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Chapter: Clinical Anesthesiology: Clinical Pharmacology: Pharmacological Principles

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Nitrous Oxide - Clinical Pharmacology of Inhalation Anesthetics

Nitrous oxide has a tendency to stimulate the sym-pathetic nervous system.

Clinical Pharmacology of Inhalation Anesthetics

NITROUS OXIDE

Physical Properties

Nitrous oxide (N2O; laughing gas) is colorless and essentially odorless. Although nonexplosive and nonflammable, nitrous oxide is as capable as oxygen of supporting combustion. Unlike the potent volatile


agents, nitrous oxide is a gas at room temperature and ambient pressure. It can be kept as a liquid under pressure because its critical temperature lies above room temperature. Nitrous oxide is a relatively inex-pensive anesthetic; however, concerns regarding its safety have led to continued interest in alternatives such as xenon (Table 8–5). As noted earlier, nitrous oxide, like xenon, is an NMDA receptor antagonist.

Effects on Organ Systems

A. Cardiovascular

Nitrous oxide has a tendency to stimulate the sym-pathetic nervous system. Thus, even though nitrous oxide directly depresses myocardial contractility in


vitro, arterial blood pressure, cardiac output, and heart rate are essentially unchanged or slightly ele-vated in vivo because of its stimulation of catechol-amines (Table 8–6). Myocardial depression may be unmasked in patients with coronary artery disease or severe hypovolemia. Constriction of pulmonary vascular smooth muscle increases pulmonary vas-cular resistance, which results in a generally modest elevation of right ventricular end-diastolic pressure. Despite vasoconstriction of cutaneous vessels, periph-eral vascular resistance is not significantly altered.

B. Respiratory

Nitrous oxide increases respiratory rate (tachy-pnea) and decreases tidal volume as a result of CNS stimulation and, perhaps, activation of pulmonary stretch receptors. The net effect is a minimal change in minute ventilation and resting arterial CO 2 levels. Hypoxic drive, the ventilatory response to arterial hypoxia that is mediated by peripheral chemorecep-tors in the carotid bodies, is markedly depressed by even small amounts of nitrous oxide. This is a con-cern in the recovery room.

C. Cerebral

By increasing CBF and cerebral blood volume, nitrous oxide produces a mild elevation of intracra-nial pressure. Nitrous oxide also increases cerebral oxygen consumption (CMRO2). These two effects make nitrous oxide theoretically less attractive than other agents for neuroanesthesia. Concentrations of nitrous oxide below MAC may provide analgesia in dental surgery, labor, traumatic injury, and minor surgical procedures.

D. Neuromuscular

In contrast to other inhalation agents, nitrous oxide does not provide significant muscle relaxation. In fact, at high concentrations in hyperbaric cham-bers, nitrous oxide causes skeletal muscle rigidity. Nitrous oxide is not a triggering agent of malignant hyperthermia.

E. Renal

Nitrous oxide seems to decrease renal blood flow by increasing renal vascular resistance. This leads to a drop in glomerular filtration rate and urinary output.

F. Hepatic

Hepatic blood flow probably falls during nitrous oxide anesthesia, but to a lesser extent than with the volatile agents.

G. Gastrointestinal

Use of nitrous oxide in adults increases the risk of postoperative nausea and vomiting, presumably as a result of activation of the chemoreceptor trigger zone and the vomiting center in the medulla.

Biotransformation & Toxicity

During emergence, almost all nitrous oxide is eliminated by exhalation. A small amount diffuses out through the skin. Biotransformation is limited to the less than 0.01% that undergoes reductive metabolism in the gastrointestinal tract by anaero-bic bacteria.

By irreversibly oxidizing the cobalt atom in vitamin B12, nitrous oxide inhibits enzymes that are vitamin B12 dependent. These enzymes include methionine synthetase, which is necessary for myelin formation, and thymidylate synthetase, which is necessary for DNA synthesis. Prolonged expo-sure to anesthetic concentrations of nitrousoxide can result in bone marrow depression (mega-loblastic anemia) and even neurological deficiencies (peripheral neuropathies). However, administration of nitrous oxide for bone marrow harvest does not seem to affect the viability of bone marrow mono-nuclear cells. Because of possible teratogenic effects, nitrous oxide is often avoided in pregnant patients who are not yet in the third trimester. Nitrous oxide may also alter the immunological response to infec-tion by affecting chemotaxis and motility of poly-morphonuclear leukocytes.

Contraindications

Although nitrous oxide is insoluble in comparison with other inhalation agents, it is 35 times more soluble than nitrogen in blood. Thus, it tends to diffuse into air-containing cavities more rapidly than nitrogen is absorbed by the bloodstream. For instance, if a patient with a 100-mL pneumothorax inhales 50% nitrous oxide, the gas content of the pneumothorax will tend to approach that of the bloodstream. Because nitrous oxide will diffuse into the cavity more rapidly than the air (princi-pally nitrogen) diffuses out, the pneumothorax expands until it contains 100 mL of air and 100 mL of nitrous oxide. If the walls surrounding the cavity are rigid, pressure rises instead of volume.

Examples of conditions in which nitrous oxide might be hazardous include venous or arterial air embolism, pneumothorax, acute intestinal obstruction with bowel distention, intracranial air (pneumocephalus following dural closure or pneumoencephalography), pulmonary air cysts, intraocular air bubbles, and tympanic mem-brane grafting. Nitrous oxide will even diffuse into tracheal tube cuffs, increasing the pressure against the tracheal mucosa. Obviously, nitrous oxide is of limited value in patients requiring high inspired oxygen concentrations.

Drug Interactions

Because the high MAC of nitrous oxide prevents its use as a complete general anesthetic, it is frequently used in combination with the more potent volatile agents. The addition of nitrous oxide decreases the requirements of these other agents (65% nitrous oxide decreases the MAC of the volatile anesthet-ics by approximately 50%). Although nitrous oxide should not be considered a benign carrier gas, it does attenuate the circulatory and respiratory effects of volatile anesthetics in adults. Nitrous oxide potentiates neuromuscular blockade, but less so than the volatile agents. The concentration of nitrous oxide flowing through a vaporizer can influence the concentration of volatile anesthetic delivered. For example, decreasing nitrous oxide concentration (ie, increasing oxygen concentration) increases the concentration of volatile agent despite a constant vaporizer setting. This disparity is due to the relative solubilities of nitrous oxide and oxygen in liquid vol-atile anesthetics. The second gas effect was discussed earlier. Nitrous oxide is an ozone-depleting gas with greenhouse effects.

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