key: cord-317383-uqg0xwdw authors: Weiskopf, Richard B.; Glassberg, Elon; Guinn, Nicole; James, Michael F.M.; Ness, Paul M.; Pusateri, Anthony E. title: The Need for an Artificial Oxygen Carrier for Disasters and Pandemics, Including COVID‐19 date: 2020-09-26 journal: Transfusion DOI: 10.1111/trf.16122 sha: doc_id: 317383 cord_uid: uqg0xwdw nan Transfusion of red cells has saved countless lives owing to (a) the ability to perform far more extensive surgery; (b) treatment of acute hemorrhagic anemia, both civilian and military; and (c) treatment of illnesses of red cell destruction or impaired (including, but not limited to chemotherapy-induced suppression of hemopoiesis) production. There are extensive, largely efficient, blood collection and banking systems in developed countries that ordinarily provide stored red cells (at 2-6 C) for these functions, despite relatively brief periods of local or national shortages. Blood banking systems require operational collection and processing facilities, sufficient number of healthy donors with access to a blood collection center, together with functional blood processing and transportation systems to provide the needed products in appropriate quantities. Depending on the circumstances, any or all of these are likely to be severely degraded or completely non-operational in some civilian mass casualty events or on a military battlefield. These systems are also stressed at times of pathogen dissemination, owing to a decreased availability of healthy, acceptable donors, and healthy, non-infected health care personnel. For example, considering only the donation issue, with the onset of the current coronavirus pandemic the American Red Cross "faced a severe blood shortage" 1 with the cancelation of thousands of blood drives, and a "precipitous decrease" in blood donations in Seattle was reported. 2 Earlier viral epidemics noted a 21% donation decrease in a prefecture in Japan, 3 and a greater than 90% decrease in Beijing; 4 furthermore, COVID-19 has been detected in asymptomatic donors whose donations had entered the blood supply in China. 5 Nevertheless, the U.S. blood banking community points to their past capability in domestic cases of mass casualty, such as the Twin Towers destruction on 9/11, focusing on blood supply and donations [6] [7] [8] and that the above functions remained preserved throughout the 9/11 crisis, but has paid far less attention the isolated nature of this disaster 9 . Only 224 units of packed red blood cells (PRBCs) were required to satisfy the needs 6, 7 Accepted Article (less than 300 units were needed for other U.S. disasters 10, 11 ) a . In addition, the conditions are expected to be very different for other disasters (such as detonation of a thermonuclear device [12] [13] [14] , when the number of injuries will be far greater and capabilities for donation, testing, and transportation will be degraded. While there have not been reports of an overwhelming strain on the blood supply following a nuclear event such as that at Chernobyl, b a nuclear detonation would be expected to result in a far larger mass casualty (including combined injuries) surge situation. 14 It has been estimated that a 10 kiloton nuclear detonation in a major city could require hundreds of thousands of units of plasma, and presumably a commensurate need for red cells. [19] [20] [21] The financial 22 and logistic 4 stresses on civilian blood collection and processing facilities add to the problem. c Early on in the COVID-19 pandemic, volunteer blood donations at fixed sites and reduced demand with the cancellation of elective procedures enabled the blood supply to be successfully maintained in its early phases, but the effect on the blood supply if the pandemic intensifies or become more chronic could be problematic. Paradoxically, at least in the early phases of COVID-19, societal lockdown may have unexpected results. In South Africa there was a marked initial decrease in trauma admissions and a reduced demand for blood. However, this does not rule out a later upsurge in blood demand coupled with a delayed lack of availability through inadequate donation and reduced transfusion service staffing. When elective surgery was restored at some institutions in the U.S., shortages did occur as some blood banks/ centers were not prepared for the sudden demand increase and collection difficulties caused by new rules. Due to their unique operational challenges, a The Las Vegas shooting injuries, perpetrated by only a single person, required 278 rbc units transfused, 67% in the first 24 hours, met by fully stocked in-hospital and local blood centers supplies. 11 b The nuclear disaster at Chernobyl [15] [16] [17] [18] was an operator-and design caused steam explosion followed by a fire and a nine-to-ten day release of a substantial quantity of radioactive material with resultant many long-term medical issues including bone marrow suppression, but with relatively lesser immediate transfusion need, with two deaths in the first 5 hours, and apparently 31 in the first three days, predominantly from burns. c An HHS-commissioned RAND study 23 concluded that disruption of the U.S. blood supply was unlikely, but, as pointed out by Klein et al. 22 that was shown to be off the mark when the system could not function properly during the Zika virus outbreak without a major financial infusion by the U.S. government. military organizations appear to be far more cognizant of these challenges than are their civilian counterparts. Nevertheless, these systems are unprepared to fulfil the needs should the systems become severely degraded, as has been recognized in coordinated US Government multi-agency (NIH, FDA, BARDA, DoD) efforts to develop alternative products as countermeasures in these scenarios. 14 Limited shelf-life and cold-chain constraints make the systems dependent on continuous donor availability and uninterrupted laboratory operations. Blood collection, processing, and distribution is highly regulated. There are no products approved in the U.S. and most other countries that provide the primary physiologic functions of plasma or red cells that do not require continuous cold storage and a multitude of regulatory constraints and checks. However, there are products approved in some countries that fulfil these functions, have a prolonged shelf-life at 22C, and do not require recipient blood typing and cross-matching. Dried plasma is produced in Germany, France, and South Africa, with limited availability of these products outside these countries; a hemoglobin-based oxygen carrier (HBOC) is approved for use in South Africa and Russia. The need and rationale for a dried plasma has been published recently. 24 Here, we address the need and rationale for a non-red cell oxygen carrier. The quest for an efficacious non-red cell oxygen carrier is many decades old. [25] [26] [27] Research and development intensified when it became apparent that hepatitis C [28] [29] [30] and HIV 31 could be transmitted by transfusion, with the intent that an artificial oxygen carrier could replace RBC transfusion. However, donor screening and testing has reduced greatly the risk of transmission of these pathogens. 32 That coupled with the perception of a slightly increased risk of infusion of an HBOC in comparison to red cell transfusion, 33, 34 resulted in a substantial decrease of research and development and in the number of companies in this field despite the latter meta-analysis having been widely criticized. [35] [36] [37] [38] [39] [40] Subsequently, attention has turned to an alternative potential purpose for the use of such biologics, viz when RBC transfusion is not an option. For this indication, the appropriate comparator for the evaluation of product safety is untransfused severe This article is protected by copyright. All rights reserved. 44 The data for the HBOC administration for "all-comer" hospitalized patients are less robust and come from "expanded access" use. 53 This article is protected by copyright. All rights reserved. in untransfused anemic patients that myocardial infarction, as defined by troponin elevation, increased with decreasing nadir Hb below 8 g/dL, with an overall rate of 10.5%. 57 The HBOC orthopedic trial 52 did not analyze the adverse event data according to nadir native Hb, e and the data provided by clinicians who treated patients with HBOC in the expanded access program is inadequate for analysis. 58 The recent report of Guinn et al. has added an additional important novel piece of information to our knowledge of the mortality associated with severe anemia: the time to death as a function of Hb. 55 The analyses above have documented well that for Hb concentrations less than 8 g/dL, decreasing Hb is associated with increased mortality. However, those analyses do not provide information regarding the window for therapy, should any be available. Guinn et al. found that decreasing Hb was not only associated with increased mortality, but also with decreased time to death. With nadir Hb  5 g/dL median time to death from that Hb value was 2 days; at nadir Hb 5-8 g/dL, median time to death was 4-6 days. 55 These times are likely maximal for the period available for therapy, should any be available, as it is probable that the anemia-induced damage became irreversible with death inevitable some time prior to death. The above analyses and considerations regarding efficacy and safety of use of the HBOC for severe anemia when RBC transfusion is not an option (mortality is the ultimate expression of a severe adverse event) is supported by real-world experience emanating from South Africa, where Hemopure® is approved by the national regulatory authority for use in severe anemia when blood transfusion is not an option. Levien reviewed the hemovigilance program of 336 patients who received Hemopure for acute surgical anemia owing to when blood was not an option, when blood avoidance was medically desirable, or physician or patient e There was a greater SAE rate in the HBOC group compared with PRBCs, with most attributed to fluid overload or undertreatment. preference, finding no pattern of significant adverse events attributable to the HBOC. 59 No deaths were attributable to the HBOC. 59 oxidation. 65 When infused into patients with proven clinically significant myocardial vascular disease, Hemopure® appears not to be harmful, but rather protective. 66, 67 A small incomplete safety trial in hemorrhagic shock in trauma, in South Africa, found no mortality difference between those randomized to receive Hemopure (4/10) and those treated with standard of care (5/9; P>0.99), but a 40% lesser need for crystalloid (11.5 L / patient v 19.3 L/ patient, respectively; P<0.0001). f The large crystalloid volume difference is of substantial importance, as increased crystalloid administration in trauma is associated with increased mortality. 69 The data presented and discussed suggest that HBOCs could fill the critical underdosing, and volume overloading as may occur with the administration of any intravenous fluid, including rbcs or plasma. Nevertheless, our assessment is that for the described potential use, when red cell transfusion is not an option, the benefit:risk profile for the treatment of severe anemia by administration of the HBOC discussed is favorable, in comparison to that of untreated severe anemia. In conclusion, there are international needs for ensuring the large-scale availability of an artificial oxygen carrier for use when the civilian or military blood collection, processing, or delivery systems are degraded. The COVID-19 pandemic has shown how vulnerable health care systems are to major disasters in the absence of proper preparation. Freeze-dried plasma is approved in some countries, but HBOCs are approved only in two: South Africa and Russia. There are products (FDP and HBOC) not approved in most countries that can be so positioned now, for such emergency purposes. It is our opinion that the evidence supports that the relatively small risk of doing so with these products even where unapproved, for emergency use, greatly outweighs the risk of untreated severe anemia or decrease in coagulation factors. Key Message • World-wide blood collection and processing facilities and systems are illprepared to provide adequate amounts of red blood cells when transfusion is not an option, such as for major disasters: civilian mass casualty, pandemics, and extensive military operations. • At least one hemoglobin-based oxygen carrier under such circumstances has a favorable benefit-risk profile, and several year shelf-life at 22C, and should be considered for advance deployment to meet the needs in the above circumstances. 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Rationale, protocol design and haemodynamic results Haemodynamic effects, safety, and tolerability of haemoglobin-based oxygen carrier-201 in patients undergoing PCI for CAD Briefing Book for the 14 Crystalloid resuscitation in trauma patients: deleterious effect of 5L or more in the first 24h. BMC Surg 2018whom blood transfusion was not an option. This relationship from the New Zealand database 44,51 () and from Duke University All whom blood transfusion was not an option, comparing all hospitalized patients in the databases of Beliaev et al. 51 plus Guinn et al. 55 () with patients treated with an HBOC, Hemopure®, in an expanded access program All authors participated in the writing of this manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. No others contributed to the writing in any manner.No medical writers or editors have been involved in any way. RBW produced the figures. Nobody other than the authors have influenced the writing of this manuscript.No funding or compensation of any kind (including from NIH, Wellcome Trust, or HHMI) was received by any of the authors for this manuscript.The corresponding author confirms that he has had full access to all data and has had final responsibility for the decision to submit this manuscript for publication. This manuscript has not been published elsewhere. R.B. Weiskopf has consulted for sponsors of hemoglobin-based oxygen carriers in the past, but has not received any compensation from these entities in the past 3 years.M.F.M. James has consulted with sponsors of hemoglobin-based oxygen carriers in the past but has received no financial compensation for these activities at any time.P. Ness has consulted for sponsors of hemoglobin-based oxygen carriers in the past, but has not received any compensation from these entities in the past 3 years. E. Glassberg, N. Guinn, and A.E. Pusateri report no competing interests. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.