key: cord-0690955-ktxzud5v authors: Lupon, Elise; Lellouch, Alexandre G.; Zal, Franck; Cetrulo, Curtis L.; Lantieri, Laurent A. title: Combating hypoxemia in COVID-19 patients with a natural oxygen carrier, HEMO(2)Life® (M101) date: 2020-11-24 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110421 sha: 05db6942edb1dc17e25241e4941f6b1ba4a4a0dd doc_id: 690955 cord_uid: ktxzud5v BACKGROUND: Infection with SARS-CoV-2 is responsible for the COVID-19 crisis affecting the whole world. This virus can provoke acute respiratory distress syndrome (ARDS) leading to overcrowed the intensive care unit (ICU). Over the last months, worldwide experience demonstrated that the ARDS in COVID-19 patients are in many ways “atypical”. The mortality rate in ventilated patients is high despite the application of the gold standard treatment (protective ventilation, curare, prone position, inhaled NO). Several studies suggested that the SARS-CoV-2 could interact negatively on red blood cell homeostasis. Furthermore, SarsCov2 creates Reactive Oxygen Species (ROS), which are toxic and generate endothelial dysfunction. Hypothesis/Objective(s) We hypothesis that HEMO2Life® administrated intravenously is safe and could help symptomatically the patient condition. It would increase arterial oxygen content despite lung failure and allow better tissue oxygenation control. The use of HEMO2Life® is also interesting due to its anti-oxidative effect preventing cytokine storm induced by the SARS-CoV-2. Evaluation of the hypothesis: Hemarina is based on the properties of the hemoglobin of the Arenicola marina sea-worm (HEMO2Life®). This extracellular hemoglobin has an oxygen capacity 40 times greater than the hemoglobin of vertebrates. Furthermore, the size of this molecule is 250 times smaller than a human red blood cell, allowing it to diffuse in all areas of the microcirculation, without diffusing outside the vascular sector. It possesses an antioxidative property du a Superoxide Dismutase Activity. This technology has been the subject of numerous publications and HEMO2Life® was found to be well-tolerated and did not induce toxicity. It was administered intravenously to hamsters and rats, and showed no acute effect on heart rate and blood pressure and did not cause microvascular vasoconstriction. In preclinical in vivo models (mice, rats, and dogs), HEMO2Life® has enabled better tissue oxygenation, especially in the brain. This molecule has already been used in humans in organ preservation solutions and the patients showed no abnormal clinical signs. CONSEQUENCES OF THE HYPOTHESIS: The expected benefits of HEMO2Life® for COVID-19 patients are improved survival, avoidance of tracheal intubation, shorter oxygen supplementation, and the possibility of treating a larger number of patients as molecular respirator without to use an invasive machine. , is a specific disease, whose distinctive features are severe hypoxemia often associated with near normal respiratory system compliance 5 . Over the last 5 months, worldwide experiences demonstrated that the ARDS in patients are in many ways "atypical". The mortality rate in ventilated patients is high 6 despite the applying the gold standard treatment (protective ventilation, curare, prone position, inhaled Nitric Oxide (NO)). Furthermore, Guiseppe et al., revealed a decrease of hemoglobin content in some patients 7 . Indeed, the mean hemoglobin difference of the four individual studies reporting continuous values of this parameter showed that the hemoglobin value was significantly lower in COVID-19 patients with severe disease than in those with milder forms, yielding a Weighted Mean Difference (WMD) of -7.1 g/L; 95% CI, -8.3 to -5.9 g/L). Several elements suggested that the SARS-CoV-2 could interact negatively on red blood cell homeostasis. Firstly, direct signs seem to confirm this theory as the modification of O2 concentration in the bloodstream by using a hyperbaric oxygen therapy report a condition improvement in severe COVID-19 patients ("Naval Specialty Medical Center Program Team" document uploaded in the attachment section) Indirect signs also support this interaction as acidosis, high level of lactate, anemia, a high level of ferritin 8 in severe patients are correlated with a high mortality rate. Therefore, an important physiopathology feature is not thoroughly taken into account: "the oxygenation component". We suggest and provide to the physicians a new therapeutic tool to help to struggle symptomatically the hypoxemia with a Natural Oxygen carrier off-shelf, ® , also called M101. We hypothesize that the intravenous injection of HEMO 2 Life ® in cases of acute respiratory failure, attributable to COVID-19, would allow an improvement in oxygen transport to the tissues and that this could avoid the progression to multiorgan failure in case of persistence or worsening of hypoxemia. This molecule has been administered on human for transplantation as an additive in conservative solution 9 , but never directly intravenously (IV), this study revealed the safety of this product considered as a medical device of class III. However, several published preclinical data showed an effective way to transfer oxygen to hypoxia, in particular to the brain, in a study published in the journal of Neurotrauma by the Naval Medical Research Centers on Trauma brain injury animal model. This work was accomplished across a Cooperative Research and Development Agreement (CRADA) with the US Navy 10 . The use of HEMO2Life ® is also interesting due to its anti-oxidative effect preventing cytokine storm induced by the SARS-CoV-2. Indeed, HEMO2Life ® has a superoxide-dismutase activity that can address this problem and a recent Canadian study revealed an anti-IL6 action during lung transplantation 11 . The first reason to use HEMO 2 Life ® is because of its oxygen carrier properties with the main hypothesis that it can improve tissue oxygenation without modifying ventilation for COVID-19 patients. HEMO 2 Life ® is composed by an extracellular hemoglobin coming from the lugworm Arenicola marina. This extracellular hemoglobin has an oxygen capacity 40 times higher than the HbA of vertebrates. Furthermore, the size of this molecule is 250 times smaller than a human red blood cell, allowing it to diffuse in all areas of the microcirculation, without diffusing outside the vascular sector. This product has been the subject of numerous publications [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] . This worm is farmed in aquaculture in a very strict good manufacturer practice conditions under ISO-13485 regulation. This molecule is composed of 156 globin chains and 42 linker chains for a molecular weight of 3.6 MDa (Mega Dalton). The quaternary structure of this molecule is a hexagonalbilayer with a dimension of 25 nm (face view) and 15 nm (profil view) 13 . Each globin chain has a heme group similar to human and the linker chains possess an anti-oxidative property due to a Superoxide Dismutase Activity (SOD) activity-like based on copper and zinc 15 . Thus, HEMO 2 Life ® can carry up to 156 molecules of O2. Oxygen is released against a gradient in the absence of allosteric effectors, providing the environment with just the right amount of O2; is active across a wide range of temperature (from 4°C to 37°C) [25] [26] . We showed that this molecule does not have immunogenic effect, neither an allergenic effect. Its oxygen affinity is p 50 = 7.5 mm of Hg and a cooperativity of 2.5 14 and it does not need cofactor in order to release oxygen, these parameters are similar to the HbA inside the red blood cells 12 . O 2 releasing is just done in a partial oxygen gradient, when p O2 is below the p 50 , the oxygen is released passively to the tissues, and consumed by cells or tissues, avoiding oxidative damages. Two important points, the p 50 of the myoglobin is 2.6 mm of Hg, so below the p 50 of this oxygen carrier and even this molecule is high oxygen affinity the p 50 is similar of the hemoglobin A (HbA) inside the red blood cell 15 . HEMO2Life ® has a red color, it is sterile, is pyrogen-free and frozen at -20 ° C (+ / 3 ° C). HEMO 30 . If the hypothesis of an improvement in oxygen transport by transfusion has been put forward 31 , we did not find in our literature review any comparative study specifically looking at the role of treatment by increasing oxygen transport by blood transfusion in COVID-19 patients. Only a case report from the early days of the pandemic reports improved in a patient after a blood transfusion 32 . In July 2020, a Lancet study 33 stated that there is no data available to inform whether patients with SARS-CoV-2 infection, with substantial respiratory symptoms and oxygen dependency, might benefit from red blood cell transfusion to maintain a hemoglobin concentration above 70 g/L. Convalescence plasma is a treatment strategy that has been further studied. However, the results are disappointing with no reduction in the progression of the virus to a severe form 34, 35 . HEMO2Life ® is not contained in a cell nucleus and therefore, it will not be a target since the COVID-19 will not recognized this oxygen carrier not contained in red blood cells. In the paper of Liu Wenzhong et al 36 , it seems that the virus must hang on the red blood cell with more affinity of AB blood typing which will be not possible with an extracellular hemoglobin. Consequently, this molecule seems to be well adapted to deliver oxygen in order to avoid hypoxia responsible of dyspnea while avoiding being targeted by virus. Another reason to use HEMO2Life ® is related to its properties to reduce oxidative stress. Indeed, SarsCov2 has an action on Angiotensin Converting Enzyme (ACE) receptor 37, 38 . Tissue hypoxia, although it has been rarely evaluated in the literature, could represent an interesting complementary evaluation measure. Indeed, a recent study assesses the presence of sublingual microcirculatory and skin perfusion alterations in COVID-19 pneumonia and reveal that COVID-19 patients showed altered tissue perfusion 42 . Hypoxia of this component could be further evaluated using subcutaneous probes. Furthermore, in another Lancet study 15% of the patients will require essential care of critical illness or oxygen 43 . Red blood cells carry oxygen from the lungs to all organs and the rest of the body. Red blood cells can do this thanks to hemoglobin, a protein made up of four "hemes "44 . Hemes have a special type of iron ion, which is usually quite toxic in its free form, enclosed in its center with a porphyrin acting as its "container". In this way, the iron ion can be caged and transported safely by hemoglobin but used to bind oxygen when it reaches the lungs. When the red blood cells reach the alveoli where all gas exchange occurs, this small iron ion switches between the Fe 2+ to Fe 3+ states and binds to oxygen, then leaves to deliver the O 2 elsewhere. Once the body has gotten out of control, with all the oxygen carriers circulating in a vacuum and tons of the toxic form of iron floating in the bloodstream 45, 46 , other defenses are triggered. While the lungs are occupied with all of this oxidative stress that they cannot handle, the organs are starving for O 2 and the liver is trying its best to remove and store iron 47 . However, this organ is overwhelmed and starving for oxygen too and releases an enzyme called alanine aminotransferase (ALT). The patient's immune system does not fight the virus in time before its oxygen saturation in the blood drops too low, ventilator or not, the organs start to stop. The only way to try to keep them alive is the maximum amount of oxygen, and perhaps the best would be with a hyperbaric chamber 48 , if available, with 100% oxygen at several atmospheres of pressure, just to give functional hemoglobin a chance to transport enough oxygen to the organs and keep them alive. There is not enough hyperbaric chamber and it is currently estimated that more than 1,350 hospitals in the US offer Hyperbaric Oxygen Therapy (HBOT) services and Medicare covers HBOT for more than a dozen conditions 49 . Furthermore, HBOT could create oxidative damages since O2 needs to be delivered to the patients in a physiological way, not the case with HBOT at the opposite of HEMO2Life ® . Otherwise, HEMO2Life ® may be important in addressing the microthrombosis phenomena CoV-2. This hypothesis is also supported by the fact that we have shown in a rat model affected with traumatic brain injury 10 and therefore highly susceptible to intravascular microthrombosis 60 that our oxygen carrier could rapidly reduce acute brain hypoxia tissue, by overcoming classic, post-traumatic vascular size reduction without inducing vasoconstriction itself. Indeed, HEMO2Life ® does not have a vasoconstriction effect compared to with other HBOC of first or second generation developed so far 15, 19 . Finally, the hypothesis that the COVID-19 could remove the heme on β-globin chain and removed its iron has been put forward 36 at least on red blood cell progenitors with the nucleus. If this hypothesis proves to be correct, the use of HEMO2Life ® will find here an additional reason for its usefulness in the treatment of COVID-19 hypoxemia. However, this potential inactivation of the Hemoglobin by fixation of SarsCov2 on hemoglobin has been called into question by a recent study. It tends to disprove the plausibility of this last, theoretical hypothesis 61 . The biocompatibility of HEMO 2 Life ® has been verified experimentally. The preclinical studies were selected according to International Organization for Standardization SO 10993 (Biological evaluation of medical devices, part 1), using a biological risk assessment methodology and considering the intended use of the product. The following evaluations were performed: cytotoxicity, inflammation by cytokines, platelet interaction, the effect on the complement, skin irritation, delayed hypersensitization, systemic toxicity, genotoxicity, biodegradation in human plasma, immunotoxicity and pyrogenicity. All these studies have demonstrated the safety of HEMO 2 Life ® . HEMO 2 Life ® was found to be well tolerated and did not induce toxicity. It is non-pyrogenic and devoid of mutagenic effects, is not cytotoxic and is not irritant 14 . When administered intravenously to hamsters and rats by Pr. Intagliatta group in San Diego, a well-known group specialist on Hemoxygen-Based Oxygen Carriers (HBOC), HEMO 2 Life ® showed no acute effect on heart rate and blood pressure and did not cause microvascular vasoconstriction 14 . In another study 12 , fluorescently labeled HEMO 2 Life ® was administered to mice (60mg/kg, 600mg/kg, 1200 mg / kg) and was found to be safe, the animals showed no abnormal clinical signs and a half-life of 2.5 days was found. In these preclinical in vivo models, HEMO 2 Life ® has enabled better tissue oxygenation, especially in the brain (direct tissue measurements) 10 . Extracellular hemoglobin HEMO 2 Life ® was evaluated in humans' kidney transplantation in the OXYOP study (NCT02652520) 9 . Given its oxygen carrier property and its oxidative stress reduction action, we suggest adding HEMO 2 Life ® (i.e. M101) to the current treatment protocols of COVID-19 as it might be effective in tackling hypoxia and oxidative stress due to SARS-CoV-2. From our previous studies, we evaluate that the intake of 5 g of HEMO 2 Life ® for a subject of 70 kg (70 mg / kg) whose blood volume is estimated at 5 liters represents an increase in arterial O2 content of 1 mL of O2 per 100 mL of blood (or 5% of "physiological" oxygen content of arterial blood (CaO2) or 7% if Partial pressure of oxygen (PAO2) is at 80 mmHg). The administration will start with a 10 mg "test dose" to check for an anaphylactic reaction. Then, each 20 mL (1 g) vial will be administered intravenously using an electric syringe (20 mL in 10 min). A tolerance assessment will be performed after administering of each 20 mL vial, checking for skin rash, bronchospasm, hypotension or sudden tachycardia for the next 5 minutes before proceeding to the next vial. 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