Episode #78 Nitrous Oxide for Labor Analgesia

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show.

Before we dive into the episode today, we’d like to recognize BD, a major corporate supporter of APSF. BD has generously provided unrestricted support to further our vision that “no one shall be harmed by anesthesia care”. Thank you, BD – we wouldn’t be able to do all that we do without you!”

To get the show started today, we are featuring one of the recent APSF Grant Recipients. For more information, head over to APSF.org and click on the Grants and Awards heading, then third one down is grant recipients. I will include a link in the show notes as well. The goal for these awards is to stimulate and fund research studies focused on improved patient safety by preventing mortality and morbidity that results from anesthesia mishaps. We are excited to feature the grant recipient for the APSF/Medtronic Research Award as well as the Ellison C. “Jeep” Pierre Jr MD Merit Award for the grant titled, “Development of Novel Machine Learning Tool to Predict Risk for Severe Maternal Morbidity and Optimize Anesthesiology Resources.” I will let her introduce herself now.

[VK] Hello, my name is Vesela Kovacheva. I am an assistant professor of anesthesia at the Harvard Medical School and the director for translational and clinical research in the division of obstetric anesthesia. My lab is focused on using novo bioinformatics approaches to predict and prevent adverse pregnancy outcomes.

[Bechtel] Congratulations on your award and now, let’s take a listen as Kovacheva tells us a little more about her project.

[VK] The United States is the only developed country in which the rates of severe maternal morbidity have been steadily increasing over the past decade and this is a critical patient safety priority. Safety in the perioperative period is also one of APSF’s top patient safety priorities and is the focus of our study. Specifically, we will create a more precise and practical prediction tool that will identify those patients at risk for severe maternal morbidity and provide decision support about the optimal timing of care escalation and involvement of the anesthesia provider. As part of this study, we will identify the predictors most relevant for the anesthesiology practice using our prior research and closed claim analysis and an established obstetric comorbidity score. Subsequently, we will utilize various machine learning approaches to develop a high performing and clinically relevant model that demonstrates the decision making process. We also plan to investigate the role of racial disparities and ensure a fair decision making algorithm. After selecting the best performing model, we will evaluate it prospectively. We envision that this innovative tool will support the anesthesiology provider in preparing for and managing the highest risk patients. Our long term goal is to improve maternal outcomes during delivery. Thank you APSF for the award and propelling this exciting research.

[Bechtel] Thank you so much to Kovacheva for discussing your research project with us. This is exciting research that may be able to improve maternal outcomes in the future. Just hearing from Kovacheva, it is obvious that she is passionate about this work. Let’s take a listen as she describes her drive and passion in this critical area.

[VK] Now, I will tell you why I feel so passionate about maternal safety research. Every year in the United States, more than 50,000 women experience severe maternal morbidity. The adverse outcomes are highly preventable and consider a near miss as without timely treatment of adequate resources, they may result in maternal death. This is a tremendous opportunity to improve maternal care.

[Bechtel] Thank you so much to Kovacheva for contributing to the show today. We couldn’t agree more that this is a huge threat to maternal patient safety and we are looking forward to your research in this area. What a great way to kick off the show today. We are going to continue with an article from our archives section, but don’t worry we stay on the topic of maternal patient safety. This article is from our recent archives, the June 2020 APSF Newsletter. Our featured article is “Safety and Utility of Nitrous Oxide for Labor Analgesia” by Arnolds and Scavone. Do you use nitrous oxide for labor analgesia in your practice? This may have changed during the Covid-19 pandemic and the authors include a disclaimer in their article that the article is for non-Covid-19 patient care. Patient care has changed throughout the Covid-19 pandemic and care of pregnant patients is no different. The Society for Maternal and Fetal Medicine and SOAP revised their Labor and Delivery COVID-19 Considerations on October 9, 2020. I will include a link in the show notes. Regarding nitrous oxide use during labor, there is not sufficient information regarding the physiologic safety of inhaled nitrous oxide for patient with suspected or confirmed Covid-19. Labor and delivery units may consider suspending use of nitrous oxide for patients with suspected or confirmed Covid-19 or for patients with unknown Covid-19 negative status. For patients who test negative for Covid-19, nitrous oxide may be considered as an option for labor analgesia.

And with that, let’s start with a history of nitrous oxide and its use. Did you know that it was first discovered in 1772 and by the 1800s it was first used for its analgesic properties. It has been part of anesthetic practice for over 150 years. Now, that’s some history!! So, what is it and how does it work? Well, nitrous oxide is a colorless, non-pungent, poorly soluble gas that undergoes minimal metabolism and has a quick onset and offset. It is a noncompetitive inhibitor at the NMDA receptor. The analgesia is likely mediated by supraspinal activation of opioidergic and noradrenergic neurons. This drug can be used as part of a general anesthesic, but not the sole agent and is often used for sedation taking advantage of the analgesic and anxiolytic properties.

These properties also make nitrous oxide an option for labor analgesia and it is common in the United Kingdom, Finland, Australia, and New Zealand. The use of nitrous oxide has increased in the United States from only being used at 5 centers in the US in 2014 to being used at about 500 centers by 2020. This increased use has occurred along with new FDA-approved devices for self-administration of 50% nitrous oxide with 50% oxygen for labor analgesia. It is important to understand the use and effectiveness of nitrous oxide for labor analgesia as well as the maternal, fetal, and occupational safety considerations on the labor and delivery unit.

Let’s start with the utility of nitrous oxide and the effectiveness. The most effective modality for treating labor pain is epidural analgesia. Parenteral opioids also provide effective labor analgesia. The use of nitrous oxide in labor has been studied, but further research is necessary in this area. The results from some of these studies include the following:

• No decrease in pain scores compared to placebo in early labor in the 1994 study by Carstoniu and colleagues.
• No significant decrease in pain scores in the more recent 2017 study by Sutton and colleagues.
• Insufficient data or low strength evidence for the effectiveness of nitrous oxide for labor analgesia in the 2014 systemic review published in Anesthesia and Analgesia.

Despite these results, there are indicators that patient satisfaction is high with nitrous oxide use. This may be due to the anxiolytic effects as well as the partial analgesic effects. In addition, patients may benefit from being about to continue to ambulate, the sense of control from self-administration, and the non-invasive option. The authors point out that pain relief is likely not the only component of patient satisfaction with anesthesia care during labor and delivery. Nitrous oxide administration has a role in the management for patients who want to avoid neuraxial or parenteral options for pain control or who are unable to receive neuraxial analgesia due to a contraindication.

Now it’s time to move on to the safety of nitrous oxide. Let’s review the safety considerations now. Keep in mind that nitrous oxide can expand air-filled spaces leading to serious complications in patients with a pneumothorax or recent inner ear or retinal surgery. Table 1 in the article includes the absolute and relative contraindications to nitrous oxide use and we are going to run through these now. You can take notes, but I will also include this table in the show notes as well.

Here are the absolute contraindications:

• Pneumothorax
• Recent retinal surgery
• Middle ear or sinus infection
• Pulmonary Hypertension
• Vitamin B-12 or folate deficiency

And the relative contraindications include these:

• Risk for B-12 or folate deficiency (i.e., vegan diet, history of bowel resection)
• Recent opioid administration
• Acute intoxication
• Requirement for supplemental O2

Side effects of nitrous oxide use may include nausea, dizziness, sedation, and claustrophobia from the mask. Another effect of nitrous oxide is irreversible inhibition of the vitamin B-12 dependent enzyme methionine synthase. Studies of nitrous oxide use during general anesthesia supports that it is likely safe for most patients without contraindications. Patients with vitamin B12 or folate deficiency may be at risk for subacute combined degeneration of the spinal cord and that is why known B12 and folate deficiencies are absolute contraindications. Pregnant patients do not have B12 levels checked during pregnancy, but almost 30% of patients in the third trimester may be deficient in vitamin B12. An important consideration to help keep patients safe would be to test vitamin B12 and folate levels or avoid nitrous oxide administration in patients who follow a vegan diet or with a history of bowel resections.

Other important considerations for nitrous oxide use include the following:

• High nitrous oxide concentrations leading to diffusion hypoxia (but this is unlikely with the 50/50 blend of nitrous oxide and oxygen used for labor analgesia.
• Avoid use in patients who require supplemental oxygen for maternal oxygenation as well as for intrauterine fetal resuscitation
• Nitrous oxide as a recreational drug of abuse (further studies are needed to determine if exposure to nitrous oxide during labor leads to an increased risk for future recreational drug abuse)

An important step that anesthesia professionals can take to keep laboring patients safe is to screen for any contraindications prior to nitrous oxide administration.

Let’s shift gears slightly as we consider fetal safety with nitrous oxide use. Nitrous oxide does cross the placenta, but there are limited neonatal effects due to the rapid offset time. Studies have not revealed any short-term adverse neonatal outcomes associated with maternal nitrous oxide use when evaluating umbilical cord gases and Apgar scores. There are concerns about possible long term hematologic or neurodevelopmental effects. We are concerned about long term consequences since adults with more than 6 hours of nitrous oxide exposure during general anesthesia have inhibition of hematopoiesis. Neurological complications including subacute combined spinal cord degeneration has been reported in adults with prolonged recreational use, rare congenital disorders, and patients with vitamin B12 and folate deficiency as we mentioned earlier in the show. Another concern for neurologic toxicity stems from the action of nitrous oxide as a NMDA receptor antagonist since NMDA receptor antagonists are associated with neuroapoptosis in the developing brain in animal models. However, when nitrous oxide used alone has been studied, it has not been associated with neuroapoptosis. Looking at the literature, there are no studies focused on neurologic toxicity in neonates following maternal nitrous oxide use, but there are also no case reports demonstrating this either and as I mentioned earlier nitrous oxide has been used for labor analgesia around the world for a long time. Other areas for further investigation following maternal nitrous oxide use are potential adverse effects in premature infants and the effects on the initiation of breastfeeding. Remember, nitrous oxide has a rapid offset so there is little concern for transfer to breast milk.

One final area for safety concern is the occupational risks associated with nitrous oxide use on labor and delivery units.  The data in this area comes from retrospective survey data with a possible link between occupational exposure to nitrous oxide and increased risk for spontaneous abortion and or low birth weight. The evidence is not clear, but the National Institute of Occupational Safety and Health recommends a max time-weighted average level of exposure to nitrous oxide that is set at no more than 25ppm over an 8-hour time period. There is a higher risk for occupational exposure in labor suites given that it is not administered through a closed circuit, the rooms may not be as well ventilated as operating rooms, and there may not be scavenging available. Even if scavenging is available, compliance is difficult for laboring patients to exhale into the tight fitting mask. This is a set up to exceed the maximal exposure limits. Labor and delivery units that offer nitrous oxide for labor analgesia may need to develop and follow a monitoring plan to limit occupational exposure and keep members of the healthcare team safe as well.

What a great review for nitrous oxide use for labor analgesia. We have time for a quick summary before we wrap up and send you on your way to ring in the new year!! Nitrous oxide has been used in other countries with extensive experience revealing that its use is likely safe for the mother, neonate, and members of the healthcare team on the labor and delivery unit. Further research is vital to demonstrate the safety of this practice as well as the impact on general anesthesia rates for cesarean delivery following maternal nitrous oxide use. In addition, nitrous oxide is not a substitute for neuraxial analgesia and even after initiating nitrous oxide therapy, 40-60% of patients will go on to request neuraxial analgesia. Don’t forget to screen patients for contraindications prior to initiating nitrous oxide administration and provide information about the amount of analgesia expected from use, side effects, and uncertainty of long-term effects of fetal exposure. It is also important to keep healthcare team members safe with patient education, scavenging, and monitoring to prevent any complications from occupational exposure.

If you have any questions or comments from today’s show, please email us at [email protected]. Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. We hope that you will visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.

Before the year is up and as we head into the new year, we would love to connect with you on twitter, Instagram, Facebook and LinkedIn. What are you waiting for? Go ahead and tag us in a patient safety related tweet or like our next post on Instagram, like us on Facebook, or connect with us on LinkedIn!! We are also sharing the latest news and updates in perioperative and anesthesia patient safety on TikTok. Thank you so much for listening throughout the year and we hope you will tune in again next year, which is next week!!

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2021, The Anesthesia Patient Safety Foundation