The effect of SANGUINATE^® (PEGylated carboxyhemoglobin bovine) on cardiopulmonary bypass functionality using a bovine whole blood model of normovolemic hemodilution

Abstract

Background: Cardiac surgery using cardiopulmonary bypass carries a high risk of bleeding and need for blood transfusion. Blood administration is associated with increased rates of morbidity and mortality. Perioperatively, strategies are often employed to reduce blood transfusions in high-risk patients or in situations where blood transfusion is contraindicated. Normovolemic hemodilution is a blood conservation technique used during cardiac surgery that involves replacement of blood with fluids. SANGUINATE® (PEGylated carboxyhemoglobin bovine) is a novel hemoglobin-based oxygen carrier that can deliver oxygen effectively to tissues in the presence of severe hypoxia. The use of a hemoglobin-based oxygen carrier during hemodilution may augment tissue oxygen delivery and reduce blood transfusion. Methods: Six standardized cardiopulmonary bypass runs simulating normovolemic hemodilution using varying proportions of bovine whole blood and SANGUINATE were performed. Pump speed, flow rate, line pressures, hemoglobin concentration, oxygenation, and degree of anticoagulation were assessed at regular intervals. Membrane oxygenators and arterial line filters were inspected for evidence of clotting following each run. Results: Increases in the pressure drop across the membrane oxygenator were detected during runs 5 and 6. Median activated clotting time values were able to be maintained at goal during the runs, and SANGUINATE did not appear to be thrombogenic. Hemoglobin concentration decreased following the addition of SANGUINATE. Oxygenation was maintained during all runs that included SANGUINATE. Conclusion: SANGUINATE does not impact the performance of the cardiopulmonary bypass circuit in a bovine whole blood model. The results support further evaluation of SANGUINATE in the setting of normovolemic hemodilution and cardiopulmonary bypass.

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“…Once it enters into the circulation, it binds to the Heme group of hemoglobin, displacing the oxygen and forming a hematic complex called carboxyhemoglobin, which hinders oxygen transport to cells and tissues, causing generalized cellular hypoxia. Hypoxia is known to affect cells with higher oxygen demand, particularly myocytes and neurons, which might have been linked to a higher risk of cardiovascular and neurodegenerative diseases [56,57]. Recently, novel epigenetic signatures were identified to be associated with the uptake of carbon monoxide (DLCO) per alveolar volume (VA) (DLCO/VA), using the single-breath technique in 2674 individuals.…”

Role of Carbon Monoxide in Host–Gut Microbiome Communication

“…130−132 Along the same line, Ford, 133 Mascharack, 134 Schmalz, 135 Schatzschneider, 136 Ramao, 137 Matson and Stupp, 138,139 Schiller, 140 and many others have developed CORMs using metals such as ruthenium, iron, molybdenum, and manganese 14 including enzyme-controlled 135,141 and encapsulated metal-based CORMs, 138,142−146 and CO immobilized on modified hemoglobin. 147,148 Motterlini and colleagues also published CORMs conjugated with an additional agent that induces HMOX1 expression to create synergy. 149,150 Similarly, photo- sensitive organic CORMs 151−156 and a CO oral formulation 157 have been reported.…”

“…Later, the further development of carbonyl-metal complex chemistry laid a strong foundation for the development of such complexes for the exploitation of their pharmacological functions. Motterlini and Mann were the first to examine carbonyl-metal complexes for their pharmacological actions and coined the term CO releasing molecules (CORMs). − Along the same line, Ford, Mascharack, Schmalz, Schatzschneider, Ramao, Matson and Stupp, , Schiller, and many others have developed CORMs using metals such as ruthenium, iron, molybdenum, and manganese including enzyme-controlled , and encapsulated metal-based CORMs, ,− and CO immobilized on modified hemoglobin. , Motterlini and colleagues also published CORMs conjugated with an additional agent that induces HMOX1 expression to create synergy. , Similarly, photosensitive organic CORMs − and a CO oral formulation have been reported. Recently, metal-free organic CO prodrugs ,,, capable of releasing CO under physiological conditions without the need for light activation have been reported.…”

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

“…Glutaraldehyde-polymerized bovine hemoglobin (HBOC-201, BioPure company), was approved for the treatment of acute pernicious anemia in South Africa and Russia in 2001 and 2010, respectively [ 46 , 47 ]. PEGylated carboxyhemoglobin bovine (Sanguinate, Prolong Pharmaceuticals, USA), was registered in 2015 under the FDA classification as an “orphan drug” for the treatment of sickle cell anemia; it is currently in phase III clinical trials [ 48 ]. Despite these advancement, HBOCs development is also complicated by issues such as vasoactivity caused by nitric oxide (NO) scavenging [ 49 ], nephrotoxicity from dissociated dimers [ 50 ], oxidative toxicity of hemoglobin [ 51 ], and short circulation time [ 52 ], resulting in many HBOCs varieties being discontinued or excluded from further research due to safety concerns.…”