Nitrous Oxide for Labor Analgesia: What We Know to Date

HISTORY

The discovery of N₂O is attributed to English scientist Joseph Priestley in 1772; however, the first reported use of N₂O for vaginal delivery did not occur until 1881.⁵ Polish physician Stanislav Klikovich used an 80% N₂O/20% oxygen (O₂) mixture in 25 laboring women and found that it provided analgesia without adverse fetal effects.¹ The utility of N₂O progressed during the early 20th century; however, its use was not without challenges. The lack of a systematic device to administer N₂O and a way to ensure the delivery of safe concentrations were the two greatest limitations to the use of N₂O in obstetrics. British anesthetist Robert James Minnitt was a pioneer of inhalational analgesia. Minnitt, along with instrument maker Charles King, produced the first gas/air apparatus in 1933. This device allowed women in labor to inhale a mixture of nitrous and air, providing one of the only forms of labor analgesia at the time. After being used for approximately 3 decades, this apparatus was withdrawn because of delivery of the hypoxic mixture of N₂O and air.⁶ After multiple revisions to the apparatus, the British began using an N₂O/O₂ delivery system—named Entonox—in 1961.⁷ As of 2011, only 3 US academic centers were using N₂O for labor analgesia. In 2011, Nitronox (Porter Instrument) became the first US Food and Drug Administration–approved N₂O delivery system, which is set to deliver a fixed concentration of 50% N₂0/50% O₂. According to a 2012 review by Collins et al, the University of California, San Francisco, was at the forefront of institutions offering N₂O for labor analgesia, at that point having offered the option for more than 30 years.¹ Vanderbilt University and the University of Washington were the next large academic centers to offer N₂O to parturients, and many other centers have followed. By 2018, more than 500 birthing centers and hospitals across the country had adopted N₂O use.^8,9

MECHANISM OF ACTION

N₂O is a tasteless, odorless vapor with peak brain concentrations occurring within 60 seconds after the onset of administration.¹⁰ Among the several proposed mechanisms for the pharmacokinetics of N₂O are (1) N-methyl-D-aspartate antagonism, (2) pain perception modulation at the alpha-2 receptors in the dorsal horn of the spinal cord, and (3) the release of endogenous opioids in the brain. These various mechanisms are believed to reduce pain sensitivity and provide analgesia; however, these mechanisms are still not well understood. Despite insufficient evidence on the precise mechanism of action, N₂O used for labor analgesia has not been associated with any major side effects and is generally well tolerated. However, as with any treatment therapy, N₂O is associated with adverse reactions and has contraindications to its use. Nausea, vomiting, and dizziness are among the most common maternal side effects, reported by up to 46%, 14%, and 23% of parturients, respectively.⁷ Respiratory depression is rare unless N₂O is used in the setting of systemic opioids.

With regard to neonatal outcomes, no significant adverse effects have been reported.^3,11 Stefani and colleagues found no differences in neurobehavioral assessments of neonates of mothers receiving nitrous concentrations of 30% to 50%.¹¹ Concerns about neurotoxic effects associated with N₂O were raised when studies on the effects of anesthetics showed neuronal apoptosis in rodents; however, N₂O by itself caused little or no apoptosis in the infant rat brain.¹² Likis and colleagues analyzed 29 studies reporting fetal or neonatal outcomes based on umbilical cord gases and Apgar scores and found no significant difference between mothers who received N₂O during labor vs mothers who did not.³

Contraindications to the use of N₂O are limited and principally include administration to patients at risk for its accumulation in enclosed spaces (ie, pneumothorax, small bowel obstruction). Parturients with congenital heart defects and/or pulmonary hypertension should avoid N₂O because it increases pulmonary vascular resistance.

Controversy regarding environmental exposure to N₂O among healthcare workers and its association with increased risk of adverse reproductive outcomes has been ongoing. The use of scavenger systems and vigilant monitoring of exposure levels with dosimetry badges can keep exposure below the National Institute for Occupational Safety and Health (NIOSH) limit of 25 ppm. Long-term effects of N₂O exposure are unclear; however, compliance with NIOSH standards is not associated with an increased risk of reproductive complications.^1,13

CLINICAL USE

N₂O can be used for analgesia during the first, second, or third stage of labor; during postpartum procedures (eg, laceration repair, manual extraction of placenta); and to facilitate epidural placement. N₂O is self-administered via a mask without straps that could keep the mask fixed to the face and potentially lead to excessive drowsiness and/or hypoxia. Studies evaluating the benefits of N₂O state that the self-administration aspect of N₂O improves the parturient's sense of control and ability to cope with labor.^5,9 Some women do not like to be confined to a bed throughout their labor. The majority of neuraxial anesthetics cause weakness of the lower extremities, requiring a patient to remain in bed once the anesthetic is administered. While most N₂O policies require the patient to remain in bed or a chair during use, the effects dissipate in less than 5 minutes. This short half-life gives the patient freedom to move about when not using N₂O.¹⁴ Administration begins with the patient's inhalation that triggers the opening of a negative pressure valve and permits the flow of N₂O. Educating the patient and practicing the correct technique with the patient is critical for successful pain relief.⁹ Because the onset of N₂O is approximately 30 to 50 seconds, it should be initiated prior to the onset of a contraction so that peak serum concentrations are present at the height of the contraction.

EFFICACY AND SATISFACTION

Varying results regarding the effectiveness of N₂O for labor analgesia have been reported.^3,4 A 2002 systematic review of 11 trials examining the efficacy of N₂O revealed the complexity of this assessment.⁴ Several factors are responsible for the variability of findings: concentration of N₂O used, method of administration, administration of other intravenous medications, and unsatisfactory study design. Because of this variability, drawing conclusions about the efficacy of N₂O is difficult. In a postpartum survey of 2,482 Swedish women, 84% of nulliparous and 72% of parous women rated neuraxial techniques as very effective compared to 38% of nulliparous and 49% of parous women who rated N₂O as very effective.¹⁵ Despite the lower percentage of satisfied parturients who used N₂O, the study provides evidence that N₂O has analgesic benefit. In a study comparing various analgesic modalities—including N₂O, epidural alone, and epidural following other modalities (eg, N₂O, meperidine)—33% of patients who used nitrous alone rated its analgesia as good.¹⁶ Subsequent studies continued to show a wide range of analgesic efficacy.^3,9 Importantly, based on postpartum surveys of labor and delivery experience, analgesia is not the only factor associated with satisfaction. Other factors such as bodily sensations of labor, mobility, and perceived situational control are also major determinants of labor and delivery experience.⁹

PREDICTORS OF SUCCESS

Sutton et al retrospectively analyzed the use of N₂O and predictors of conversion to epidural labor analgesia.¹⁷ Three percent of parturients used N₂O during the study period; the majority were nulliparous (71.2%), and more than half (51.9%) expressed preference for a nonmedical birth. Of the 146 women included in the analysis, 63% converted from N₂O to neuraxial analgesia. Factors associated with conversion from N₂O to neuraxial analgesia were labor induction, labor augmentation, and lower cervical dilation at the time of N₂O request.¹⁷ Richardson et al analyzed qualitative comments from women who used N₂O for labor to try to better understand the determinants of satisfaction despite variable analgesic effects. Of the 264 women who responded, 90% were highly satisfied with their use of N₂O for labor. Many of these women reported coping benefits of N₂O, such as relaxation, reduced anxiety, and dissociation from pain. Richardson et al reported that among patients who used N₂O and delivered vaginally, 40% converted to neuraxial analgesia.⁹