Impact of parenteral arginine therapy on mitochondrial activity and biomarkers of oxidative stress in children with sickle cell disease during acute vaso-occlusive pain episodes at admission compared to discharge. (A) Enzymatic activities of complex V, (B) complex IV, and (C) citrate synthase in platelet-rich plasma on the day of ED presentation for pain (VOE-baseline) compared with the day of hospital discharge (discharge) across 3 IV arginine dosing schemes: 100 mg/kg per dose TID vs a loading dose (200 mg/kg) followed by 10 0mg/kg per dose TID (loading + TID) vs a loading dose followed by a continuous infusion (300 mg/kg per day) (loading + CI). (D) Mitochondrial DNA, (E) protein carbonyl levels, and (F) malondialdehyde (MDA) levels across 3 arginine dosing schemes at VOE-Baseline compared with Discharge. Notably, complex-V activity, low at VOE-baseline compared with steady-state, was increased at discharge in subjects with VOE treated with arginine across all 3 dosing schemes, with greatest increase noted when using a loading dose (P < .001). Although complex IV and citrate synthase activities were not changed in VOE platelets vs steady state, the activities of these enzymes were significantly increased in VOE subjects after arginine treatment when using a loading dose (P < .01). These changes are not due to increased mitochondrial number because quantification of mitochondrial DNA before and after IV arginine was not different. Arginine therapy also significantly decrease levels of protein carbonyls and malondialdehyde in platelet-rich plasma across all treatment doses (P < .01), suggesting a decrease in oxidative stress. All panels show n = 4 subjects for each treatment arm. (A) There is substantial overlap between 2 subjects in both the TID and load + TID arms.