Nitrous Oxide for Treating Vaso‐Occlusive Crisis Pain in Children With Sickle Cell Disease: A Pilot Study

The treatment of vaso-occlusive crisis (VOC) pain in children with sickle cell disease (SCD) presenting to the emergency department (ED) is challenging and currently dependent primarily on opioids, with much interest in identifying effective nonopioid alternatives [1, 2]. The use of nitrous oxide for treating VOC pain has been described in France, with its inclusion as an analgesic in recent guidelines published by three French medical societies for the management of emergencies in adults and children with SCD [3]. In a survey of 85 French pediatric emergency departments, 46% of respondents reported using nitrous oxide for analgesia when morphine was insufficient [4]. What specifically piqued our interest was a report of two children with SCD admitted for management of VOC pain [5]. Their pain was refractory to morphine infusions administered for at least 36 h, with one child receiving escalating infusion rates over the course of three days. Both children received 15- or 20-min administrations of 50% nitrous oxide and experienced sustained analgesia lasting as long as 4 h after the nitrous oxide was discontinued. The mechanism behind this prolonged pain relief was unclear, as the duration of analgesia after nitrous oxide discontinuation is typically short-lived (e.g., < 5 min) [5]. There are compelling reasons to further explore the use of nitrous oxide as a treatment for VOC pain in children with SCD. Nitrous oxide has been used in other settings (e.g., labor and delivery) for providing nonopioid analgesia that persists as long as it is being inhaled. In addition, nitrous oxide may alleviate opioid-induced hyperalgesia and neuropathic pain, which would have positive implications for chronic pain in children with SCD [6, 7]. However, there is a paucity of data describing the effectiveness of nitrous oxide for treating VOC pain in children with SCD, as well as no mention of nitrous oxide as a potential analgesic in the most recent American Society of Hematology SCD guidelines for the management of acute and chronic pain [8]. To address this gap in knowledge, we enrolled a convenience sample of children with SCD who presented to our ED with VOC pain with the aim of generating preliminary data describing the effectiveness of nitrous oxide for reducing pain intensity and providing sustained pain relief. Our institutional review board approved this study with written informed consent and assent. We enrolled children between the ages of 8 and 17 years whose initial self-reported pain score was ≥ 7 out of 10 on presentation to the ED, but did not decrease below 7 out of 10 when assessed 15 min after receiving intravenous (IV) morphine (0.1 mg/kg) and IV ketorolac (0.5 mg/kg). Pain was reassessed at 15 min in accordance with our local SCD VOC pain protocol. Fifteen minutes was the time at which the analgesic efficacy of parenteral analgesics was expected to peak and a decision would be made to give additional opioids or not. Each child received 50% nitrous oxide for 20 min using a continuous flow delivery system. Patients were monitored with continuous pulse oximetry and no other analgesics were administered during this time. Five minutes after discontinuing the nitrous oxide, pain assessments were conducted by a trained study team member at standardized intervals using the Verbal Numerical Rating Pain Scale until the patient required additional parenteral opioid analgesics (i.e., rescue medication) or was discharged (Figure 1). We enrolled five patients. Four were female and four had HbSS. Four of the patients had been previously admitted for VOC pain at least three times, with one previously admitted more than 10 times. Three of the patients were taking hydroxyurea. These patients presented after experiencing between 1 and 4 days of pain, with three patients presenting after 3 days of pain. All patients had taken ibuprofen and three had taken oxycodone regularly each day prior to presenting to the ED. All patients received additional parental opioid analgesics within 2 h after completing the nitrous oxide administration. Three patients had pain relief (defined a priori as a pain score < 7 out of 10) for at least 60 min after discontinuing the nitrous oxide, with one patient experiencing pain relief for 2 h. One patient did not experience any reduction in pain intensity after the nitrous oxide administration. One patient experienced nausea without vomiting, and one patient vomited. There were no other adverse events, including no cardiopulmonary events or interventions. All patients were minimally sedated, sleepy, but appropriately responsive to verbal conversation while receiving nitrous oxide. All patients returned to their baseline mental status shortly after discontinuing the nitrous oxide. Four patients were admitted for inpatient treatment of their VOC pain. In this pilot study of five children, where a single 20-min administration of 50% nitrous oxide was given to treat VOC pain refractory to one dose of IV morphine and ketorolac, the ability of nitrous oxide to provide sustained pain relief was variable. Although there appeared to be some degree of sustained pain relief in three of the five children, the effectiveness observed was not as marked as that previously reported [5]. The observed difference could be due to the continued receipt of morphine in the prior report (as opposed to the single dose of morphine that children in our cohort received), as the investigators suggested that the sustained pain relief they observed could have been due to an additive effect of providing both nitrous oxide and morphine. It is unclear from our study whether a single, 20-min administration of 50% nitrous oxide given after a dose of IV morphine and ketorolac will be effective without continued inhalation. Our findings raise the questions of whether 50% nitrous oxide is the optimal dose; what is the necessary duration of administration to facilitate sustained pain relief; whether it is most effective as a sole or adjunct analgesic; and if it should be used as a first-line, second-line, or on-demand treatment for VOC pain. The aforementioned guidelines from France recommend short-term use of 50% nitrous oxide during the initial phase of pain treatment for children with VOC pain while waiting for effective pain relief from another route of administration [3]. However, there is no recommendation given for its use after the initial phase of management. Notably, the guideline recommendations for adults differ in that although nitrous oxide is not recommended as a first-line treatment, its use is allowed for a maximum of 1 h cumulative exposure per day [3]. It may be that the optimal use of nitrous oxide is not as a single, limited administration (i.e., for only 20 min), but rather as providing analgesia through continuous inhalation as is done in other settings (e.g., labor and delivery); in brief aliquots on an as needed basis to alleviate breakthrough pain; or as a temporizing measure while awaiting the administration of IV analgesics. The use of nitrous oxide by continuous inhalation, however, needs to be applied judiciously because prolonged and repeated exposure (as opposed to brief and repeated exposure) may interfere with vitamin B12 metabolism, which can lead to peripheral neuropathies [9]. In addition, its use as a temporizing measure needs to be weighed against the availability of other rapidly deployable analgesics, such as intranasal fentanyl, hydromorphone, or ketamine [10, 11]. In summary, a 20-min administration of 50% nitrous oxide after a dose of IV morphine and ketorolac was associated with a variable degree of pain reduction and sustained relief of VOC pain in this pilot study of children with SCD. It remains unclear whether nitrous oxide administered in this fashion is able to provide consistent, sustained pain relief in this population. Given the favorable properties and potential short- and long-term benefits of nitrous oxide, future work may be warranted to explore other ways of administering nitrous oxide to determine the optimal means of implementing it safely as an analgesic in the ED setting; better delineate its impact on short- and long-term outcomes and potential adverse events; and identify patient characteristics that may be associated with a greater and more sustained analgesic response to nitrous oxide. Daniel S. Tsze, Robert M. Kennedy and Peter S. Dayan: conceptualized the study. All authors designed the trial. Daniel S. Tsze: supervised the conduct of the trial, patient enrollment, and data collection. Daniel S. Tsze and Maureen Licursi: undertook the recruitment of participants. Daniel S. Tsze: drafted the manuscript, and all authors contributed substantially to its revision. Daniel S. Tsze takes responsibility for the manuscript as a whole. The authors have nothing to report. No large language models were used to write any part of the submission. The authors declare no conflicts of interest. Research data are not shared.