Continuing Education Activity

Nitrous oxide is an odorless, colorless, non-flammable gas. While nitrous oxide is not flammable, it will support combustion to the same extent as oxygen does. It leads to a state of euphoria explaining its nickname ‘laughing gas.’ Nitrous oxide is the least potent inhalational anesthetic. Compared to other anesthetic agents, nitrous oxide causes minimal effects on respiration and hemodynamics. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of nitrous oxide, so providers can direct patient therapy to optimal outcomes in anesthesia and other conditions where nitrous oxide has therapeutic benefit.

Objectives:

• Summarize the indications for using nitrous oxide.
• Describe the mechanism of action of nitrous oxide.
• Identify the contraindications and adverse events associated with nitrous oxide.
• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from the administration of nitrous oxide.

Indications

Nitrous oxide is an odorless, colorless, non-flammable gas. While nitrous oxide is not flammable, it will support combustion to the same extent as oxygen does. It leads to a state of euphoria explaining its nickname 'laughing gas.' Nitrous oxide is the least potent inhalational anesthetic. Nitrous oxide requires a concentration of 104% to reach one minimum alveolar concentration (MAC). Thus it cannot be a sole anesthetic agent, and it is often combined with a more potent and volatile anesthetic. The combination of analgesic and anesthetic effects make nitrous oxide a valuable adjunct. Nitrous oxide has a low blood solubility (blood-gas partition coefficient of 0.47), leading to a quick onset and offset.  The low solubility leads to a concentrating effect for additionally administered volatile agents in the lungs and is known as the second gas effect.[1]

Nitrous oxide can be used for general anesthesia, procedural sedation, dental anesthesia, and to treat severe pain. Nitrous oxide's potent analgesic properties can be useful in providing analgesia in settings such as the obstetrical ward or emergency department. In these settings, its administration is often as a 50% mixture with oxygen. 

Compared to other anesthetic agents, nitrous oxide causes minimal effects on respiration and hemodynamics. It leads to decreased tidal volume and increased respiratory rate but has a minimal impact on overall minute ventilation. Nitrous oxide leads to direct myocardial depression, but nitrous oxide's sympathetic stimulation reduces this effect and the net effect is minimal. Unlike other volatile anesthetics, nitrous oxide has no muscle relaxation properties.

Mechanism of Action

Nitrous oxide has multiple supraspinal and spinal targets. The anesthetic effect of nitrous oxide is through non-competitive NMDA inhibition in the central nervous system. The analgesic effects occur through the release of endogenous opioids that act on opioid receptors; its analgesic actions are like morphine. The anxiolytic effects are through GABA-A activation.  Nitrous oxide has a central sympathetic stimulating activity that supports blood pressure, systemic vascular resistance, and cardiac output. Nitrous oxide stimulates cerebral blood flow and increases intracranial pressure.[2]

Administration

Nitrous oxide administration is via inhalation utilizing a simple face mask, laryngeal mask airway, or an endotracheal tube. The excretion of nitrous oxide is primarily unchanged through the lungs. A small amount diffuses through the skin. 

Adverse Effects

Adverse effects of nitrous include: 

• Respiratory Depression: When used alone, nitrous has limited respiratory effects, but when used in combination with other sedatives, hypnotics, or opioids, it can potentiate the respiratory depressant effects of these agents. 
• Diffusion hypoxia: Following discontinuation of nitrous oxide, the concentration gradient between the gases in the lung and alveolar circulation rapidly reverses.  This can lead to rapid dilution of the oxygen in the alveoli, and subsequent hypoxia and 100% oxygen administration should follow nitrous oxide cessation.
• Postoperative Nausea and Vomiting: Nitrous has an increased risk of postoperative nausea and vomiting (PONV) compared with other agents, but this is controllable with prophylactic anti-emetics.[3] The ENIGMA I trial showed an increased incidence of PONV with nitrous oxide use.  The ENIGMA II trial showed that severe PONV with nitrous oxide use is more common in procedures lasting over 2 hours.  This study also showed that the use of nitrous oxide is not associated with increased mortality, cardiovascular complications, or wound infections.[4]

Contraindications

Many contraindications to nitrous use are relative and may vary based on the provider.  These include: 

• Critically ill patients: Nitrous oxide inactivates methionine synthase via oxidation of the cobalt in vitamin B12 and may lead to megaloblastic anemia.  This enzyme is essential for vitamin B12 and folate metabolism and plays a role in DNA and RNA synthesis and synthesis of other substances.  In otherwise healthy patients, the impact is subclinical. In critically ill patients, this may lead to neurologic or hematologic consequences and should be avoided. 
• Severe cardiac disease: Methionine synthase is also required to convert homocysteine to methionine, and elevated serum homocysteine levels are associated with an increased risk for adverse coronary events. In the setting of severe cardiac disease, the clinician should avoid using nitrous oxide, but further studies are needed to determine the actual impact.
• The first trimester of pregnancy: Due to the above-referenced impact on B12 and folate metabolism, nitrous use is not recommended in the first trimester of pregnancy.
• Pneumothorax, small bowel obstruction, middle ear surgery, and retinal surgeries involving the creation of an intraocular gas bubble: Nitrous oxide is 30 times more soluble than nitrogen.  Nitrous oxide diffuses more rapidly into closed spaces than nitrogen can diffuse out, leading to increased gas volume and pressure within closed spaces.  Thus nitrous oxide is contraindicated in pneumothorax, small bowel obstruction, middle ear surgery, and retinal surgeries involving the creation of an intraocular gas bubble.  In laparoscopic cases, nitrous oxide can accumulate in the pneumoperitoneum, and some avoid its use in these cases.   
• Severe psychiatric disorders: Nitrous oxide can cause dreaming and hallucinations and should be avoided in patients with severe psychiatric disorders.
• Pulmonary hypertension: Nitrous oxide can increase pulmonary artery pressures and pulmonary wedge pressures via sympathetic stimulation, and clinicians often avoided it in patients with pulmonary hypertension.[5]
• Head and neck procedures with cautery use: While nitrous oxide is non-flammable, it supports combustion, and its use should be avoided in these procedures.  

Monitoring

No specific monitoring is necessary for nitrous oxide use. An in-line oxygen analyzer with an alarm should be in use to prevent the delivery of a hypoxic gas mixture. Modern anesthetic machines have fail-safe mechanisms to prevent this from occurring (nitrous oxide-oxygen proportioning systems). Standard ASA monitoring is necessary when administering nitrous oxide for any indication.

Toxicity

While nitrous oxide inactivates methionine synthase, intraoperative use results in a transient metabolic abnormality that soon reverses upon replacement of the degraded enzyme. 

When nitrous oxide is used recurrently (during occupational exposure or as a drug of abuse), it may lead to megaloblastic anemia with neurologic dysfunction. This situation also may occur in patients with an unrecognized cobalamin deficiency (vegans, pernicious anemia, hereditary disorders of cobalamin, and folate metabolism).[6]

Enhancing Healthcare Team Outcomes

Nitrous oxide is a widely used option for labor analgesia in other countries. One reason for limited use in the United States is due to the limited availability of anesthesia coverage. Nitrous oxide administration and management by nursing staff has shown to be a safe, cost-effective option for labor analgesia.[7] The pharmacy should verify the dosing and administration times when nitrous oxide is in use and alert the ordering clinician or nursing staff of any issues or potential interactions. [Level 5]

Administration of nitrous oxide by registered nursing staff has also been used to provide procedural sedation in pediatric radiology and resulted in fewer adverse effects and a quicker return to baseline compared with oral midazolam.[8][9] [Level 5]