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Nitrous oxide: Drug information

Nitrous oxide: Drug information
(For additional information see "Nitrous oxide: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Pharmacologic Category
  • Dental Gases;
  • General Anesthetic
Dosing: Adult
Surgical sedation and analgesia

Surgical sedation and analgesia (adjunctive agent): Note: Minimal alveolar concentration, which can be considered the ED50 of inhalational anesthetics, is ~104% to 105%; therefore, delivery in a hyperbaric chamber is necessary to use as a sole agent for complete anesthesia. Use decreases requirements of other inhaled or IV anesthetics (ESA [Buhre 2019]; Gropper 2020).

Procedural sedation: Inhalation: Concentrations of 30% to 50% nitrous oxide with oxygen (Bahn 2005; ESA [Buhre 2019]).

General anesthesia: Inhalation: Concentrations of 50% to 70% via mask or endotracheal tube (ESA [Buhre 2019]; Gropper 2020; Myles 2007; Myles 2014).

Dental sedation and analgesia

Dental sedation and analgesia: Inhalation: Concentrations of 30% to 50% nitrous oxide with oxygen (ESA [Buhre 2019]; Gropper 2020).

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Pediatric

Refer to adult dosing.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Supplied in blue cylinders

Generic Equivalent Available: US

Yes

Use: Labeled Indications

Sedation and analgesia: Sedation, analgesia, and amnesia; principal adjunct to inhalation and intravenous general anesthesia.

Medication Safety Issues
High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined.

Cardiovascular: Hypotension

Central nervous system: Central nervous system stimulation, confusion, dizziness, headache

Gastrointestinal: Nausea and vomiting

Respiratory: Apnea

Contraindications

Although there are no contraindications listed in the manufacturer's labeling, use of nitrous oxide should be avoided in the following situations: patients with disorders of vitamin B12 deficiency, folate, or methionine synthesis or metabolism; patients having undergone vitreoretinal surgery and presence of intraocular gas bubble; and patients with pneumothorax, pneumocephalus, and closed dura, or those at high risk for vascular air embolus (ESA [Buhre 2019]; Fu 2002; Gropper 2020; Lee 2004).

Warnings/Precautions

Concerns related to adverse effects:

• Addictive: May be associated with abuse and/or addiction (Zafirova 2018).

• Body space volume expansion: Both compliant (eg, bowel gas, pneumothorax) and poorly compliant (eg, middle ear) body spaces may be prone to changes in volume due to nitrous oxide transfer; avoid use in pneumothorax, pneumocephalus, middle ear surgery, or bowel obstruction (Miller 2010; Ohryn 1995; Sprehn 1992).

• Bone marrow suppression: Prolonged use may produce bone marrow suppression; patients with vitamin B12 deficiency (pernicious anemia) and those with other nutritional deficiencies (alcoholics) are at increased risk (ESA [Buhre 2019]).

• Nausea/vomiting: Occurs postoperatively in ~15% of patients (Sun 2015); risk may be reduced by antiemetics (Myles 2016).

• Neurologic effects: Prolonged use may produce neurologic dysfunction; patients with vitamin B12 deficiency (pernicious anemia) and those with other nutritional deficiencies (alcoholics) are at increased risk.

Disease-related concerns:

• Vitreoretinal surgery: Detached retina and other ocular disorders treated with vitreoretinal surgery where intraocular gas was used: Nitrous oxide can increase intraocular pressure which may result in retinal artery occlusion, ischemia, or optic nerve damage and vision loss in these patients. Nitrous oxide should not be used in patients who have had an intravitreal gas bubble unless it can be confirmed that the bubble has been completely resorbed (Fu, 2002; Lee, 2004).

Other warnings/precautions:

• Handling: Never allow any unprotected part of the body to touch uninsulated pipes or vessels that contain cryogenic liquids.

• Oxygen use: Oxygen should be administered for several minutes before and after discontinuing nitrous oxide to prevent diffusion hypoxia (Gropper 2020).

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Bupivacaine: Nitrous Oxide may enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Isoflurane: May enhance the CNS depressant effect of Nitrous Oxide. Nitrous Oxide may enhance the therapeutic effect of Isoflurane. Specifically, isoflurane MAC values may be decreased. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrexate: Nitrous Oxide may enhance the adverse/toxic effect of Methotrexate. Risk X: Avoid combination

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

Infertility has been reported following prolonged occupational exposure. This risk is related to dose and duration of exposure and is decreased with proper administration procedures (Becker 2008; Rooks 2011; Zafirova 2018).

Pregnancy Considerations

Nitrous oxide crosses the placenta.

Concentrations of nitrous oxide in the fetal circulation are ~80% of those in the maternal plasma. The half-life in the neonate is ~3 minutes and it is quickly eliminated from neonatal lungs with the onset of breathing (Rooks 2011).

Spontaneous abortion and congenital abnormalities have been reported in health care providers following prolonged occupational exposure (Becker 2008; Brodsky 1986; Rooks 2011). However, these adverse events are related to dose and duration of exposure and risks are decreased with proper administration procedures (Rooks 2011; Zafirova 2018). Short duration of exposure to the pregnant patients during obstetric procedural anesthesia is not associated with an increased risk of adverse events to the fetus (Neuman 2013).

Nitrous oxide is used in labor analgesia, as well as occasionally postpartum (ACOG 2019b; Collins [AWHONN 2018]; Likis 2014; Rooks 2011; Rosen 2002) and may be used when needed for dental treatments that cannot be postponed during pregnancy (or delayed until after the first trimester) (Becker 2008).

ACOG recommends that pregnant patients should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 2019a).

Nitrous oxide administration may be considered an aerosol-generating procedure; therefore, use in labor analgesia may be of concern in patients with confirmed or unknown COVID-19 infection (Khan 2021; Pavlidis 2021). Consider suspending use of nitrous oxide for labor analgesia in patients with COVID-19 due to insufficient data related to physiologic safety. Patients who are confirmed to be COVID-19 negative may continue to be offered nitrous oxide as an option for labor analgesia (ACOG 2022).

Breastfeeding Considerations

Nitrous oxide was not found to influence the initiation or continuation of breastfeeding when used during labor (Zanardo 2017).

The Academy of Breastfeeding Medicine recommends postponing elective surgery until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).

Mechanism of Action

General CNS depressant action; may act similar to inhaled general anesthetics by stabilizing axonal membranes to partially inhibit action potentials leading to sedation; may partially act on opiate receptor systems to cause mild analgesia; central sympathetic stimulating action supports blood pressure, systemic vascular resistance, and cardiac output; it does not depress carbon dioxide drive to breath. Nitrous oxide increases cerebral blood flow and intracranial pressure while decreasing hepatic and renal blood flow; has analgesic action similar to morphine.

Pharmacokinetics

Onset of action: Inhalation: 2-5 minutes

Absorption: Rapid via lungs; blood/gas partition coefficient is 0.47

Metabolism: Body: <0.004%

Excretion: Primarily exhaled gases; skin (minimal amounts)

Brand Names: International
  • Dusikov (HR);
  • Maxicool (IL);
  • Niontik (DE);
  • Niontix (CZ, DK, FI, IS, LT, NL, NO, PT, RO, SE, SI, SK);
  • Nitrous EP (BD)


For country abbreviations used in Lexicomp (show table)
  1. American College of Obstetricians and Gynecologists (ACOG). ACOG committee opinion no. 775: nonobstetric surgery during pregnancy. Obstet Gynecol. 2019a;133(4):e285-e286. [PubMed 30913200]
  2. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin no. 209: obstetric analgesia and anesthesia. Obstet Gynecol. 2019b;133(3):e208-e225. [PubMed 30801474]
  3. American College of Obstetricians and Gynecologists (ACOG). COVID-19 FAQs for obstetrician-gynecologists, obstetrics. https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics. Accessed April 7, 2022.
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  8. Collins M. Use of nitrous oxide in maternity care: AWHONN practice brief number 6. Nurs Womens Health. 2018;22(2):195-198. [PubMed 29628059]
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  12. Lee EJK. Use of nitrous oxide causing severe visual loss 37 days after retinal surgery. Br J Anaesthes. 2004;93(3):464-6. [PubMed 15220168]
  13. Likis FE, Andrews JC, Collins MR, et al. Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg. 2014;118(1):153-167. doi: 10.1213/ANE.0b013e3182a7f73c. [PubMed 24356165]
  14. Miller RD, Miller’s Anesthesia, 7th ed, Philadelphia PA: Churchill Livingstone, 2010.
  15. Myles PS, Chan MT, Kasza J, et al. Severe nausea and vomiting in the evaluation of nitrous oxide in the gas mixture for anesthesia II trial. Anesthesiology. 2016;124(5):1032-1040. doi:10.1097/ALN.0000000000001057 [PubMed 26904965]
  16. Myles PS, Leslie K, Chan MT, et al; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007;107(2):221-231. doi:10.1097/01.anes.0000270723.30772.da [PubMed 17667565]
  17. Myles PS, Leslie K, Chan MT, et al; ANZCA Trials Group for the ENIGMA-II investigators. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014;384(9952):1446-1454. doi:10.1016/S0140-6736(14)60893-X [PubMed 25142708]
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  19. Ohryn M. Tympanic membrane rupture following general anesthesia with nitrous oxide: A case report. AANA J. 1995;63(1):42-44. [PubMed 7762371]
  20. Pavlidis P, Eddy K, Phung L, et al. Clinical guidelines for caring for women with COVID-19 during pregnancy, childbirth and the immediate postpartum period. Women Birth. 2021;34(5):455-464. doi:10.1016/j.wombi.2020.10.015 [PubMed 33191126]
  21. Reece-Stremtan S, Campos M, Kokajko L; Academy of Breastfeeding Medicine. ABM clinical protocol #15: analgesia and anesthesia for the breastfeeding mother, revised 2017. Breastfeed Med. 2017;12(9):500-506. [PubMed 29624435]
  22. Rooks JP, "Safety and Risks of Nitrous Oxide Labor Analgesia: A Review," J Midwifery Womens Health, 2011, 56(6):557-65. [PubMed 22060215]
  23. Rosen MA. Nitrous oxide for relief of labor pain: a systematic review. Am J Obstet Gynecol. 2002;186(5 Suppl):S110-S126. [PubMed 12011877]
  24. Sprehn M, Faber T, Osgaard O. Life-threatening tension pneumocephalus after nitrous oxide anaesthesia. Anaesthesia. 1992 Feb;47(2):174.
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