Resolution of Acute Priapism in Two Children with Sickle Cell Disease who Received Nitrous Oxide

Overview of Priapism in Patients with Sickle Cell Disease

Priapism, an unwanted, persistent, painful penile erection unrelated to sexual stimulation, is a serious complication of sickle cell disease (SCD). The prevalence of priapism among males with SCD is high, with estimates ranging from 27.5% to 42%¹ and the majority of individuals thought to have at least one episode by age 20². Priapism in SCD is primarily ischemic and is a urologic emergency. Males with SCD may also experience recurrent intermittent priapism (RIP), with recurrent self-limited episodes of prolonged erections which are associated with, and can progress to, major ischemic priapism. Ischemic priapism and RIP have an adverse impact on quality of life, are associated with high rates of erectile dysfunction^3,4, higher inpatient SCD costs,⁵ and are more likely to lead to hospital admission in males than vaso-occlusive pain events (VOE)⁶. The mechanism is likely multifactorial but includes hemolysis-mediated dysregulation of the arginine-nitric oxide signaling pathway, downregulated phosphodiesterase-5 protein expression, and dysregulation of adenosine-mediated vasodilation in the penis^3,4,7-11. Testosterone deficiency and oxidative stress have also been implicated^12,13.

Overview of Treatment Options for Priapism in Sickle Cell Disease

Treatment options for priapism in SCD are limited and not evidence based, including hydration, alkalization, analgesia, oxygenation to prevent further sickling, and exchange transfusion^4,14-16. A 2017 Cochrane Database analysis found a lack of evidence for the benefits or risks of treatment options that included stilboesterol, sildenafil and ephedrine compared to placebo¹⁴. Patients who do not respond to treatments within 4 hours often require a painful invasive procedure that includes aspiration of blood from the corpus cavernosum and phenylephrine injections. Despite the time-dependent nature of treatment, these procedures are performed less often and with longer times to intervention in patients presenting with priapism and SCD than those patients with priapism alone¹⁷. Case reports have described a therapeutic benefit from oral pseudoephedrine, sildenafil^7,8,18, IV arginine⁹, and IV ketamine¹⁹ however controlled clinical trials are lacking. Boys with SCD who receive care at the Aflac Cancer and Blood Disorder Center of Children’s Healthcare of Atlanta (CHOA) are educated to trial oral pseudoephedrine at home for episodes of priapism, and to present to the ED in the case of treatment failure with sustained priapism of greater than 2–4 hours, depending on the severity. Once in the ED, these individuals are initially placed on our institutional nurse-initiated SCD pain protocol²⁰, which includes oral and/or parenteral opioids, IV ketorolac, and hypotonic maintenance intravenous fluids. In addition, a urology consultation is obtained for potential surgical interventions.

Overview of Nitrous Oxide Gas

Nitrous oxide (N₂O) is an inhalational medication that has anxiolytic, amnestic, potent venodilatory and mild-to-moderate analgesic properties commonly used in the emergency department (ED) setting^21,22. N₂O has a rapid onset of action (<5 minutes) and recovery (<5 minutes) and can be quickly titrated to effect without the need for intravenous (IV) access. It has few side effects, does not require renal or hepatic metabolism for excretion and has no reports of allergic reaction. N₂O can be used in ED settings for analgesia during painful procedures, such as IV placement, venipuncture, laceration repair, foreign body removal, and incision and drainage of abscesses²¹, but it is not typically used in the treatment of pain in SCD in the United States. Of interest, a 50:50 nitrous oxide/oxygen mix is commonly used in France to enhance analgesia in patients with SCD and VOE not sufficiently responding to IV morphine, although there are no reports of its use to treat priapism²³. We describe a case series of two patients with three instances of SCD-related priapism that had failed treatment with oral pseudoephedrine at home and that resolved completely after administration of N₂O. This work received an institutional IRB determination of not human subjects research.

Case Series

Over the last four years (January 2015 – December 2018), a total of 71 episodes of priapism were evaluated in the ED in 26 unique patients at CHOA. Prior to this case series, a sentinel patient with sickle cell disease presented with priapism that resolved with N₂O administration. The details of this patient have been lost to memory, but the treating physician (MHG) made note of the association. In our case series, patient 1 was an 8-year-old male with HbSS SCD at the time of his first of two ED presentations reported here (Table 1). He had a history of recurrent priapism which had required surgical intervention in the past. Oral pseudoephedrine, ibuprofen, and hydrocodone were taken at home, and he received intranasal fentanyl in the ED prior to IV placement. His second presentation occurred 13 months later, when he was 10-years-old. He had failed oral pseudoephedrine at home. No additional medications were given in the ED prior to IV placement. Patient 2 was a 15-year-old male with HbSS SCD and recurrent priapism. He had failed oral pseudoephedrine at home, and was given opiates and NSAIDs on arrival to the ED. At all 3 presentations, N₂O (maximum 60%) was used to facilitate IV placement; patient 1 experienced detumescence after 15 minutes of N₂O on his first presentation and after 5 minutes on his second presentation. At the second presentation, IV placement with N₂O was trialed early in the visit prior to initiation of the SCD-pain guidelines as the ED physician recognized him as the same patient whose previous priapism had rapidly resolved with N₂O administration. Patient 2 experienced detumescence after 4 minutes. In all 3 instances, there was no recurrence of priapism requiring intervention in the subsequent week. Although the sample size of this case series is small and causality cannot be assumed, our observations suggest that N₂O may be a novel treatment modality for SCD-related priapism. The mechanism for this finding is not clear and warrants further investigation.

Table 1.

Sickle Cell Disease Patient Characteristics

Patient	Age	SCD Genotype	time to Detumescence with N2O1
1	8	HbSS	15 min
1	10	HbSS	5 min
2	15	HbSS	4 min

¹Max 60% N₂O in all instances

Discussion

N₂O has few side effects and rare serious adverse effects when used infrequently²²; however, recurrent N₂O use or abuse can cause neurologic complications through impact on vitamin B12 (cobalamin) metabolism²⁴. Ogundipe et al. reported 3 cases of peripheral neuropathy in young adults with SCD who had frequent, prolonged N₂O exposure²⁵. In all 3 patients, the neuropathy resolved after administration of intramuscular vitamin B12. Another case report of combined spinal cord degeneration was reported in a 20-year-old man with SCD due to abnormal cobalamin metabolism induced by repeated use of nitrous gas as treatment for recurrent VOEs²⁶. Patients with SCD may be at higher risk of B12 deficiency due to increased erythrocyte turnover resulting from hemolysis, or coexisting folate deficiency²⁷. Indeed, several studies have demonstrated lower plasma cobalamin levels in patients with SCD compared to African Americans without SCD^27,28. Kamineni and colleagues found B12 deficiency (defined as a serum cobalamin level of <200pg/ml) in 18.1% (19/105) of patients with SCD compared to 9.8% (11/112) in non-SCD patients²⁷. None of the SCD patients with low B12 levels had neurological symptoms that would help to identify them clinically²⁷. However, N₂O use for anxiolysis in the pediatric ED is typically brief, and in our case series all episodes of priapism resolved within 15 minutes with N₂O. One-time brief use of N₂O should be safe, however repeated or prolonged exposure may pose neurological risks in the B12-deficient patient. Given the low cost of intramuscular B12 injection, co-administration of cobalamin during N₂O therapy could mitigate risk of neurologic sequelae, and warrants further consideration.

Priapism is a challenging complication of SCD associated with long-term morbidity and a paucity of treatment options. Given the risks and inconsistent results of current recommended therapy, N₂O may represent a novel treatment option for priapism presenting to the ED after treatment failure with oral vasodilators that warrants further investigation.