Impact of Oral Arginine Therapy on Global Arginine Bioavailability in Nigerian Children with Sickle Cell Anemia and Vaso-Occlusive Pain

Introduction: Severe vaso-occlusive pain episodes (VOE) are a major cause of morbidity and mortality in sickle cell anemia (SCA). Low arginine bioavailability is associated with pain severity and predicts need for pediatric hospitalization (Morris et. al, 2000). Arginine supplementation has opioid-sparing effects and was found to significantly decrease pain scores in children hospitalized with SCA-VOE compared to placebo in phase-2 randomized placebo-controlled trials (RCT) performed in the United States (US, Morris et. al, 2013) and Nigeria (Onalo et al, ASH 2019), while also significantly decreased time-to-crisis-resolution and length of hospital stay (LOS) in Nigerian children (Onalo et al, ASH 2019). Its mechanism-of-action and impact on arginine bioavailability is unclear.

Objectives: To determine the impact of oral arginine supplementation on arginine bioavailability and total opioid use in children with SCA-VOE.

Methods: A double-blind RCT of oral L-arginine (100 mg/kg/dose every 8 hours until discharge; up to 15 doses maximum) was performed in children with SCA hospitalized with severe VOE defined as a Numerical Pain Scale Score (PS) of at least 7 on a scale of 0-10, at one of two hospitals in Abuja, Nigeria (clinical outcomes previously reported, Onalo et al ASH 2019). Plasma arginine concentration and the global arginine bioavailability ratio (GABR, defined as arginine/[ornithine+citrulline]) was measured with high performance liquid chromatography tandem mass spectrometry before supplementation and at day 5 or discharge, whichever came first. Indices of arginine bioavailability were calculated and compared between the study groups. Demographics, clinical characteristics and total opioid use (mg/kg of morphine equivalents) were obtained. The impact of oral arginine supplementation on arginine bioavailability, and correlation of changes in arginine bioavailability with total opioid use was assessed.

Results: Sixty-eight children with SCA were recruited, aged 5-17years (mean: 10.6±0.4 years), and 85% were male; 35 children were randomized into the arginine arm and 33 into the placebo arm. Baseline characteristics were similar between arms. Clinical outcomes of significantly lower total analgesic use, lower pain scores, decreased time-to-crisis resolution and shorter LOS in the arginine group vs. placebo were previously reported (Onalo et al, ASH 2019). Oral arginine supplementation increases plasma arginine levels by 125% [95% CI, 61-187%] in the arginine as against 29% [1-58%] in the placebo group (Table 1), p=0.007. GABR was higher after supplementation in patients treated with arginine: 59% [20-98%] vs. -2% [-27-22%] in the placebo group (p=0.009). Patients with the lowest arginine level at presentation experienced the greatest increase in plasma arginine concentration, particularly patients with acute chest syndrome (ACS). Percent increase in GABR inversely correlated with total opioid used (mg/kg; r=-0.35;p=0.02, figure 1).

Conclusion: Arginine deficiency plays a role in acute pain requiring hospitalization in Nigerian children with SCA, similar to what has been reported in the US. Plasma arginine levels significantly increased with arginine supplementation, and improved global arginine bioavailability was inversely associated with total opioids used in VOE management. Lowest arginine levels were found in children with ACS, as previously reported in the US (Morris et al, 2000), a phenomenon that warrants further investigation. Low arginine bioavailability in children with SCA-VOE is improved by oral arginine supplementation.

Funded by Tertiary Education Trust Fund (to RO) and in part by NIH/NCCIH K24AT009893 (to CRM); Pan African Clinical Trial Registry number PACTR 201611001864290).