Nitrous Oxide - American Society of Anesthesiologists (ASA)

Review compiled by:
Curtis Baysinger, M.D.
Department of Anesthesiology
Vanderbilt University Medical Center

The Agency for Healthcare Research and Quality (AHRQ), as part of its Effective Health Care Program, recently issued a call for a key question on the use of nitrous oxide for the management of labor pain. According the AHRQ, a key question is designed to "help make sure that the research stays focused on the findings that patients, clinicians and health care policymakers need to make good decisions." The ASA Committee on Obstetrical Anesthesia, led by Craig Palmer, M.D., along with Curtis Baysinger, M.D., helped develop the ASA comments submitted under the leadership of ASA President Mark Warner, M.D.

Efficacy and maternal satisfaction
Comparison of efficacy with other methods of labor analgesia
Adverse effects
Management of inhaled nitrous oxide analgesia

Inhaled nitrous oxide was introduced to provide pain relief during labor in 1881 and its routine use for labor analgesia began after introduction of an apparatus for self-administration in 1934.1,2 The technique is used by 60 percent of laboring women in the United Kingdom,2 50 percent of laboring women in Australia,3 and almost 50 percent of women who deliver in Finland and Canada.4 In contrast, one recent survey reported that only 1 percent of women reported the use of nitrous oxide for labor analgesia in the United States5 and there appear to be only two centers in the United States where it is routinely available. Other inhalational agents alone or in combination with nitrous oxide have been studied for labor analgesia, but these reports are largely from the United Kingdom. Furthermore, only nitrous oxide has been used for inhalational analgesia to any great extent elsewhere.1,6

Studies that evaluate the efficacy of techniques used for labor analgesia are difficult to design. Severe pain is experienced by most women at some point in labor, but its intensity is highly variable, and depends upon maternal factors, the size and presentation of the fetus, whether labor is spontaneous or augmented, the rate of cervical dilation during the first stage, and parity.7 The experience of pain for women during labor and vaginal delivery depends on numerous psychosocial factors as well.8 Labor pain typically increases as labor progresses and most studies which use women as their own control assume that the pain of labor remains constant. Only recently have mathematical techniques been described to adjust for changes in labor pain as labor progresses.9 In addition, studies that ask for patients’ assessment of labor pain 2-3 days after delivery show a marked difference from pain assessed during labor1 and thus the validity of post-delivery survey studies would suffer from recall bias. Randomized controlled trials that assign patients to a group that offers no analgesia in order to assess the efficacy of a particular technique are not ethical. The known superior pain relief offered by epidural analgesia (associated with reductions in visual analog pain scores from 8 out of 10 to 3 out of 10)10 and higher maternal satisfaction scores in comparison to other forms of labor analgesia may make recruitment of suitable study subjects difficult.11

Efficacy and maternal satisfaction:
The efficacy and safety of nitrous oxide for labor analgesia has not been recently evaluated. The most recent review,1 in 2002, summarized the results of 11 randomized controlled trials, of which only one was published after 1996. This review concluded that current published work does not provide clear quantitative objective evidence of the analgesic efficacy of nitrous oxide.1 While one study in that review reported moderate decreases in visual analog pain scores (from 8 out of 10 to 6 out of 10) when the concentration of inspired nitrous oxide was increased from 0 percent to 70 percent,12 another study by Carstinou et al. showed no difference in visual analog pain scores when inhaled 50 percent nitrous oxide in oxygen was compared to air administration during labor.13 However, many of the women in that study wished to continue its use after the study period. In addition, many of the women in other studies have reported significant “benefit” to its use and the majority who used it during labor stated that they would choose it as a form of pain relief for subsequent labors.1,2 These data suggest that further study to define the nature of maternal pain relief during labor with inhaled nitrous oxide administration is warranted and that there are other as yet undefined factors that seem to promote patient satisfaction with its use.1,2,4,14

The peak analgesic effect of nitrous oxide lags the start of its administration by 50 seconds; however, uterine contractions typically peak 30 seconds after they start and stop 30 seconds later, out of phase with the analgesic effects of nitrous oxide administered beginning at the start of a contraction.1 Studies designed to determine the best techniques for its intermittent administration to attain the highest concentrations at the time of peak pain during a contraction are indicated.1

Comparison of efficacy with other methods of labor analgesia:
Nearly all efficacy studies of inhaled nitrous oxide have compared its use to placebo (inhaled air administration), the analgesic benefit of increasing the inhaled concentration, or the effects of adding other volatile agents to the inhaled mixture.1 Most studies have shown that other volatile inhaled agents provide analgesia equal to or better than nitrous oxide when administered alone, or when added to nitrous oxide, but at the expense of increased maternal sedation.1 Only one study has directly compared the efficacy of nitrous oxide to intravenous opioid administration. Volmanen, et al.15 compared intermittent patient-controlled administration of intravenous remifentanil to self-administered nitrous oxide and noted that remifentanil decreased visual analog pain scores (mean reduction in pain score of 1.5 points on a 0–10 scale) compared to nitrous oxide (mean reduction in pain score of 0.5 points on a 0–10 scale), but with increased maternal sedation scores (sedation score 2 with remifentanil and 0.5 with nitrous oxide, both on a 0–3 scale).15 Such small reductions in pain scores with either technique are probably not clinically significant and are much smaller than the reductions of 5 points (on a 0–10 scale) typically seen with epidural analgesia. These reductions in pain score are associated with the very high rates of maternal satisfaction seen with epidural analgesia when compared to other methods of pain relief.10,11 Reductions in pain scores with inhaled nitrous oxide use seem similar to that of systemic opioids,16 which some authors suggest have little effect on labor pain.14

A few studies of nonpharmacologic methods of pain relief suggest that the analgesia is similar to that associated with nitrous oxide use with similar levels of patient satisfaction.1,17,18 One nonrandomized study comparing nitrous oxide to transcutaneous electrical nerve stimulation, intramuscular meperidine and promazine administration, and epidural analgesia demonstrated the superior pain relief associated with epidural analgesia; however, 90 percent of women also reported partial relief with nerve stimulation or nitrous oxide and only 54 percent reported some pain relief with meperidine/promazine.1,19 There are no studies comparing nitrous oxide to pudendal block for the relief of pain during the second stage of labor. Randomized controlled studies that compare nitrous oxide to paracervical blockade would be difficult to conduct. Paracervical block is not widely used for labor analgesia because of the relatively high incidence of fetal heart rate abnormalities that accompany the block, despite recent improvements in technique designed to improve its safety.6

Adverse effects:
Inhaled nitrous oxide analgesia for labor has been used for several decades in the United Kingdom with good safety outcomes for both mother and child. Its use does not seem to appreciably affect the rates of maternal nausea or vomiting during labor.1,14 The direct respiratory depressant effect of nitrous oxide in combination with the maternal hypocapnia that accompanies labor may increase the rate of maternal oxygen desaturation in between labor contractions,1,14,20 although one small well conducted study failed to show a significant effect.13 The addition of systemic opioid administration may be expected to increase the likelihood of maternal hypoxemia.20,21 One small study reported that the rate of maternal desaturation was higher with nitrous oxide administration when compared to epidural analgesia.22 The significance of mild maternal hypoxemia upon the fetus is unknown.14 Most studies have failed to show significant adverse neonatal effects measured by Apgar score1,23 or umbilical artery and vein blood gases.24 This is in contrast to studies of systemic opioid administration for labor analgesia in which significantly higher rates of neonatal depression have been reported, especially in comparison studies with epidural analgesia for labor.25
Maternal drowsiness is reported to occur in 0 to 24 percent of laboring women1 and rates of maternal unconsciousness appear to increase in a dose dependent fashion from approximately 1 percent when 50 percent nitrous oxide are used to 5 percent when 80 percent nitrous oxide is used.14,26 These rates would be expected to be higher during the continuous administration of nitrous oxide.14

Recent work has demonstrated the neurotoxic effects of anesthetic agents on the developing rodent27 and primate brain.28 Nitrous oxide administration may have more risk for creating these changes than other agents.29,30 The effects on human fetuses exposed to nitrous oxide or other anesthetic agents in utero is unknown.27

Environmental pollution occurs frequently during inhaled administration and health care workers are often exposed to levels of nitrous oxide in excess of occupational exposure limits.29,30 Although the long term effects on the health of workers are unclear30,31 there may be an increased risk of adverse reproductive outcomes in health care workers due to such occupational exposure.32 Nitrous oxide administration does not affect uterine activity and thus would not be expected to affect the course of the first and second stages of labor and rates of cesarean delivery. By way of comparison, epidural analgesia does not affect the incidence of cesarean section, or length of the first stage of labor, although slight prolongation of the second stage of labor can be expected.33

Management of inhaled nitrous oxide analgesia:
Procedures for the administration of inhaled nitrous oxide for labor have to comply with the sedation policies developed within each institution’s Department of Anesthesiology. These policies should be in accordance with recent Centers for Medicare and Medicaid Services guidelines for anesthesia care34; its administration should be performed in health care facilities with written protocols for its use and where pulse oximetry and gas scavenging systems are available.1 Although nitrous oxide has a long history of safe use, several case series documenting maternal hypoxemia indicate this occurrence may put an “at risk” fetus in jeopardy.14 Environmental pollution is frequent if adequate methods of scavenging of unbreathed and exhaled gas are not employed. This may pose health risks to exposed health care workers and other participants in the mother’s care, and may contribute significantly to global warming (nitrous oxide is a “greenhouse gas”).14

Appropriate patient consent should be obtained and in particular reflect the possibility of long term adverse effects on child neurologic development.27 Nursing and obstetric providers should receive instruction on its safe use with periodic assessment of competence and perhaps certification. Because the efficacy of inhaled nitrous oxide in relieving pain during labor has not been established, alternative means of pain relief should be available and considered (such as pudendal nerve block during the second stage of labor, and systemic opioids if neuraxial analgesia techniques are not available). Systemic opioids would be expected to increase the risk of respiratory depression associated with nitrous oxide use,1,14,20 and pulse oximetry monitoring of the mother would be indicated in this situation. Rosen1 has suggested areas for continued research to include: techniques to improve the timing of administration to better coincide with the pain of uterine contraction; safety of administration by non-anesthesia personnel; the efficacy of additional co-administered methods to improve analgesia; and the development of methods to better measure the degree of maternal pain relief when nitrous oxide is used during labor.

1. Rosen MA. Nitrous oxide for relief of labor pain: A systematic review. Am J Obstet gynecol 2002; 186: S110-126.
2. Clyburn P. The use of Exntonox for labour pain should be abandoned. Opposer. Int J Obstet Anesth 2001; 10: 25-39.
3. Australian Institute of Health and Welfare. Australian mother and babies 2007: Perinatal status report.
4. Rooks JP. Nitrous oxide for pain in labor-why not in the United States? Birth 2007; 34: 3-5.
5. Hawkins J, Gibbs C, Orleans M, et al. Obstetric anesthesia ; a national survey. Anesthesiology 1986; 65: 298-306.
6. Paech M. Newer techniques of labor analgesia. Anesthesiology Clin N Am 2003; 21; 1-17.
7. Caton D, Corry MP, Frigoletto FD, Hopkins DP, Lieberman E, Mayberry L, Rooks JP, Rosenfield A, Sakala C, Simkin P, Young D. The nature and management of labor pain; Executive summary. Am J Obstet Gynecol 2002; 186: s1-15.
8. Lowe NK. The nature of labor pain. Am J Obstet Gynecol 2002; 186: S16-24.
9. Debiec J, Conell-Price J, Evansmith J, Shafer SL, Flood P. Mathematical modeling of the pain and progress of the first stage of nulliparous labor. Anesthesiology 2009; 111: 1093-110.
10. Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, Balnchard JW. A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg 2004; 99: 1532-8.
11. Wong CA. Epidural and spinal analgesia/anesthesia for labor and vaginal delivery. In, Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Anesthesia: Principles and Practice. Philadelphia, PA, Mosby Elsevier 2009: 429-492.
12. Westling F, Milsom I, Zetterstrom H, Ekstorom-Jodal B. Effects of nitrous oxide oxygen inhalation on the maternal circulation during vaginal delivery. Acta Anaesthesiol Scand 1992; 36; 175-181.
13. Carstoniu J, Levytam S, Norman P, Daley D, Katz J, Sandler AN. Nitrous oxide in early labor-safety and analgesic efficacy assessed by a double-blind, placebo-controlled study. Anesthesiology 1994; 80: 30-35.
14. Yentis SM. The use of Entonox for labour pain should be abandoned. Proposer. Int J Obstet Anesth 2001; 10; 25-29.
15. Volmanen P, Akural E, Raudaskoski T, Ohtonen P, Alahutta S. Comparison of remifentanil and nitrous oxide in labour analgesia. Acta Anaestheiol Scand 2005; 49: 453-458.
16. Olofsson C, Ekblom A, Ekman-Orderberg G, Hjelm A, Irestedt L. Lack of analgesic effect of systemically administered morphine or pethidine on labour pain. Br J Obstet Gyencol 1996; 103: 968-972.
17. Minnich ME. Childbirth preparation and nonpharmacologic analgesia. In Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Aneshtesia: Principles and Practice. Philadelphia, PA, Mosby Elsevier 2009: 405-414.
18. Ranta P, Jouppila P, Spalding M, Kangas-Saarela T, Hollmen A, Jouppila R. Parturients’ assessment of water blocks, pethidine, nitrous oxide, paracervical and epidural blocks in labour. Int J Obstet Anesth 1994; 4: 193-8.
19. Harrison RF, Shore M, Woods T, Mathews G, Gardiner J, Unwin A. . A comparative study of transcutaneous electrical nerve stimulation(TENS) entonox, pethidine+promazine, and lumbar epidural for pain relief in labor. Acta Obstet Gyncol Scand 1987; 66: 9-14.
20. Lucas DN, Siemaszko O, Yentis SM. Maternal hypoxaemia associated with the use of Entoonx in labour. Int J Obstet Anesth 2000; 9: 270-2.
21. Deckardt R, Fembacher PM, Schneider KT, Graef H. Maternal arterial oxygen saturation during labor and delivery: Pain-dependent alterations and effects on the newborn. Obset Gynecol 1987; 70: 21-5.
22. Arfeen A, Armstrong PJ, Whitfield A. The effects of Entonox and epidural analgesia on arterial oxygen saturation of women in labour. Anaesthesia `1994; 49: 32-4.
23. Stefani S, Hughes S, Shnider S, Levinson G, Abboud TK, Henriksen EGH, Williams V, Johnson J. Neonatal neurobehavioral effects of inhalation analgesia for vaginal delivery. Anesthesiology 1982; 56: 351-5.
24. Griffin RP, Reynolds F. Maternal hyopxaemia during labour and delivery: the influence of analgesia and effect on neonatal outcome.
25. Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, Blanchard JW. A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg 2004; 99: 1532-8.
26. McAneny T, Doughty AG. Self-administration of nitrous oxide/oxygen in obstetrics. Anaesthesia 1963; 18: 488-97.
27. Creely CE, Olney JW. The young: Neuroapoptosis induced by anesthetics and what to do about it. Anesth Analg 2010; 110: 442-8.
28. Bambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creely CE, Olney JW. Isoflurane-induced neurapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010; 112: 834-41.
29. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide. Anesthesiology 2008; 109: 707-22.
30. Mills GG, Singh D, Longan M, O’Sullivan J, Caunt JA. Nitrous oxide exposure on the labour ward. Int J Obstet Anesth 1996; 5: 160-4.
31. Fernando R, Jones T. Systemic analgesia: parenteral and inhalational agents. In, Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Aeeshtesia: Principles and Practice. Philadelp;hia, PA, Mosby Elsevier2009: 415-427.
32. Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-7.
33. Leighton BL, Halpern SH. The effects of epidural analgesia on labor, maternal, and neonatal outcomes: A systematic review. Am J Obstet Gyencol 2002; 186: S69-77.
34. Revised Hospital Anesthesia Services Interpretive Guidelines-State Operations Manual(SOM) Appendix A. Centers for Medicare and Medicaid Services, December 11, 2009.

This committee work product/resource has not been approved by ASA’s Board of Directors or House of Delegates and does not represent an ASA Policy, Statement or Guideline.

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