nitrous oxide for labor analgesia: expanding analgesic...

Women in the United States have fewer options for pain relief in labor than women in many other parts of the developed

world.1 Although epidural analgesia is the most com-mon and complete method of pain relief available, a

majority of women surveyed in the 2006 Listening to Women Survey expressed interest in less invasive methods (Table 1).2 Recent reports support wider access to safe, less invasive options for comfort and labor pain as part of a program to achieve improved

Nitrous Oxide for Labor Analgesia: Expanding Analgesic Options for Women in the United States Michelle R. Collins, PhD, CNM,1 Sarah A. Starr, MD,2 Judith T. Bishop, MSN, CNM,3 Curtis L. Baysinger, MD4

1Vanderbilt University School of Nursing, Nurse-Midwifery Specialty, Nashville, TN; 2Department of Anesthesiology, Division of Obstetric Anesthesia, Vanderbilt University Medical Center, Nashville, TN; 3Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco School of Medicine, San Francisco, CA; 4Department of Anesthesiology, Division of Obstetric Anesthesia, Vanderbilt University Medical Center, Nashville, TN

Nitrous oxide (N2O) is a commonly used labor analgesic in many Western countries, but

is used infrequently in the United States. The University of California at San Francisco has been offering N

2O for labor analgesia for more than 30 years. Vanderbilt University

Medical Center recently began offering N2O as an option for pain relief in laboring

women. Many women report that N2O provides effective pain relief during labor and

argue that it should be made more widely available in the United States. This article discusses the use of N

2O for pain management during labor, including its history,

properties, clinical indications, and use and environmental safety issues. Practical issues regarding implementation of N

2O service in a medical center setting are also discussed.

[ Rev Obstet Gynecol. 2012;5(3/4):e126-e131 doi: 10.3909/riog0190]

© 2012 MedReviews®, LLC

Key words

Nitrous oxide • Labor analgesia

e126 • Vol. 5 No. 3/4 • 2012 • Reviews in Obstetrics & Gynecology

ManageMent Update

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Kingdom.10 Entonox has never been approved by the US Food and Drug Administration (FDA) for use in the United States; the only deliv-ery apparatus used for this purpose in the United States is Nitronox® (Porter Instrument Division, Parker Hannifin, Hatfield, PA). This deliv-ery system combines 50% N2O and 50% oxygen in a set concentration that cannot be altered, which differs from the apparatus used primar-ily in dental offices. The equipment used in dental practices allows for variable concentrations of N2O delivery, and is not intended to be used for patient-controlled N2O delivery. Although other approaches (such as continuous administra-tion of concentrations , 50% N2O in oxygen and intermittent admin-istration of higher concentrations) have been employed and may offer modest improvements in pain relief, the intermittent use of 50% N2O in oxygen probably optimizes patient safety and has thus been most widely adopted.

Clinical Use N2O can be used for analgesia dur-ing the first, second, and third stages of labor, as well as during postdelivery procedures such as

laceration repair, manual removal of the placenta, and uterine curet-tage.11 It may also facilitate the ini-tiation of epidural analgesia.11 N2O is self administered and has a rapid onset of 30 to 50 seconds, which correlates with volume and rate of inhalation. N2O administration is intermittent and delivered via face mask. The patient’s inhalation trig-gers the opening of a negative pres-sure demand valve and is timed by the patient to coincide with uterine

A need for further research on N2O for labor has been proposed.

BackgroundN2O is a nonflammable, tasteless, odorless gas. It was first synthesized by the English scientist and theolo-gian Joseph Priestly in 1772,7 and was first used as a labor analgesic by Stanislav Klikovich in Poland in 1881.8 Klikovich published the results of his study wherein he

utilized 80% N2O with 20% oxygen in 25 laboring women, and demon-strated pain relief with no adverse fetal outcomes.8 Self-administration of N2O for laboring women became widely available with the develop-ment of the Minnitt apparatus in 1933.9 In 1961, the British Oxygen Company introduced a single-tank delivery system marketed under the trade name Entonox® (The Linde Group, Munich, Germany) that con-tinues to be used today in the United

maternal-child outcomes.3,4 The inhaled self-administered blend of 50% nitrous oxide (N2O) and 50% oxygen is a common form of labor analgesia long used in other coun-tries (eg, Great Britain, Canada, Australia, and Finland), yet it is available at only a few institutions in the United States.5 The University of California, San Francisco (UCSF) has offered N2O as a labor analge-sic for over 30 years. Most recently, Vanderbilt University Medical Center (VUMC) successfully initi-ated a program to make N2O anal-gesia available to laboring women. The steps and resources involved in the development of this program are discussed herein.6 A recent Agency for Healthcare Research and Quality review noted that few good quality studies evaluating the use of N2O analgesia for labor have been reviewed elsewhere.6 That review also concluded that an assessment of efficiency and patient satisfaction was complicated by confounding factors, and that a lack of protocol standardization affected measures of efficacy and patient satisfaction.

Epidural Nitrous Oxide

Dense pain relief Variable pain reduction

Superior pain reduction compared with nitrous oxide

Pain is reduced but still present

No effect on anxiety Significant anxiolysis

Invasive Noninvasive

Serious side effects uncommon No serious side effects or risks as used in labor

Laboring woman is bed bound Woman has freedom to move about

Must have IV access and urinary catheter

Does not require IV access or urinary catheter

IV, intravenous.

Methods of Analgesia

TABLe 1

N2O can be used is indicated for analgesia during the first, sec-ond, and third stages of labor, as well as during postdelivery procedures.

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contractions. Anecdotal reports have noted patient report of great-est relief when the woman begins inhalation approximately 30 sec-onds prior to the start of her con-traction. This pattern of inhalation allows for peak serum levels of N2O to coincide with the peak of the uterine contraction. Offset is rapid, with elimination of the N2O by exhalation occurring within a few minutes of discontinuation. It is important that the N2O be admin-istered by the patient herself using a hand-held face mask; no straps or other devices should be used to secure the mask to the patient’s face that could lead to excessive

drowsiness. Learning the correct technique by practicing with the first few contractions is impor-tant in order to maximize results.12 Patient satisfaction and success with therapy can be enhanced by thorough teaching with a focus on the timing of breathing. Pain relief is generally less effective than with neuraxial analgesia utilizing local anesthetics.13 One earlier review examining N2O efficacy as a labor analgesic reported little change in maternal verbal and visual analog scale scores of pain during use in labor, but noted that many women still expressed satisfaction with the relief that it provided.13 When compared with patient-controlled administration of short-acting nar-cotics such as fentanyl and remi-fentanil, pain relief is reportedly similar.14,15 N2O administration is noninvasive and does not carry the serious (although rare) risks associated with regional analge-sia.16 Indeed, in patients in whom regional analgesia is not possible, N2O may be the only alternative choice available for pain relief.

The mechanism of action of N2O is complex and not clearly estab-lished. Endogenous opioid release occurs with associated analgesia, and N-methyl-d-aspartate recep-tor inhibition reduces hyperalge-sia. Anxiolysis mediated by central gamma-aminobutyric acid recep-tors may enhance the euphoric properties.17 Of note, intermittent use of 50% oxygen and 50% N2O does not significantly alter the maternal hypocapnia that accom-panies labor.18,19 The most com-monly reported side effects are nausea and vertigo, although N2O use does not significantly increase the rates of maternal nausea or

vomiting during labor.13 Fatigue may occur when used for prolonged periods. Also, although it is self administered, some women still find the sensation of breathing into a mask during contractions to be unpleasant. Newborn adverse side effects have not been described.20

Ingestion of modest amounts of clear fluids during uncomplicated labor appears safe.21 Although research specifically examining oral intake and safety of N2O use has not been undertaken, N2O analgesia should not be an impetus for altering an institution’s existing

guidelines for oral intake during labor. Laboring women who have experienced nausea prior to initiat-ing N2O therapy may benefit from prophylactic antiemetics prior to initiation of N2O therapy.

Safety Considerations The use of N2O as a labor analgesic in the United Kingdom has produced a long track record of safe outcomes for both mother and child. Recent animal studies have suggested that some anesthetic agents may induce apoptotic changes within develop-ing rodent and primate fetal brains if exposed either in utero or shortly after birth.22,23 Although short duration and modest concentra-tions of such analgesics would be expected to have negligible effects, high concentrations for prolonged periods may be deleterious.24-26 N2O is one of numerous agents that have been associated with these apop-totic changes in animal studies. Although an FDA advisory issued in 2007 recommended no change in anesthetic practice for chil-dren or fetuses, the precise effects on brain development in human fetuses exposed to N2O or other anesthetic agents in utero remain largely unknown.22

Environmental pollution occurs frequently during inhaled anes-thetic administration, and health care workers exposed to

When compared with patient-controlled administration of short- acting narcotics such as fentanyl and remifentanil, pain relief is reportedly similar.

Figure 1. Laboring woman inhaling nitrous oxide.


Nitrous Oxide for Labor Analgesia continued

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inhalational agents where scaven-ger systems are not simultaneously used are often exposed to levels of N2O in excess of occupational expo-sure limits.27 For this reason, FDA requirements necessitate the use of a blender device with a scavenger, which provides superior environ-mental hygiene when compared with European delivery systems. One effective way to monitor staff exposure is through the use of commercially available dosimetry badges. This method of surveillance has been used by UCSF and VUMC as part of their safety monitoring system for N2O. Badge dosimetry data from UCSF indicate ambi-ent levels well below the current National Institute for Occupational Safety and Health threshold limit of 25 ppm for 8-hour time-weighted average values (J.T. Bishop, personal communication, 2010).28 Although the long-term effects on the health of workers exposed to N2O are unclear, there does not appear to be an increased risk of adverse repro-ductive outcomes as a result of occupational exposure.29 Periodic

environmental air sampling should be performed in accordance with current Occupational Safety and Health Administration standards.30

Monitoring ConsiderationsThe recommendation rationale for monitoring standards regarding the use of N2O for labor rests upon the designation of the therapy as anx-iolysis/minimal sedation. This def-inition is assigned by the American Society of Anesthesiologists (ASA)31; N2O, when used at con-centrations of , 50% and as a sole agent, is defined by ASA criteria

as analgesia minimal sedation.31 The patient is responsive and airway, ventilation, and cardio-vascular function remain unaf-fected. Assuming these specific conditions, the use of pulse oxim-etry is not required. With intermit-tent use, room air entrainment will result in varying N2O concentra-tions of , 50%. If N2O is used by the patient continuously or is used intermittently in conjunction with intravenous or intramuscular nar-cotics, pulse oximetry should be employed.

Initiating an N2O ServiceIncreased access to N2O services in hospitals and birth centers has long been advocated by the mid-wifery profession.5 A position state-ment on Nitrous Oxide for Labor Analgesia issued by the American College of Nurse-Midwives in 2009 advocates for the availability of N2O to all laboring women, and recom-mends that all certified nurse- midwives and certified midwives be trained “to administer and over-

see safe use of N2O analgesia during labor.”32 The American Congress of Obstetricians and Gynecologists does not currently have a position statement regarding N2O use for labor analgesia.

UCSF has had an N2O service for over 30 years, in which therapy is now administered by midwives, having been under the direction of the Department of Anesthesiology at its inception. Development of the N2O program at VUMC was a joint effort between the Nurse-Midwifery Service of the School of Nursing and the Obstetric Anesthesia Division of the

Department of Anesthesiology with support from the Department of Obstetrics and Gynecology. N2O therapy is provided at VUMC by anesthesia providers under the Division of Obstetric Anesthesia. It is our belief that recent success-ful implementation was due to the committed support of key figures from both departments working together toward a common goal of making N2O available to laboring women.

At VUMC, a working interest group was established with rep-resentatives from neonatology, obstetrics, maternal-fetal medicine, newborn nursery, nursing manage-ment, midwifery, obstetric anes-thesia, risk management, and labor and delivery staff. Exchange of ideas was conducted in a group for-mat. Each representative member of the group had unique concerns and the process of addressing these individual concerns within the working group was critical to the eventual success of the program.

Once all members’ concerns were addressed and available evidence reviewed, the initiative was able to move forward with the devel-opment of guidelines and policies (Table 2). Initial policy develop-ment was done by core team mem-bers using published guidelines from UCSF as a model template.11 The proposed policy was evalu-ated and approved by numerous bodies, including the Sedation and Analgesia Committee, in accor-dance with Centers for Medicare and Medicaid Services mandate. Educational materials and compe-tency standards for staff were also developed and implemented prior to initiation of the service.

Visible sponsorship of the pro-posed change was also crucial to the successful implementation of change. In the VUMC experience, this equated to recruiting advo-cates for implementation from

Although the long-term effects on the health of workers exposed to N2O are unclear, there does not appear to be an increased risk of adverse reproductive outcomes as a result of occupational exposure.



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individuals whose influence was highly valued within the organi-zation. Feedback at every step of the process and from all involved participants was the last impor-tant key to success. As guidelines and policies were drafted, the input of key members of the inpatient care delivery team was necessary to continually make meaningful revisions. This feedback from key members at every step along the

way in guideline and policy for-mation and implementation was a major contributing factor to the smooth transition from policy to practice.

EquipmentOne major barrier to implementa-tion of N2O services in the United States has been the limited avail-ability of N2O delivery equipment. The device must be equipped with

a demand valve capable of intermit-tent high-volume delivery capacity. Most commercially available N2O analgesia systems, such as those used in the dental industry, employ continuous-flow low-volume sys-tems and are unsuitable for inter-mittent use with laboring women. As previously mentioned, single-cylinder Entonox systems used in Europe have not been approved for use by the FDA and are not avail-

able for purchase in the United States. Currently, Nitronox is the only FDA-approved apparatus for the self-administration of N2O. Matrx Medical (Orchard Park, NY), the initial manufacturer of Nitronox equipment, discontinued production several years ago, which made the purchase of new units impossible. Recently, however, the Porter Instrument Division of Parker Hannifin Corporation has

secured the rights to manufac-ture the Nitronox apparatus, and have indicated that they intend to have a device on the market by the end of 2012 (M. Civitello, per-sonal communication, June 2012). Reintroduction of Nitronox equip-ment will remove a major barrier to N2O availability.

ConclusionsInhaled N2O has a long history of use in pregnancy, and provides a safe option for pain relief in labor. Currently, access to this therapy is limited in the United States, and a need for increased access has been proposed. We believe that a system-atic approach, similar to that under-taken at VUMC, can lead to the introduction of N2O delivery ser-vices for labor at many more institu-tions throughout the United States. The improved availability of N2O for labor analgesia would increase options for pain management for laboring women.

References1. Marmor TR, Krol DM. Labor pain management in the

United States: understanding patterns and the issue of choice. Am J Obstet Gynecol. 2002;186:S173-S180.

2. Declercq ER, Sakala C, Corry MP, Applebaum S. Listening to Mothers II: Report of the Second National US Survey of Women’s Childbearing Experiences. New York, NY: Childbirth Connection; 2006.

3. Sakala C, Corry MP. Evidence-Based Maternity Care: What It Is and What It Can Achieve. New York, NY: Milbank Memorial Fund; 2008.

4. Carter MC, Corry M, Delbanco S, et al. 2020 vision for a high-quality, high-value maternity care system. Womens Health Issues. 2010;20:S7-S17.

5. Rooks JP. Use of nitrous oxide in midwifery practice–complementary, synergistic, and needed in the United States. J Midwifery Womens Health. 2007;52:186-189.

6. Likis FE, Andrews JA, Collins MR, et al. Nitrous Oxide for the Management of Labor Pain. Comparative Effectiveness Review No. 67. Rockville, MD: Agency for Healthcare Research and Quality; 2012. http://www.effectivehealthcare.ahrq.gov/ehc/ products/260/1175/CER67_NitrousOxideLaborPain_FinalReport_20120817.pdf. Accessed Sept. 17, 2012.

7. Riegels N, Richards MJ. Humphry Davy: his life, works, and contribution to anesthesiology. Anesthesiology. 2011;114:1282-1288.

8. Richards W, Parbrook GD, Wilson J. Stanislav Klikovich (1853-1910). Pioneer of nitrous oxide and oxygen analgesia. Anaesthesia. 1976;31:933-940.

9. O’Sullivan EP. Dr. Robert James Minnitt 1889-1974: a pioneer of inhalational analgesia. J R Soc Med. 1989;82:221-222.

10. Tunstall ME. Obstetric analgesia. The use of a fixed nitrous oxide and oxygen mixture from one cylinder. Lancet. 1961;2:964.

Establish lead partnership between obstetrical (OB/GYN, CNM) and anesthesia personnel

Review available research and papers regarding use of nitrous oxide for labor analgesia

Obtain sponsorship/buy-in from principal organization members

Form working group of representatives from all involved (anesthesia, obstetrics, newborn nursery, neonatal intensive care, staff nursing, nursing management, maternal fetal medicine, risk management, building engineering)

Address group concerns

Construct unit policy/procedure

Design method of staff education and proof of competency

Obtain equipment

OB/GYN, obstetrics and gynecology; CNM, certified nurse-midwife.

Key Points to Establishing a Nitrous Analgesia Service

TABLe 2

Most commercially available N2O analgesia systems, such as those used in the dental industry, employ continuous-flow low-volume systems and are unsuitable for intermittent use with laboring women.


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27. Mills GH, Singh D, Longan M, et al. Nitrous oxide exposure on the labour ward. Int J Obstet Anesth. 1996;5:160-164.

28. Centers for Disease Control and Prevention. The National Institute of Occupational Safety and Health (NIOSH). http://www.cdc.gov/niosh/docs/1970/77-140.html. Accessed September 17, 2012.

29. Fernando R, Jones T. Systemic analgesia: parenteral and inhalational agents. In: Chestnut DH, Polley LS, Wong C, eds. Obstetric Anesthesia: Principles and Practice, 3rd ed. Philadelphia, PA: Mosby Elsevier; 2009:415-427.

30. United States Department of Labor. Occupational Safety & Health Administration. Anesthetic gases: guidelines for workplace exposures. http://www.osha.gov/dts/osta/anestheticgases/index.html. Accessed Sept. 17, 2012.

31. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002;96:1004-1017.

32. American College of Nurse-Midwives. Position statement: nitrous oxide for labor analgesia. http : / /www.midwife .org/ index.asp?bid=59& cat=3&button=Search. Accessed Sept. 17, 2012.

11. Bishop JT. Administration of nitrous oxide in labor: expanding the options for women. J Midwifery Womens Health. 2007;52:308-309.

12. Ahonen J, Tarvonen M, Sainio S. Dinitrogen mon-oxide in the treatment of labor pains. Duodecim. 2009;125:1060-1068.

13. Rosen MA. Nitrous oxide for relief of labor pain: a sys-tematic review. Am J Obstet Gynecol. 2002;186:S110-S126.

14. Westling F, Milsom I, Zetterström H, Ekström-Jodal B. Effects of nitrous oxide/oxygen inhalation on the maternal circulation during vaginal delivery. Acta Anaesthesiol Scand. 1992;36:175-181.

15. Douma MR, Verwey RA, Kam-Endtz CE, et al. Obstetric analgesia: a comparison of patient- controlled meperidine, remifentanil, and fentanyl in labour. Br J Anaesth. 2010;104:209-215.

16. Ranta P, Jouppila P, Spalding M, et al. Parturients’ assessment of water blocks, pethidine, nitrous oxide, paracervical and epidural blocks in labour. Int J Obstet Anesth. 1994;3:193-198.

17. Maze M, Fujinaga M. Recent advances in under-standing the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311-314.

18. Lucas DN, Siemaszko O, Yentis SM. Maternal hypox-aemia associated with the use of Entonox in labour. Int J Obstet Anesth. 2000;9:270-272.

19. Deckardt R, Fembacher PM, Schneider KT, Graeff H. Maternal arterial oxygen saturation during labor and delivery: pain-dependent alterations and effects on the newborn. Obstet Gynecol. 1987;70:21-25.

20. Camann W, Alexander K. Easy Labor: Every Woman’s Guide to Choosing Less Pain and More Joy During Childbirth. New York, NY: Ballantine Books; 2006.

21. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 441: Oral intake during labor. Obstet Gynecol. 2009;114:714.

22. Creeley CE, Olney JW. The young: neuroapoptosis induced by anesthetics and what to do about it. Anesth Analg. 2010;110:442-448.

23. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neona-tal rhesus macaque brain. Anesthesiology. 2010;112:834-841.

24. Davidson AJ. Anesthesia and neurotoxicity to the developing brain: the clinical relevance. Paediatr Anaesth. 2011;21:716-721.

25. Hudson AE, Hemmings HC Jr. Are anaesthetics toxic to the brain? Br J Anaesth. 2011;107:30-37.

26. Istaphanous GK, Loepke AW. General anesthetics and the developing brain. Curr Opin Anaesthesiol. 2009;22:368-373.

MAIN PoINTs

• Nitrous oxide (N2O) is a nonflammable, tasteless, odorless gas; it is commonly used as a labor analgesic in many Western countries, but is used infrequently in the United States.

• Anecdotal reports have noted patient report of greatest relief when the woman begins inhalation approximately 30 seconds prior to the start of her contraction. This pattern of inhalation allows for peak serum levels of N2O to coincide with the peak of the uterine contraction.

• The use of N2O as a labor analgesic in the United Kingdom has produced a long track record of safe outcomes for both mother and child. Although short duration and modest concentrations of such analgesics would be expected to have negligible effects, concentrations . 50% nitrous and 50% oxygen for prolonged periods may be deleterious.

• The improved availability of N2O for labor analgesia would increase options for pain management for laboring women.



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nitrous oxide for labor analgesia: expanding analgesic...

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