Preparation

Nitrous oxide (N₂O, dinitrogen monoxide) is prepared commercially through the heating of ammonium nitrate crystals to 240° C, at which point the ammonium nitrate decomposes into N₂O and H₂O.

The gas is then chemically scrubbed to remove any alkaline and acid substances and is then compressed in stages so that the less easily liquefied gases, such as nitrogen (N₂) and oxygen (O₂), are separated out. Finally, it is compressed and stored in metal cylinders, in which approximately 30% of the N₂O in the full cylinder is liquefied. According to the U.S. Pharmacopeia, N₂O must be 97% pure; however, with the manufacturing processes in use today, the gas usually approaches a purity of 99.5% (Figure 13-1).¹

Figure 13-1 A typical manufacturing plant in which N₂O is prepared.

(Courtesy Airgas Nitrous Oxide Corp.)

The most common impurities associated with the manufacture of N₂O are N₂, nitric oxide (NO), nitrogen dioxide (NO₂), ammonia (NH₄), water vapor, and carbon monoxide (CO). NO is the most dangerous impurity because, like CO, it may combine with hemoglobin and prevent the absorption of O₂, or it may react with water vapor to form acids that may damage the pulmonary epithelium and produce pulmonary edema. NO is formed when N₂O is heated above 450° C.

As prepared, N₂O is anhydrous. The absence of water in the gas is of importance because water vapor would freeze as it passes through the reducing valve (see Chapter 14), leading to a drop in the gas pressure.

Properties

Solubility

N₂O is relatively insoluble in the blood (its blood-gas solubility coefficient is 0.47 at 378° C) and is carried in the blood in physical solution only, not combining with any blood elements. The O₂ in the N₂O molecule is not available for use by the tissues because N₂O does not break down in the body.

Solubility is a term used to describe how a gas is distributed between two media (e.g., gas and blood). If the concentration of an anesthetic gas in blood is 2 volumes percent and this is in equilibrium with a concentration in the alveolus of 1 volume percent, the blood-gas solubility would be 2.

When an anesthetic gas is first inspired, blood entering the alveolus by the pulmonary artery contains none of it. When reaching the pulmonary capillary, the blood is suddenly exposed to the tension of the gas present in the alveolus. If the gas is totally insoluble in the blood (blood-gas partition coefficient of 0), none of the agent will be taken up by the circulation and the alveolar concentration will rise rapidly and will soon equal the inspired concentration (Figure 13-2).

Figure 13-2 Primary saturation of a gaseous agent with a blood-gas solubility coefficient of 0.00 (totally insoluble) occurs within a very brief period. Both onset and recovery are extremely rapid.

If, on the other hand, the anesthetic is slightly soluble in blood, only small quantities will be carried by the bloodstream. Alveolar concentration will again rise rapidly (Figure 13-3).

Figure 13-3 N₂O, with a blood-gas solubility coefficient of 0.47 (relatively insoluble), demonstrates both rapid onset and rapid recovery. Primary saturation of blood occurs within 3 to 5 minutes.

Because alveolar concentration determines the tension of the anesthetic in the arterial circulation, the tension will also rise rapidly, even though only a small volume of the agent is present in the blood. As the blood travels through the various tissues of the body, the anesthetic is given up and the venous blood returns to the lungs with a decreased anesthetic gas tension.

N₂O and desflurane are examples of anesthetic gases with low blood solubility (Table 13-1). On inhalation, these gases rapidly diffuse across the alveolar membrane into the blood. Because of their poor blood solubility, only a small quantity is absorbed and the alveolar tension rises rapidly so that the tension of the gas in the blood is also increased quickly (see Figure 13-3). Because of the rich cerebral blood supply, the tension of these gases within the brain also rises rapidly and the onset of clinical actions is quickly apparent. Likewise, the rate of recovery from sedation or anesthesia produced by these gases is equally rapid once delivery of the anesthetic ceases.^2,3

Table 13-1 Blood-Gas Partition Coefficients of Inhalation Anesthetics

Agent	Blood-Gas Solubility Coefficient
Desflurane	0.42
Nitrous oxide	0.47
Sevoflurane	0.068
Isoflurane	1.40
Enflurane	1.91
Halothane	2.36
Chloroform	10.30
Diethyl ether	12.10
Methoxyflurane	13.00

Conversely, gases with high blood solubility require longer periods of time for the onset of action to develop. Large volumes of the gas are absorbed by the blood (as by a piece of absorbent paper) so that the alveolar tension rises quite slowly (Figure 13-4). Tension of the gas within the blood also rises slowly in this case, and the induction of sedation or anesthesia is noticeably slower, as is the return to the preanesthetic state after termination of drug administration.

Figure 13-4 Primary saturation of a gaseous agent with a high blood-gas solubility coefficient (quite soluble) occurs quite slowly. Both onset and clinical recovery are prolonged. Methoxyflurane is an example of a very soluble agent.

N₂O is not flammable. However, it does support combustion of other agents, even in the absence of O₂, because at temperatures above 450° C, N₂O breaks down into N₂ and O₂.

Potency

N₂O is the least potent of the anesthetic gases; however, it remains the most frequently administered inhalation anesthetic. At one time, it was thought that any anesthetic effects of N₂O were a result of the exclusion of O₂ from cells in the brain because N₂O is 35 times more soluble in plasma than N₂ and 100 times more soluble than O₂.⁴ It has since been demonstrated that N₂O can, in the presence of adequate O₂, produce CNS depression. Guedel classification stage II anesthesia (delirium) is often produced if the patient is not monitored properly.

With a MAC (the minimal alveolar concentration of anesthetic that prevents movement in 50% of subjects in response to a standard surgical incision) of 105%, N₂O is unable to produce adequate anesthesia unless it is administered under hyperbaric conditions. More realistically, surgical-depth anesthesia is usually not obtainable unless a more potent inhalation or intravenous (IV) anesthetic is combined with N₂O. Such IV agents include the barbiturates, propofol, and opioids, and inhalation anesthetics include sevoflurane, isoflurane, and desflurane. These are discussed in Section VI.

That N₂O in subanesthetic doses produces analgesia, a change in the patient’s perception of pain, is no longer doubted. It is estimated that a 20% : 80% mixture of N₂O-O₂ produces the analgesic effectiveness of 10 to 15 mg of morphine.⁵ However, biologic variability can significantly alter these figures in individual patients.

Pharmacology

After N₂O is inspired through the mouth and/or nose, the gas is transported through the respiratory tract into alveolar sacs, where it is rapidly absorbed into the pulmonary circulation. Because of the high inspired concentration of N₂O and the large gradient of N₂O between the alveolar sacs and the blood, up to 1000 ml of N₂O may be absorbed every minute. N₂O replaces N₂ in the blood; the N₂ is eliminated as the N₂O-O₂ mixture is inhaled. Because N₂O is 35 times as soluble in the blood as the N₂ it replaces, large volumes of N₂O may be absorbed over prolonged periods of administration.^4,6

Potential changes may occur within air-filled body cavities during the administration of N₂O because of the extent of its absorption. During the induction of N₂O-O₂ sedation or anesthesia and during long procedures, N₂O enters a closed air-filled space 35 times more rapidly than N₂ leaves the cavity. This produces an increase in the pressure or volume of that cavity or space. Specific examples of this include increased intestinal distention if bowel obstruction is present, increased pressure in the pleural space aggravating a pneumothorax, and expansion of the middle ear airspace to the point of actually displacing a tympanoplasty graft.⁷

Because of its rapid uptake, two interesting phenomena—the so-called concentration effect and the second-gas effect—are seen when N₂O is administered. The concentration effect occurs when high concentrations of a gas are administered. The higher the concentration of the gas inhaled, the more rapidly the arterial tension of the gas increases. For example, a patient receiving N₂O-O₂ in a ratio of 75% : 25% will absorb up to 1000 ml/min of N₂O during the initial stages of induction. As the volume of N₂O is removed from the lungs into the blood, fresh gas is literally sucked up into the lung from the anesthesia machine, thereby increasing the rate at which the N₂O arterial tension increases. If, however, a patient receives only 10% N₂O (a figure more appropriate in dentistry than 75%), the uptake of N₂O by the blood will be only 150 ml/min, which results in no significant change in the rate at which the agent is absorbed or the rate of rise of N₂O arterial tension.⁸

The second-gas effect occurs when a second inhalation anesthetic is administered along with N₂O-O₂. The second-gas effect is also related to the rapid uptake of as much as 1000 ml/min of N₂O-O₂ during the induction of anesthesia. Because of the extremely rapid uptake of a large volume of N₂O, a form of vacuum develops in the alveoli that forces even more fresh gas (N₂O-O₂ plus other inhalation anesthetics) into the lungs. For example, if halothane (1%) is administered along with N₂O-O₂ in a ratio of 75% : 25%, its uptake will be more rapid than predicted. This is the second-gas effect.⁹

N₂O is absorbed rapidly from the alveolar sacs into the pulmonary circulation. Primary saturation of the blood and brain with N₂O is accomplished by the displacement of N₂ from the alveoli and the blood and occurs within 3 to 5 minutes of the onset of N₂O-O₂ administration.¹⁰ Clinically, this is significant because the patient should be permitted to remain (ideally) at a given level of N₂O for 3 to 5 minutes before the inspired N₂O concentration is increased. This permits the full clinical effect of the given concentration of N₂O to develop before additional gas is added. In actual clinical practice, the 3- to 5-minute wait is not necessary. A thorough discussion is presented in Chapter 15. Tissues with a greater blood flow, including the brain, heart, liver, and kidneys, will receive more N₂O and consequently absorb greater volumes of the gas. The remaining tissues, with a relatively poor blood supply, fat, muscle, and connective tissues, absorb only a small portion of N₂O until primary saturation is completed. At this time, these tissues play a major role in N₂O absorption. Because the uptake and absorption of N₂O by these tissues is slow (denitrogenation may require 6 to 7 hours), there is no reservoir of N₂O present in them to impede recovery when N₂O delivery is terminated.

For years it was believed that N₂O did not undergo biotransformation in the body. However, it is demonstrated that anaerobic bacteria in the bowel metabolize N₂O through a reductive pathway with the production of free radicals. There is no convincing evidence that these free radicals cause any specific organ damage.¹¹ Despite this, the vast majority of inhaled N₂O is exhaled through the lungs within 3 to 5 minutes after termination of its delivery. Approximately 1% of the inhaled N₂O will be eliminated more slowly (over 24 hours) through the lungs and skin.¹²

At the completion of the procedure, the N₂O flow is terminated. N₂O diffuses out of the blood and into the alveoli as rapidly as it diffused into the blood during induction. If the patient is allowed to breathe atmospheric air at this time, a phenomenon known as diffusion hypoxia (and the Fick principle) may develop.¹³ Diffusion hypoxia is responsible for most reports of headache, nausea, and lethargy occurring after N₂O administration—a hangover effect. The alveoli of the patient breathing atmospheric air become filled with a mixture of N₂, O₂, CO₂, water vapor, and N₂O. During the first few minutes the patient breathes atmospheric air, large volumes of N₂O diffuse through the blood into the lungs and are exhaled. As much as 1500 ml of N₂O may be exhaled in the first minute by a patient having breathed N₂O-O₂ in a ratio of 75% : 25%. This figure falls to 1200 ml in the second minute and 1000 ml in the third. The concentration effect, discussed previously, is now reversed, and gases rush out of the lungs. More CO₂ is removed from the blood than usual because of this effect, lowering the CO₂ tension of the blood. Decreased CO₂ tension of the blood reduces the stimulus for breathing and produces a depression of respiration.

More important, the rapid diffusion of large volumes of N₂O into the alveoli produces a significant dilution of the O₂ present. In the normal alveolus, approximately 14% O₂ is present. This may be reduced to as little as 10% during the first few minutes after termination of N₂O flow. Hypoxia results, producing headache, nausea, and lethargy.

The adverse effects of diffusion hypoxia may be prevented through the routine administration of 100% O₂ for a minimum of 3 to 5 minutes at the termination of the procedure.¹⁴ After N₂O-O₂ inhalation sedation as usually employed in dentistry, diffusion hypoxia is unlikely to develop, and when it does, it is usually clinically insignificant.

Recovery from the effects of N₂O is usually rapid and complete. If in the opinion of the drug administrator the patient has fully recovered, the patient may be permitted to leave the office unescorted, to drive his or her motor vehicle, and to return to normal activities with no prohibitions. This vitally important aspect of N₂O-O₂ sedation is discussed thoroughly in Chapter 15.

N₂O is nonallergenic. There has never been a reported allergic reaction to N₂O. It is less toxic than any other inhalation anesthetic.

Central Nervous System

The actual mechanism of action of N₂O is unknown, but almost all forms of sensation are depressed (sight, hearing, touch, and pain). Memory is affected to a minimal degree, as is the ability to concentrate or perform acts requiring intelligence.¹⁵ When administered in conjunction with physiologic levels of O₂ (greater than 20%), N₂O produces a mild depression of the CNS, primarily the cerebral cortex. At therapeutic levels, N₂O does not exert any other actions on the CNS. The area postrema (the vomiting center) of the medulla is not affected by N₂O unless hypoxia or anoxia is present. Nausea and vomiting occurring after the administration of N₂O are uncommon in the absence of anoxia or hypoxia.¹⁶