Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19

Overview

Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients with COVID-19 (SARS-CoV2) Illness. To evaluate safety and efficacy of a bolus loading dose and continuous intravenous infusion of L-Citrulline compared to placebo in patients hospitalized with COVID-19 infection (SARS-CoV-2).

Intravenous L-citrulline (Turnobi) administration will safely restore the homeostasis of nitric oxide synthase by increasing both plasma citrulline and arginine levels. Investigators also reason that restoration of citrulline/arginine balance through citrulline administration will safely re-establish homeostasis of NOS, lower oxidative stress, and reduce inflammation, thereby delaying and potentially preventing the need for invasive mechanical ventilation in participants hospitalized with COVID-19 infection (SARS-CoV-2). The body lives in a delicate balance of homeostasis. The urea/NO cycle plays a critical role in maintaining redox homeostasis and as such, also plays a role in regulating inflammation. The biochemical relationships are complex and depend on inter-organ transfer, membrane transport, and intracellular compartmentation. However, data above demonstrate that citrulline, arginine, and NO are critical in maintaining this homeostasis through their regulation of NOS. Inflammation, especially from infection, results in decreased activity of CPS1 and increased activity of arginase, which decreases levels of both citrulline and arginine. These decreased levels result in dysregulated and uncoupled NOS, which drives both overexuberant NO production and formation of ROS. Both the NO production and ROS further exacerbate the inflammatory cascade, resulting in other organ dysfunctions, including acute lung injury. Both inflammation and oxidative stress have been shown to be driving forces for the development of ALI and regulated NOS function is vital to reducing both. Both plasma citrulline and arginine are deficient in sepsis and levels are inversely associated with development of ALI. Furthermore, citrulline replacement safely increases plasma levels of both citrulline and arginine in healthy volunteers, BMT patients, adults with sepsis, children with sickle cell disease, and children after congenital heart surgery. It seems highly likely that citrulline therapy in the setting of COVID-19 (SARS-CoV2) induced acute hypoxemic respiratory illness will safely increase citrulline and arginine levels and help re-establish NOS homeostasis, resulting in NO production in compartments that are more homeostatically appropriate so as to reduce pulmonary vascular resistance and enhance coupling of NOS to minimize superoxide production thus reducing free radical mediated ALI.