Nitrous Oxide Administration 

Nitrous oxide (N₂ O), commonly known as laughing gas or happy gas, was first discovered in 1793 by the English scientist Joseph Priestly and has been used for more than 150 years. It has remained one of the most widely used anesthetics in both dental and medical applications.^[1]

Nitrous oxide is small inorganic chemical molecule and may also be known as dinitrogen oxide or dinitrogen monoxide. It is a colorless and nonflammable gas with a slightly sweet odor.^[2]

Nitrous oxide also has some illicit recreational uses and abuse potential. It is widely used in multiple nonmedical areas. Some of the nonmedical uses of nitrous oxide include the semiconductor industry, car racing, and food processing.^[1]

Nitrous oxide is administered by inhalation, absorbed by diffusion through the lungs, and eliminated via respiration. The elimination half life of nitrous oxide is approximately 5 minutes.^[3] It is excreted essentially unchanged (ie, nonmetabolized) via the lungs; less than 0.004% is actually metabolized in humans.

As a general anesthetic, it is very weak and is generally not used as a single agent. It may be used as a carrier gas with oxygen in combination with more potent general inhalational gases for surgical anesthesia.^[3] In dentistry, it is commonly used as a single agent (with oxygen) for partial sedation, most commonly in pediatric dental populations.

• General anesthesia, in combination with other anesthetics

  • Nitrous oxide is a weak inhalational anesthetic. Because 105% alveolar concentration is needed to induce general anesthesia when nitrous oxide is used as a sole anesthetic agent, it is ineffective as a single agent for general anesthesia. As a result, nitrous oxide is most commonly used in combination with other more potent inhalational anesthetics for general anesthesia.^[1]
  • One of the most common uses of nitrous oxide in anesthesia is during mask induction of general anesthesia in pediatric patients. It is combined with oxygen and incrementally increasing doses of a more potent inhalational anesthetic (eg, sevoflurane) and delivered via mask inhalation.
• Dentistry

  • In dentistry, nitrous oxide is indicated to decrease the pain and anxiety associated with procedures. It is commonly delivered by a nasal mask in combination with oxygen.^[1] The specially designed nasal mask fully covers the nose, allowing the mixture of nitrous oxide with oxygen to flow while the dentist works on the patient’s mouth.
  • Nitrous oxide is commonly offered by pediatric dentists to assist in inducing amnesia, as well as increasing analgesia, relaxation, and cooperation in younger patients.^[1]
  • Indications in adult dental patients include anxiety, low pain tolerance, underlying psychiatric disorders, and mental retardation.^{[1, 4]}
  • Nitrous oxide may also be useful for prolonged or more involved dental procedures as well as in patients with hyperresponsive gag reflexes.^[5]
• Other indications

  • Although not standard practice, additional described uses may include colonoscopy, sigmoidoscopy, laser procedures, obstetrical labor pain, ophthalmic procedures, emergency medical care of patients in accidents and during ambulance transport, and minor invasive medical procedures, including joint injections.^[6]
  • Less commonly, self-administered nitrous oxide is reported for chronic pain from terminal illness and pain associated with cancer treatment.^[6]
  • Nitrous oxide use in children undergoing basic procedures including lumbar puncture, venous cannulation, or dressing changes has demonstrated a significant reduction in pain levels, allowing for a shorter recovery.^{[7, 8]} The children who were administered nitrous oxide displayed less anxiety and distress during medical procedures.^[7] A 2009 prospective, randomized study showed that a 70:30 mix of nitrous oxide in oxygen, administered for 3 minutes, was effective in reducing pain in children undergoing venipuncture.^[8]
  • Nitrous oxide has been proven beneficial in young children receiving injections for juvenile arthritis.^[9] Additionally, nitrous oxide has been used successfully as an anesthetic for children undergoing minor surgeries such as cyst surgery and abscess drainage.^[5]

• Absolute contraindications

  • Overall, nitrous oxide is a very safe drug with few absolute contraindications.
  • Nitrous oxide is contraindicated in patients with significant respiratory compromise.
  • The blood:gas partition coefficient of nitrous oxide is 34 times greater than that of nitrogen. This differential solubility means that nitrous oxide can leave the bloodstream and enter air-filled cavities 34 times faster than nitrogen. As a result, nitrous is contraindicated in patients in whom expansion of these air-filled cavities could compromise patient safety. This includes patients with pneumothorax, pulmonary blebs, air embolism, bowel obstruction, and those undergoing surgery of the middle ear.
• Relative contraindications

  • Caution must be exercised in individuals with a history of stroke, hypotension, and known cardiac conditions.
  • Nitrous oxide is known to interfere with vitamin B12 and folate metabolism. In patients with these preexisting conditions, nitrous oxide should only be used with full precautionary consideration and close monitoring. Particular precautions should be taken in pediatric patients with underlying vitamin B12 deficiency (genetic or environmental) and conditions related to vitamin B12 deficiency.^[10]
  • Nitrous oxide is relatively contraindicated in pregnancy. It is known to have potential teratogenic and fetal toxic effects, particularly with chronic use.
• Dental contraindications

  • Dental nitrous oxide may be contraindicated in patients with severe nasal congestion, those who breathe through their mouths, or those unable to wear a nasal mask.
  • Some patients, especially children experiencing severe anxiety or extreme uncooperativeness, may not be good candidates for this milder therapy and may require more potent sedating intravenous or general anesthesia.

• Since its discovery, nitrous oxide has been used widely by practitioners without an extensive comprehension of the complete functions of the gas. Nitrous oxide is a weak general anesthetic and is generally not used alone. It may be used in general anesthesia in a 70% concentration (in combination with 30% oxygen) or as a carrier gas with more potent general anesthetic agents. It has a blood:gas partition coefficient of 0.46 and a minimum alveolar concentration (MAC) of 105%. Its use as an anesthetic is appealing because of its ability to initiate a timely and brisk emergence from anesthesia (generally < 3 min).^[3] Nitrogen gas is known to assist in prevention of atelectasis via splinting of the alveoli.^[1]
• Debate regarding the safety and efficacy of this commonly used inhalant anesthetic is ongoing among anesthesiologists.^[3] Some anesthesiologists advocate abandonment of the drug and others use it routinely.
• Nitrous oxide use in westernized countries seems to have decreased and is being replaced with other more potent, safe, and short-acting inhalation anesthetics (eg, sevoflurane, desflurane). However, nitrous oxide is still widely used in developing countries because it is inexpensive, readily available, easily administered, and has a long-standing safety record.
• Nitrous oxide is reported to be safe in patients with a history of malignant hyperthermia. Since it is metabolized by the lungs, it does not have any associated nephrotoxicity or hepatotoxicity.
• Nitrous oxide has been used for obstetric analgesia (primarily outside of the United States). Nitrous oxide is often times mixed in a 1:1 ratio with oxygen; the mixture is otherwise known as Entonox.^[11] Labor pains have been shown to significantly decrease with the use of Entonox.
• The mechanism of action of nitrous oxide is trifold and includes analgesia, anxiolysis, and anesthesia.

  • Its analgesic mechanism of action is described as opioid in nature and may involve a number of spinal neuromodulators.
  • The anxiolytic effect is similar to that of benzodiazepine and may involve gamma aminobutyric (GABA) receptors.
  • The anesthesia mechanism may involve GABA and possibly N-methyl-D-aspartate receptors as well.^[6] In general, the effect of nitrous oxide ceases as soon as the inhalation stops, with no residual effect.

• Nitrous oxide is stored in closed gas cylinders. Oxygen and nitrous oxide, shown in the images below, are part of the required equipment. Oxygen and nitrous oxide tanks used in anesthesia delivery equipment. Smaller unit in a dental office.
• Attached flow meters like the one shown below restrict the proportion as well as the flow rate of nitrous oxide in order to keep a minimum oxygen concentration. This minimum concentration is usually 21% (room air). Flow meters used in anesthesia delivery equipment to adjust the flow of nitrous oxide, oxygen, and air. Anesthesia machines have safety mechanisms to restrict the lower limit of oxygen delivery to 21%.
• Dental administration uses a partial mask that covers the nose but allows access to the mouth.
• Surgical anesthesia uses a full face mask that covers the nose and mouth. Alternatively, nitrous oxide may be administered via an endotracheal (ET) tube.
• For each method of administration, proper equipment, monitoring, and storage unit integrity are necessary in order to avoid unintended gas leakage or excessive exposure. An example is shown in the image below. Ceiling-mounted gas pipes used for delivery of anesthetic gases: oxygen (green), nitrous oxide (blue), air (yellow), vacuum (white).

• For general anesthesia, most patients are placed in the supine position.
• For dental anesthesia, patients are reclined in a seated position.

• Position the patient as described above.
• Secure the mask and start the flow of nitrous oxide, as in the image below.Inhalation via nasal mask.
• Most commonly, nitrous oxide gas is delivered in a 70:30 mix with oxygen. The 2:1 ratio of nitrous oxide to oxygen is also used in medical anesthesia. The typically administered mix is comparable to the 21% of oxygen present in natural atmospheric air. Less commonly, nitrous oxide may also be safely given in a 50:50 mix with oxygen.^[12]
• Frequently, patients receive 100% oxygen for 5 minutes once the nitrous oxide flow diminishes. This reduces occurrences of nausea and facilitates clearing of the euphoric and other effects of the nitrous oxide gas.^[5]

• Ideally, proper ventilation should include a fresh air ventilation system, a nitrous oxide scavenging system, or both. Because nitrous oxide is not heavily metabolized during inhalation, it may build up in the treatment area, particularly if the room is poorly ventilated. Staff may be affected by the exhaled nitrous oxide and experience some of the same effects as the patient undergoing treatment.
• Occupational contact with nitrous oxide has raised some concern regarding potential reproductive hazards of miscarriage, decreased fertility, or increased incidence of cervical cancer in female staff subject to chronic or prolonged exposure. This has been described among dental assistants and the wives of dentists.^[7] Animal testing has led to further concern of similar health hazards.^[11]
• Proper security and safety precautions for the nitrous oxide cylinders may be advised to decrease potential risk of after-hours access and abuse by medical and dental staff.

• When used properly, nitrous oxide is a very safe inhalational anesthetic gas.^[13] Complications up to and including death have been described. They are relatively uncommon with standard medical and dental use but have arisen from chronic use or recreational abuse. The described adverse effects profile below may be very uncommon and not of primary concern to standard medical practitioner.^[14]
• Adverse effects that may be associated with nitrous oxide include gagging, coughing, hypotension, asthma attack, involuntary tracheal closure (spasm), lung damage, neuropathy, tinnitus, extremity numbness, anoxia and general respiratory distress, cardiac events (including myocardial infarcts), seizures, misperception of time, and vision-altering perceptions.^[15] Additional adverse effects include possible exacerbation of vitamin B12 deficiency, anemia, and decreased hematopoiesis. Further studies may be needed to elucidate these observations.
• Postoperative nausea and vomiting (PONV) is described with nearly all inhaled anesthetics including nitrous oxide.^[3]
• Inadvertent use of nitrous oxide in pregnancy may result in teratogenic and fetal toxic effects. While decreased fertility, spontaneous abortion, and congenital abnormalities possibly associated with nitrous oxide exposure have been reported in the dental literature, the clinical significance and causation of these findings remain unknown.^[2]
• Short-term impairment in mental performance, manual dexterity, and audiovisual senses has been described with nitrous oxide use.^[16] Postoperative neurological symptoms have been described, particularly in patients with known or documented preoperative folate deficiencies.^[3] While most adverse effects are reversible, peripheral neuropathies and limb spasms may become nonreversible manifestations. Symptoms of nitrous oxide and B12 deficiency may not appear for days or weeks after known exposure.^[10]
• Nitrous oxide has been shown to potentially inhibit methionine synthetase and cause an increase in homocysteine (Hcy) levels. Elevated Hcy levels have been correlated with increased postoperative complications, including possible cardiovascular morbidity.^[17] The clinical implications of these limited studies may require further confirmation and evaluation.
• Nitrous oxide may have neurotoxic effects of unknown significance on both infantile and senescent central nervous systems.^[10] The clinical relevance or significance of these effects requires investigation.
• Vitamin B12 deficiency should be considered in the differential diagnosis of patients who present with psychiatric or neurological manifestations, especially in those with a clear history of nitrous oxide exposure.^[18] Pertinent laboratory testing should include B12, homocysteine, and methylmalonyl coenzyme A (CoA) levels. Although levels of B12 may be low to normal, levels of methylmalonyl CoA and homocysteine may be elevated.
• Because of the potential delay in the appearance of clinical symptoms, the history of nitrous oxide exposure may be days to weeks prior to the presentation date.^[18] Intramuscular administration of cobalamin may be curative in these cases. Recovery may be slow even with high doses of vitamin B12.
• As a commonly abused inhalant drug, it can be habit-forming. Long-term exposure or use has been associated with anemia and other adverse effects related to vitamin B12 deficiency.^[2]
• Potentially dangerous adverse effects include overdose, hypoxia, severe hypotension, unconsciousness, or death. High nitrous oxide concentrations have been associated with severe hypoxia and death from asphyxiation.