Objectives

To evaluate the effectiveness of the nutritional supplement arginine at increasing nitric oxide levels, improving red blood cell functioning, and reducing hospitalizations and pain medication use in people with sickle cell disease.

Background

Sickle cell disease (SCD) is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain that are called "sickle cell crises." SCD is caused by an abnormal type of hemoglobin, which is a protein inside red blood cells that carries oxygen. In people with SCD, the abnormal hemoglobin distorts the shape of the red blood cells (RBCs). This is exacerbated when RBCs experience a loss of both water and potassium salts through the Gardos channel. The distorted shape causes the RBCs to clump together, decreasing blood flow and oxygen delivery to the body's tissues. The reduced levels of oxygen can lead to sickle cell crises and tissue damage. Hemolysis, the destruction of RBCs, is also a hallmark of SCD. During hemolysis, hemoglobin is released into the bloodstream, where it removes nitric oxide (NO), a natural chemical in the body that expands blood vessels. Arginase, another protein released during hemolysis, removes arginine from the bloodstream, which can also lead to decreased NO levels. The lack of NO constricts blood vessels, further contributing to painful sickle cell crises. Arginine supplementation may increase healthy hemoglobin and NO production and, in turn, prevent or reduce sickle cell crises. The CSCC-Arginine study was initiated to evaluate the effects of supplemental arginine in people with SCD.

Participants

Eligible participants were aged 5 years and older with an established diagnosis of H SS or S-beta thalassemia, history of at least one vaso-occlusive pain event in the 12 months prior to study entry, regular compliance with comprehensive medical care, and in a steady disease state and not in the midst of any acute complication due to SCD at study entry. Exclusion criteria included liver or kidney dysfunction; receiving a blood transfusion, hydroxyurea, or any investigational drug in the 90 days prior to study entry; more than 10 hospital admissions for pain in the 12 months prior to study entry; and daily use of opioids.

128 total participants were enrolled in this study, including 51 children. 36 participants were randomly assigned to the low dose arginine group, 35 to the high dose arginine group, and 38 to the placebo group.

Design

Eligible participants were enrolled at sickle cell treatment centers across the United States. Participants were randomly assigned to receive twice daily doses of either a low dose of arginine (0.05 g/kg), a high dose of arginine (0.10 g/kg), or placebo for 12 weeks. Participants, investigators, and outcome accessors were blinded to treatment assignments. Study visits occurred at baseline, three times during month 1, and weeks 8, 12, 14, and 16. Each study visit included an echocardiogram to measure heart activity, blood collection, and a medical history review to identify adverse events, pain medication usage, headaches, emergency department visits, and hospitalizations.

Primary outcomes included nitric oxide levels, Gardos channel activity, and hemoglobin concentration at 12 weeks after randomization.

Conclusions

Oral arginine therapy does not seem to provide clinical benefit for pediatric patients with SCD based on assessment of nitric oxide, Gardos channel activity, and RBC density.

Bolarinwa AB, Oduwole O, Okebe J, Ogbenna AA, Otokiti OE, Olatinwo AT. Antioxidant supplementation for sickle cell disease. Cochrane Database Syst Rev. 2024;5(5):CD013590. Published 2024 May 22. doi:10.1002/14651858.CD013590.pub2

Request Data

Please note that researchers must be registered on this site to submit a request, and you will be prompted to log in. If you are not registered on this site, you can do so via the Request button. Registration is quick, easy and free.