of these was halothane, discovered in 1956. It provided many advantages from the previous diethyl ether anesthetics, such as decreased flammability, a pleasant order, less toxicity, and.a faster induction and emergence. However, Halothane came with its own set of side effects like fulminant hepatic necrosis and dysrhythmias. In the 1960-70s, sevoflurane and desfluane were created, followed by isoflurane in 1980. By the 80’s, these three gases were common practice for all anesthetics thanks to their low blood solubility, creating a faster indication and emergence.
Mechanism of Action
The primary sites of action for inhaled anesthetics is the brain and the spinal cord (CNS). The end result is immobility (in response to a surgical stimulus), hypnosis, and amnesia. It is not completely understood how the gases work, but it is likely from interactions with ion channels that are involved with excitatory and inhibitory pathways. Examples of the receptors include GABA, glycine, and NMDA.
Physiologic Effects
Inhaled anesthetics have many physiologic effects when a patient is in an anesthetic state. For some clarity, minimum alveoli concentration (MAC) is a well-defined scale used to describe various depths of the anesthetic state when using inhaled anesthetics. This will be covered in a different section. Starting with the central nervous system, besides the hypnotic and amnestic effects, we think about cerebral metabolic rate for oxygen (CMRO) and cerebral blood flow (CBF). These variables become particularly important in intracranial surgical cases. At 0.5 MAC, both CMRO and CBF are decreased. However, at 1.0 MAC, a phenomenon called “decoupling” occurs, which means CMRO continues to be decreased, however CBF increases. In the cardiovascular system, you commonly will see a drop in the mean arterial pressure from a profound decrease in systemic vascular resistance (SVR). This is a slight increase in heart and cardiac output is maintain. In the pulmonary system, you will see bronchial smooth muscle relaxation, a dose-depend decrease in ventilatory response to hypoxia and hypercarbia, and decreased tidal volumes with an increased respiratory rate (in a spontaneously breathing patient). The kidneys receive less blood flow, leading to a decrease in glomerular filtration rate (GFR). And the musculoskeletal system is profoundly relaxed and flaccid.
Delivery
Inhaled anesthetics are delivered via a variable-bypass vaporizer. The vaporizer contains two streams of inflowing fresh gas: one bypass the liquid reservoir and one entering the reservoir. Each anesthetic has a given saturated vapor pressure (SVP), which is the pressure at which the anesthetics is 50% liquid and 50% gas. Each vaporizer is calibrated to the specific SVP for the gas it contains. This informations correlates with the percentage dial on top of the vaporizer that allows you to increase or decrease the amount of gas your are administering. Desflurane is stored in a heated pressured vaporizer (2 atm) since its vapor pressure (700 mmHg at 20C) is so close to atmospheric pressure (760 mmHg).
Pharmacodynamics
Inhaled anesthetics first enter the lungs then via uptake enter the pulmonary arterial system. They are then distributed to the brain, a vessel-rich organ. This is where it’s anesthetic effects (as well as the spine) take place. After being redistributed to other parts of the body with less blood flow (muscle and fat), the gases return to the venous side of the alveoli and ultimately are eliminated into the expiratory limb of the ventilator circuit. At equilibrium, partial pressure of the gas in the alveoli (PA) will equal the partial pressure in the pulmonary artery (Pa), which will equal the partial pressure in the brain (Pcns). Their transportation from each of these sites is based on their differences in partial pressures of the gases. There are ways to increase the speed of induction and emergence when using inhaled anesthetics. These include high fresh gas flows gas flows, high concentrations on the vaporizer dial, increased alveolar ventilation (minute ventilation), using a gas with low blood solubility (Desflurane, Sevoflurane), and using a breathing circuit that minimizes length or volume of circuit and absorption of gases into the circuit material.
Cardiac output also has an impact on speed of induction. States of low cardiac output (shock) speeds up the rate of anesthetic induction because the partial pressures of the alveoli and pulmonary arteries quickly equalize which then leads to an equalization of partial pressure in the CNS soon after. Right to left shunts will also slow induction since blood flow will bypass the alveoli. The result is a dilution of arterial blood carrying anesthetic gas with venous blood that bypassed the lungs.
Inhaled anesthetics are eliminated when the vaporizer dial is shut off and the patients breaths out the anesthetics from their blood stream into the expiratory limb. Alveoli ventilation is the primary means of elimination. This process may take some time as the longer a patient is exposed to an anesthetic gas, the more places in the body (like fat and muscle) the gases can deposit and be stored until after partial pressure gradient is created to extract the gases from these tissues.
Differences in the Gases
Sevoflurane is the most commonly used volatile in the operating room. Is has a relatively non-pungent smell, making it useful for inhaled induction and leads to less airway irritation. It also has a low blood:gas solubility, leading to fast a induction and emergence. Desflurane has the lowest blood:gas solubility and lowest potency (highest MAC at 6%). It is the most pungent and can lead to bronchospasm and increases in sympathetic responses (increased HR and BP). Because of its high SVP of 600 mmHg at 20C, it is store in a heated, pressurized vaporizer (2 atm). It is also the worst anesthetic waste for the environment (major greenhouse gas). Isoflurane is the cheapest of the anesthetic gases. It has the highest potency (MAC 1.2%) and the highest blood:gas solubility, leading to a prolonged emergence after using Isoflurane for a long period of time. Nitrous oxide is infrequently used as a sole agent. It is impossible to reach 1.0 MAC with N2O (104%). However, it can be a useful adjunct to deepen an anesthetic in conjunction with the other volatiles. It also is not a trigger for malignant hyperthermia. Nitrous oxide interacts with NMDA receptors, providing some analgesia. It has the fastest rate of induction due to the second gas effect. When used for prolonged periods of time, it can lead to bone marrow suppression and peripheral neuropathy. It also can diffuse into air-containing space and expand them, such as obstructed bowel, middle ear, pneumothoraces, and the cuff of an endotracheal tube.
