Alexis LaPietra, DO
Medical Director of Pain Management
Department of Emergency Medicine
St. Joseph’s University Hospital
Paterson, NJ
@DrAlexisLa
Introduction
Nitrous oxide (N2O) is a colorless, non-flammable gas administered in combination with oxygen via inhalation as an analgesic, anxiolytic and sedative agent. Nitrous oxide is a volatile anesthetic with an incompletely understood and complex mechanism of action that involves activation of endogenous opioid and GABA pathways. (Emmanouil 2007) The maximum N2O delivery concentration is 70%, with a corresponding 30% concentration of oxygen. Nitrous oxide is non-irritating and rapidly absorbed via the pulmonary vasculature into the systemic circulation. It does not combine with hemoglobin or other body tissues, (Becker 2008) and reaches the central nervous system within seconds of inhalation. Nitrous oxide can achieve analgesia comparable to opioids, with the benefits of noninvasive administration, easy titration, and rapid onset and resolution. (Becker 2008, Stenqvist 1994) As anticipatory anxiety surrounding a painful event or medical illness is linked to higher levels of pain, (Craven 2013) the ability of N2O to decrease pain may be due in part to its anxiolytic properties. (Gross 1981) Nitrous oxide has a long and robust record of safety with few side effects and requires minimal monitoring when used as a sole agent.
Pediatrics
Because fear and anxiety drives so much distress in pediatric emergency patients, N2O’s potent anxiolytic effect is of particular value in children. An extensive base of literature demonstrates the benefits of N2O in safely reducing stress, anxiety, and pain in children. Nitrous oxide can be safely administered to children as young as 1 year of age (Babl 2008) and in 50-70% concentration is used to reduce pain and anxiety associated with venipuncture, dental care, bronchoscopy, lumbar puncture, joint aspiration, and laceration repair. (Furuya 2009, Annequin 2000, Cleary 2002) It can be administered in combination with agents such as intranasal ketamine, midazolam, or fentanyl for procedural sedation or combined with a hematoma block to facilitate forearm fracture reduction. (Seith 2012, Luhmann 2001, Lee 2012, Luhmann 2006) The most frequent adverse effect, nausea and vomiting, is typically seen with concentrations at or near 70% or with concomitant opioid administration. The most common serious adverse event associated with N2O, hypoventilation, occurs in fewer than 1 in 500 patients in most series, and almost always when N2O is used in combination with other sedatives. (Babl 2015, Zier 2011, Tsze 2015)
Adults
Nitrous oxide provides analgesia and anxiolysis without deep sedation and has been used in a variety of care environments for the management of acute pain in adults. (Table 1) (Parlow 2005, Klomp 2012, Aboumarzouk 2011) N2O is often effective as a sole agent when used for mild and moderate pain, an there are emerging data regarding its utility as the primary analgesic for acute pain management in the ED when used in 50-70% concentration. (Herres 2015) For more severe pain, N2O is valuable as an analgesic adjunct and especially as a pre-procedural anxiolytic. Nitrous oxide provides effective analgesia for pain associated with long bone fracture, joint dislocation, abscess, musculoskeletal pain, abdominal pain, headache, constipation, and burn care. (Herres 2015) The most common side effects when N2O is used in adults are dizziness, euphoria, and laughter with no significant effects on heart rate, respiratory rate, or oxygen saturation. (Kariman 2011) Nitrous oxide is gaining popularity as a pre-hospital analgesic due to its excellent safety profile, ease of administration, minimal monitoring requirements, and rapid onset of action. (Ducasse 2013) Additionally, N2O in combination with other analgesics can relieve exacerbations of cancer pain in terminal illness. (Parlow 2005) Evidence demonstrates N2O is a well-tolerated, safe, and effective analgesic for acute pain management in the pre-hospital and adult emergency department setting.
Table 1: Typical indications for use of nitrous oxide in the emergency department
| Lumbar puncture | Incision & Drainage | Pre-Hospital Analgesia |
| Extremity Fracture Reduction | Central Venous Access | Joint Injections |
| Musculoskeletal Pain | Dental Procedures | Joint Dislocation |
| Headache | Minor to Moderate Burns | Laceration Repair |
| Venipuncture | Foreign Body Removal | Wound Care |
Contraindications
Nitrous oxide is overall very safe, but there are important contraindications to its use. (Table 2) It is easily able to diffuse out of the bloodstream and into air filled cavities, increasing cavity size or pressure, depending on tissue distensibility. Therefore, in patients with pneumothorax, recent vitreoretinal surgery, otitis media, bowel obstruction or chronic obstructive pulmonary disease with blebs, N2O is contraindicated. (Duncan 1984, Seaberg 1995, Becker 2008, Hart 2002, Brodsky 1986) Chronic daily exposure, common in dental hygienists, may contribute to infertility or spontaneous abortion, therefore its use is contraindicated in patients during the first and second trimester of pregnancy. (Rowland 1995) Nitrous oxide may interfere with vitamin B12 function and should be avoided in patients with pernicious anemia or other vitamin B12 deficiencies. (Myles 2004) Nitrous oxide is considered safe for the majority of patients, and a routine history and physical exam will identify most at-risk patients.
Table 2: Contraindications to use of nitrous oxide
|
Severe Sinusitis |
Severe Head Injury | First and Second Trimester Pregnancy |
|
Severe Asthma/ COPD |
Altered Mentation (Intoxication or Psychiatric Disease) |
Recent Vitreoretinal surgery |
|
Otitis Media |
Pneumothorax |
Bowel Obstruction |
| History of Air Embolism | Pneumomediastinum |
Pneumocephalus |
Monitoring and Fasting
There are no fasting requirements for N2O. (Gozal 2010)
When used without co-sedatives, N2O in concentrations at or below 50% is considered minimal sedation and hemodynamic monitoring can be limited to clinical observation of the patient’s responsiveness, with continued verbal interaction demonstrating adequate airway patency and breathing. (Cote 2016, AAPD 2013, ADA 2016, Gross 2002) If N2O is used in >50% concentration, especially for longer procedures, we recommend continuous pulse oximetry. When N2O is combined with other sedatives (including opioids), full procedural sedation setup and monitoring is recommended.
Equipment
Nitrous oxide can be delivered via nasal hood or full face mask, which may be disposable or reusable depending on the vendor. For most clinical environments outside of a dental or maxillofacial surgery office, N2O is not available through a wall hook-up. However, self-contained mobile units are available for rapid, portable administration. These units generally have an area for N2O tanks and either space for oxygen tanks or a connection for wall oxygen. A scavenging system is a mandatory component of the unit as it decreases ambient N2O exposure to clinicians, and some units require a hose to be plugged into wall suction as part of the scavenging mechanism. Nitrous oxide units are made with either a demand flow or a continuous flow mechanism. A demand flow system is triggered by negative inspiratory force as a safety precaution against over-sedation. Both systems are safe and require the patient or assistant to hold the mask in place. If a patient becomes over-sedated, either it will be recognized by the assistant or the patient will allow the mask to fall off their face. The maximum percentage of N2O provided on any unit is 70%; however some units have a maximum of 50%. Although 50% is effective, higher concentrations may provide better analgesia. (Babl 2008)
Administration
Prior to or during initiation of N2O, local or regional anesthetic and other analgesic adjuncts should be used for appropriate procedures (I&D and wound management), especially if significant post-procedural pain is expected.
Nitrous oxide works rapidly and should be administered to patients immediately before a painful procedure. The mask or nasal hood should be placed on the patient with oxygen flowing to avoid breathing against dead space in the breathing circuit. Nitrous oxide can be titrated by 10-20% every 30-60 seconds to desired effect. The flow of oxygen may have to be adjusted depending on the tidal volume requirements of each patient, but the percentage of N2O will not change with adjustments in oxygen. The patient should be visually monitored for signs of oversedation such as inability to communicate. Once the procedure is completed, N2O should be discontinued and the patient allowed to breathe nitrous-free oxygen for several minutes during recovery. (American Dental Association 2017) The breathing circuit can then be removed and the patient should remain seated for 1-2 minutes before mobilizing. Once the patient has a normal mental status and stable gait, the patient can be discharged without any restrictions.
Abuse potential
Nitrous oxide is a euphoriant and prone to abuse. There have been case reports of medical professionals and hospital staff that have abused, and in rare cases died, as a result of inhaling 100% N2O. (Winek 1995) Portable delivery systems must be stored in a secure or easily monitored area, and many departments require that practitioners “sign out” the device using an ID badge to track usage. Contemporary delivery systems commonly employed in emergency departments only function when used with disposable breathing circuits which can be kept in a separate locked area, providing an additional deterrent to abuse. Lastly, many devices require attachment into wall suction and wall oxygen for delivery of the gas, confining use to clinical areas.
Chronic use of N2O is associated with signs and symptoms of vitamin B12 (cyanocobalamin) deficiency, including megaloblastic anemia, peripheral neuropathy, and a myelopathy that particularly affects the dorsal columns. The latter is akin to subacute combined degeneration seen with B12 deficiency, and is due to the ability of N2O to oxidize the cobalt ion within the vitamin. Treatment includes the administration of high doses of parenteral vitamin B12. (Long 2018)
Conclusion
The use of nitrous oxide as a single agent analgesic and anxiolytic in the management of moderate, severe, and procedural pain in the ED is a rising but still underutilized therapy. The ability to rapidly titrate N2O makes it attractive for use in emergency care, allowing clinicians to tailor effect to the analgesic needs of each patient with minimal monitoring no post-administration restrictions. The longstanding, routine use of N2O in dental practice demonstrates a compelling record of safety and efficacy. (American Dental Association 2017) Although adequate evidence supports its use in both pediatric and adult emergency department patients, the limited experience of most emergency clinicians, as well as concerns around abuse, pregnancy risks, and equipment costs present barriers for implementation. There is potential to improve the management of pain and alleviate anxiety in acute care with expanded use of N2O, especially in departments that see a significant number of children. Continued research and efforts to improve awareness in the EM community regarding nitrous oxide’s versatility and efficacy will support N2O as another important analgesic tool in the emergency clinician’s therapeutic armamentarium.
An example emergency department protocol is available here.
References
Aboumarzouk OM, Agarwal T, Syed Nong Chek SA, Milewski PJ, Nelson RL. Nitrous oxide for colonoscopy. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD008506.
American Dental Association and Council on Dental Education, 2016. Guidelines for the use of sedation and general anesthesia by dentists. http://www.ada.org/~/media/ADA/Education%20and%20Careers/Files/anesthesia_use_guidelines.pdf
American Dental Association Oral Health Topics: Nitrous Oxide. Center for Scientific Information, ADA Science Institute, 2017. https://www.ada.org/en/member-center/oral-health-topics/nitrous-oxide
American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002 Apr;96(4):1004-17.
Annequin D, Carbajal R, Chauvin P, Gall O, Tourniaire B, Murat I. Fixed 50% nitrous oxide oxygen mixture for painful procedures: A French survey. Pediatrics. 2000 Apr;105(4):E47.
Babl FE, Grindlay J, Barrett MJ. Laryngospasm With Apparent Aspiration During Sedation With Nitrous Oxide. Ann Emerg Med. 2015 Nov;66(5):475-8.
Babl FE, Oakley E, Seaman C, Barnett P, Sharwood LN. High-concentration nitrous oxide for procedural sedation in children: adverse events and depth of sedation. Pediatrics. 2008 Mar;121(3):e528-32.
Becker DE, Rosenberg M. Nitrous oxide and the inhalation anesthetics. Anesth Prog. 2008 Winter;55(4):124-30.
Brodsky JB, Cohen EN. Adverse effects of nitrous oxide. Med Toxicol. 1986 Sep-Oct;1(5):362-74.
Cleary AG, Ramanan AV, Baildam E, Birch A, Sills JA, Davidson JE. Nitrous oxide analgesia during intra-articular injection for juvenile idiopathic arthritis. Arch Dis Child. 2002 Jun;86(6):416-8.
Coté CJ, Wilson S; American Academy of Pediatrics; American Academy of Pediatric Dentistry. Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update 2016. Pediatrics. 2016 Jul;138(1).
Craven P, Cinar O, Madsen T. Patient anxiety may influence the efficacy of ED pain management. Am J Emerg Med. 2013 Feb;31(2):313-8.
Ducassé JL, Siksik G, Durand-Béchu M, Couarraze S, Vallé B, Lecoules N, Marco P, Lacombe T, Bounes V. Nitrous oxide for early analgesia in the emergency setting: a randomized, double-blind multicenter prehospital trial. Acad Emerg Med. 2013 Feb;20(2):178-84.
Duncan GH, Moore P. Nitrous oxide and the dental patient: a review of adverse reactions. J Am Dent Assoc. 1984 Feb;108(2):213-9.
Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007 Spring;54(1):9-18.
Furuya A, Ito M, Fukao T, Suwa M, Nishi M, Horimoto Y, Sato H, Okuyama K, Ishiyama T, Matsukawa T. The effective time and concentration of nitrous oxide to reduce venipuncture pain in children. J Clin Anesth. 2009 May;21(3):190-3.
Gozal D, Mason KP. Pediatric sedation: a global challenge. Int J Pediatr. 2010;2010:701257.
Gross RT, Collins FL. On the relationship between anxiety and pain: A methodological confounding. Clinical Psychology Review. 1981.
Hart RH, Vote BJ, Borthwick JH, McGeorge AJ, Worsley DR. Loss of vision caused by expansion of intraocular perfluoropropane (C(3)F(8)) gas during nitrous oxide anesthesia. Am J Ophthalmol. 2002 Nov;134(5):761-3.
Herres J, Chudnofsky CR, Manur R, Damiron K, Deitch K. The use of inhaled nitrous oxide for analgesia in adult ED patients: a pilot study. Am J Emerg Med. 2016 Feb;34(2):269-73.
Kariman H, Majidi A, Amini A, Dolatabadi AA, Derakhshanfar H, Hatamabadi H, Shahrami A, Yaseri M, Sheibani K. Nitrous oxide/oxygen compared with fentanyl in reducing pain among adults with isolated extremity trauma: a randomized trial. Emerg Med Australas. 2011 Dec;23(6):761-8.
Klomp T, van Poppel M, Jones L, Lazet J, Di Nisio M, Lagro-Janssen AL. Inhaled analgesia for pain management in labour. Cochrane Database Syst Rev. 2012 Sep12;(9):CD009351.
Lee JH, Kim K, Kim TY, Jo YH, Kim SH, Rhee JE, Heo CY, Eun SC. A randomized comparison of nitrous oxide versus intravenous ketamine for laceration repair in children. Pediatr Emerg Care. 2012 Dec;28(12):1297-301.
Long, H. Inhalants. Goldfrank’s Toxicologic Emergencies, edited by Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LS, Hoffman RS. 11th ed., New York, McGraw Hill, 2018.
Luhmann JD, Kennedy RM, Porter FL, Miller JP, Jaffe DM. A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair. Ann Emerg Med. 2001 Jan;37(1):20-7.
Luhmann JD, Schootman M, Luhmann SJ, Kennedy RM. A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children. Pediatrics. 2006 Oct;118(4):e1078-86.
Myles PS, Leslie K, Silbert B, Paech MJ, Peyton P. A review of the risks and benefits of nitrous oxide in current anaesthetic practice. Anaesth Intensive Care. 2004 Apr;32(2):165-72.
Parlow JL, Milne B, Tod DA, Stewart GI, Griffiths JM, Dudgeon DJ. Self-administered nitrous oxide for the management of incident pain in terminally ill patients: a blinded case series. Palliat Med. 2005 Jan;19(1):3-8.
Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol. 1995 Mar 15;141(6):531-8.
Seaberg DC, Yealh DM, Ilkhanipour K. Effect of nitrous oxide analgesia on pneumothorax. Acad Emerg Med. 1995 Apr;2(4):287-92.
Seith RW, Theophilos T, Babl FE. Intranasal fentanyl and high-concentration inhaled nitrous oxide for procedural sedation: a prospective observational pilot study of adverse events and depth of sedation. Acad Emerg Med. 2012 Jan;19(1):31-6.
Stenqvist O. Nitrous oxide kinetics. Acta Anaesthesiol Scand. 1994 Nov;38(8):757-60.
Tsze DS, Mallory MD, Cravero JP. Practice Patterns and Adverse Events of Nitrous Oxide Sedation and Analgesia: A Report from the Pediatric Sedation Research Consortium. J Pediatr. 2016 Feb;169:260-5.e2.
Use of Nitrous Oxide for Pediatric Dental Patients. Pediatr Dent. 2017 Sep 15;39(6):273-277. No authors listed.
Winek CL, Wahba WW, Rozin L. Accidental death by nitrous oxide inhalation. Forensic Sci Int. 1995 May 22;73(2):139-41.
Zier JL, Liu M. Safety of high-concentration nitrous oxide by nasal mask for pediatric procedural sedation: experience with 7802 cases. Pediatr Emerg Care. 2011 Dec;27(12):1107-12.