Reply Letter to Editor to Daniel Schneditz

To the Editor: We appreciate Daniel Schneditz’s1 contribution to our recently published article in ASAIO Journal.2 The author is eligible in his concern about efficiency. He recommends using a dialysate equilibrated with pure O2 to increase the amount of physically dissolved O2 significantly though, this is not an option because of the challenge posed by the low solubility of O2. Besides, we used a closed circuit with a bag of packed red blood cells (RBCs) not letting any ambient oxygen in. Therefore, the current system warrants all the oxygen is coming from peroxide. However, we agree with the author’s worry about efficiency. After completing our phase-1 trial, we initiated phase-2 studies with a rabbit model using the same 3% concentration of peroxide. We aimed to determine whether the system would function under in-vivo conditions as well. Fortunately, we have promising preliminary results unpublished yet. In that very recent trial, we observed a diminishing pattern in the increments of oxygenation values when we used peroxide with a constant dialysate bag. Recognizing that concern, we planned a continuous flow model for the peroxide to replace the dissolved part for further studies. Also, the flow rate of the dialysate may be insufficient to meet the oxygen needs of an adult but, be adequate for newborns and small children who require extracorporeal membrane oxygenation (ECMO) for respiratory insufficiency. In view of the premature nature of this innovative paradigm, further studies are needed to highlight these issues. In this preclinical study, our second aim was to ensure safety, as Dr. Schneditz raised attention. However, we did not visually observe bubble formation at a 3% concentration, which increased oxygen saturation (SO2) and partial oxygen pressure (PO2 ) levels. However, there might still be microbubbles that are not visible to the naked eye and could exceed the capacity of the venous chambers of the dialyzers.3 Therefore, incorporating a microbubble counter3 into the system would be a good option to address safety concerns. The author’s second concern about safety was that peroxide, with its smaller mass, could easily diffuse across the dialyzer membrane compared with urea. However, when we measured the peroxide levels at the post-membrane side at a 3% concentration, we did not detect any peroxide. We interpret this by noting that the peroxide was dissolved into H2O and O2 as soon as it came into contact with the dialysate solution. This is due to the peroxide’s chemical behavior when it encounters organic compounds. Even if H2O2 passes through the dialyzer membrane and diffuses into the blood, it can easily move to the cells and initiate a series of reactions. H2O2 is a nonradical oxidant that can act as a messenger for ozone (O3), triggering various biological and therapeutic effects.4 O3 therapy is used as an additional treatment for conditions like coronavirus disease 2019 (COVID-19), rheumatologic diseases, etc., which involve significant oxidative injury and O3 can activate anti-inflammatory signaling pathways at low doses.4,5 O3 therapy is also used as an additional treatment for chronic kidney diseases with oxidative injury.6,7 While O3 can cause injury as a strong reactive oxygen species (ROS) and is toxic at high doses, it has a therapeutic range at low doses. It is important to note that H2O2 formation is one of the pathways of O3, and if it crosses the dialyzer membrane, it can potentially initiate the anti-inflammatory response based on the dose. The author’s last concern was about the oxidative stress that peroxide can bring to critically ill patients who are already experiencing oxidative stress due to their illness. The larger surface area of the ECMO circuit increases inflammation and bleeding risk.8 Extracorporeal membrane oxygenation and tandem ECMO [(Continuous Renal Replacement Therapy (CRRT) on ECMO)] have a greater surface area compared with a single CRRT circuit due to the tubing and membrane sizes. Therefore, a hybrid membrane (dialo-oxygenator) with a smaller surface area is expected to result in less oxidative stress. Further experiments are warranted to investigate total oxidative and antioxidative status. We are optimistic that transforming the dialyzer membrane into a lung membrane opens up brand-new research opportunities.