Patent Description:
This invention was made with the United States government support under R44HL132172 awarded by the National Heart, Lung, and Blood Institute. The government has certain rights in the invention.

The present disclosure relates to oxygen reduced stored blood for use in the treatment of trauma and hemorrhagic shock.

In <NUM>, there were <NUM> million deaths from injuries, surpassing the number of deaths due to HIV, tuberculosis, and malaria combined (<NUM> million). See <NPL>) ("Norton <NUM>"). Injuries include unintentional injuries (e.g., road-traffic incidents, falls, and bums) and intentional injuries (e.g., self-harm, interpersonal violence, war and conflict). See Norton <NUM>. The number of deaths from injuries increased by <NUM>% between <NUM> and <NUM>, worldwide, and increased <NUM>% between <NUM> and <NUM>, in the United States. See Norton <NUM>. Additionally, at least <NUM>% of all trauma deaths are the result of survivable injuries and are therefore preventable with optimal care. <NPL>)The percentage of preventable deaths make it imperative to develop therapy for avoidable complications which lead to mortality.

Penetrating wounds (e.g., gunshot or stabbing) and blunt trauma (e.g., fall or automobile accident) are major causes of hemorrhagic trauma. The resulting shock is a condition of inadequate oxygen supply to tissues from massive hemorrhage causing oxygen debt, anaerobic metabolism and raise of plasma lactate level. Failure to reverse shock by restoring circulation and oxygen delivery can result in permanent tissue damage, multiple organ failure and mortality.

Clinical sequelae of hemorrhagic trauma and shock include mortality from exsanguination within several hours of trauma, as well as after <NUM> hours from morbidity from trauma and massive transfusion. Such morbidity includes multiple organ failure including lung, kidney, liver from acute traumatic coagulopathy or inflammation, and infection/sepsis from transfusion related immune modulation; both morbidities are heightened by lower quality of transfused blood products as well as higher volume of transfused pRBC.

One approach for treating hemorrhage shock is the use of crystalloids for resuscitation. However, the use of crystalloids result in increased morbidity and mortality by causing trauma induced coagulopathy. For at least this reason, early administration of blood components is advocated for reversing shock caused by hemorrhagic trauma. Packed red blood cells (pRBCs) are transfused into a hemorrhagic trauma patient to restore lost blood volume, restore oxygen carrying capacity in patients and restore oxidative metabolism in tissue from anaerobic metabolism. However, the use of pRBCs is not without risk of complications, including antigen mismatch, pathogen transmission, circulatory overload, and degradation of pRBCs during ex vivo storage.

When stored conventionally, stored blood undergoes a steady deterioration which is associated with various storage lesions including, among others, hemolysis, hemoglobin degradation, and reduced ATP and <NUM>,<NUM>-DPG concentrations. When transfused into a patient, the effects of the steady deterioration during storage manifest, for example, as a reduction in the <NUM>-hour in vivo recovery. The rapid decrease in the hematocrit that results from reduced <NUM>-hour recovery, when severe, can result in delayed hemolytic transfusion reaction (DHTR). Other complications, for example systemic inflammatory response syndrome (SIRS), transfusion related acute lung injury (TRALI), and transfusion related immunomodulation (TRIM) are associated with transfusion of stored blood, though identification of the underlying causes has remained unclear.

Even when transfused within the current <NUM>-week limit, stored RBCs tend to exhibit lower quality (e.g. increased fraction of RBCs removed; compromised oxygen exchange capacity; reduced deformability) and increased toxicity, often manifested as the clinical sequelae of transfusion therapy. A large and growing number of articles in the literature supports this view. See <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>). An extensive body of in vitro studies unequivocally shows the degradation of RBCs (storage lesions) during conventional storage. A body of emerging metabolomic studies show the development of storage lesions at the molecular level. See <NPL>); <NPL>);<NPL>); <NPL>); <NPL>); <NPL>); <NPL>). There is a need for reducing or preventing this degradation to increase the efficacy of transfusions (more O<NUM> delivery to peripheral tissues immediately after transfusion) and to reduce mortality due to hemorrhagic trauma.

Oxidative damage initiates many RBC storage lesions in conventionally stored blood and their downstream consequences; thus, methods to reduce the extent of oxidative stress are required to reduce the RBC storage lesions. A number of approaches have been developed aimed at minimizing storage lesions and improving transfusion outcomes. Approaches include additive solutions (for example, <CIT> and <CIT> <CIT>), frozen storage (see <CIT>, "<NPL>), and <NPL>)).

One approach that has proven successful in improving blood quality and extending its utility is through the depletion of oxygen and storage under anaerobic conditions. Among the benefits of storing blood under oxygen depleted conditions are improved levels of ATP and <NUM>,<NUM>-DPG, and reduced hemolysis. , and <CIT>are directed to the storage of red blood cells under oxygen-depleted conditions. <CIT> is directed to blood storage additive solutions. (the '<NUM> patent) discloses anaerobic storage bags for blood storage that comprise an oxygen impermeable outer layer, a red blood cell (RBCs) compatible inner layer that is permeable to oxygen, and having an oxygen scrubber placed between the inner and outer layers.

Storing blood under oxygen depleted conditions can also result in reduced microparticle levels, reductions in the loss of deformability, reduced lipid and protein oxidation and higher post transfusion survival when compared to blood stored under conventional conditions. See <NPL>) and <NPL>). Anaerobically stored RBCs further provide higher <NUM>-hour in vivo recovery after autologous transfusion, higher <NUM>,<NUM>-DPG and ATP levels, lower hemolysis, and beneficial remodeling of metabolic pathway. See<NPL>); and <NPL>).

In the present disclosure, we demonstrate that oxygen reduced (OR) or oxygen and carbon dioxide reduced (OCR) blood from rats provides improved ATP and <NUM>,<NUM>-DPG during storage compared to conventionally stored blood, as has been previously demonstrated using human blood. Thus, OR or OCR rat RBCs are expected to have similar reductions in microparticles, improved deformability, reduced lipid and protein oxidation and higher post transfusion survival.

Here we demonstrate for the first time that OR and OCR blood in rats provides for surprising improvements in clinical outcomes when transfused to treat hemorrhagic trauma. Using a rat hemorrhagic shock resuscitation model, we show that OR or OCR RBCs provide for reduced organ damage relative to conventionally stored blood. In addition, OR or OCR RBCs provide for reversal of the shock state using smaller pRBC volumes. Finally, OR or OCR RBCs, when transfused to treat hemorrhagic shock more rapidly stabilized hemodynamics compared to conventionally stored pRBC of same storage duration.

OR and OCR RBCs provide for improved methods for treatment of trauma resulting in exsanguination to reduce mortality and morbidity over conventionally stored blood. OR and OCR RBCs provide for reduced organ failure, including reductions in levels of markers of lung and liver damage. OR and OCR RBCs further provide reductions in the amounts of blood necessary to restore and stabilize hemodynamic function. Thus, OR and OCR RBCs can provide for reducing the volume of RBCs required for transfusion therapy when treating hemorrhagic trauma. The improved quality of OR and OCR, in addition to the previously demonstrated improvements to the ability of stored RBCs to deliver oxygen, also provides for unexpected reductions in organ damage, morbidity, and mortality associated with trauma. <CIT> describes methods for the storage of whole blood, and compositions thereof. <CIT> describes a system for extended storage of red blood cells and methods of use. <CIT> describes hemoglobin compositions. <CIT> describes the treatment of trauma hemorrhage with short oligopeptides. <NPL> describes red blood cell storage time and transfusion: current practice, concerns and future perspectives.

Aspects of the invention for which protection is sought are as defined in the appended set of claims. The description may contain additional technical information, which although not part of the claimed invention, is provided to place the invention in a broader technical context and to illustrate possible related technical developments. References herein to methods of treatment of the human or animal body are to be understood as references to medicaments for use in a method of treatment.

The invention provides Oxygen reduced stored blood for use in a method of treating hemorrhagic trauma in a patient in need thereof, wherein the oxygen reduced stored blood comprises an initial oxygen saturation of <NUM>% or less and is maintained at an oxygen saturation of <NUM>% or less for a storage period, wherein the hemorrhagic trauma patient in need thereof is in hemorrhagic shock prior to administration of the oxygen reduced stored blood, and wherein the hemorrhagic shock is reversed after administration of the oxygen reduced stored blood, wherein the method comprises transfusion therapy.

A volume of oxygen reduced stored blood required for transfusion therapy when treating the hemorrhagic trauma patient in need thereof may be at least <NUM>% less than a volume of non-oxygen reduced conventionally stored blood required for transfusion therapy when treating a hemorrhagic trauma patient in hemorrhagic shock. The volume of oxygen reduced stored blood required for transfusion therapy when treating the hemorrhagic trauma patient in need thereof may be at least <NUM>% less than a volume of non-oxygen reduced conventionally stored blood required for transfusion therapy when treating a hemorrhagic trauma patient in hemorrhagic shock. A hemodynamic function of the hemorrhagic trauma patient may be restored or stabilized after the administration. The hemorrhagic trauma patient in need thereof may have an elevated lactate level prior to the administration, and wherein the elevated lactate level may be reduced to between <NUM> and <NUM> millimoles per liter (mmol/L) after the administration. The hemorrhagic trauma patient in need thereof may have an elevated blood glucose level prior to the administration, and wherein the elevated blood glucose level may be reduced to between <NUM> and <NUM> milligrams per deciliter (mg/dL) after the administration. A level of an liver enzyme that indicates liver damage or injury in the hemorrhagic trauma patient in need thereof may be between <NUM>-fold and <NUM>-fold lower after the administration than in a hemorrhagic trauma patient administered non-oxygen reduced conventionally stored blood, wherein the liver enzyme may be aspartate aminotransferase (AST) or alanine aminotransferase (ALT). The hemorrhagic trauma patient in need thereof may have an elevated level of a marker of kidney function prior to the administration, wherein the marker of kidney function may be selected from the group consisting of urine neutrophil gelatinase-associated lipocalin (u-NGAL), serum creatinine, and blood urea nitrogen (BUN), and wherein the elevated level of a marker of kidney function may be reduced after the administration. A level of an inflammatory factor selected from the group consisting of CXC motif chemokine ligand <NUM> (CXCL1), interleukin-<NUM> (IL-<NUM>), and CD45+ neutrophils in the hemorrhagic trauma patient in need thereof may be reduced after the administration. The hemorrhagic trauma patient in need thereof may have a pre-existing or underlying condition selected from the group consisting of diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, chronic pulmonary obstructive disease, a coagulopathy disorder, and an autoimmune disease. The hemorrhagic trauma patient in need thereof may be a blunt force trauma patient. The hemorrhagic trauma patient in need thereof may have a low mean arterial pressure prior to the administration. The oxygen reduced stored blood may be oxygen reduced stored whole blood, oxygen reduced leukoreduced stored red blood cells (RBCs), oxygen reduced platelet reduced stored RBCs, or oxygen reduced leukoreduced and platelet reduced stored RBCs. The storage period may be up to <NUM> days. The hemorrhagic trauma patient in need thereof may be in need of two or more units of blood as transfusion therapy.

The present disclosure is provided with reference to the accompanying drawings, wherein:.

Methods of the present disclosure provide for, and include, providing a hemorrhagic trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. Methods also provide for providing a hemorrhagic trauma patient with oxygen reduced stored blood that has an oxygen saturation of between <NUM> and <NUM>% prior to and during storage. Methods also provide for providing a hemorrhagic trauma patient with oxygen reduced stored blood that has an oxygen saturation of between <NUM> and <NUM>% prior to and during storage. Methods also provide for providing a hemorrhagic trauma patient with oxygen reduced stored blood that has an oxygen saturation of between <NUM> and <NUM>% prior to and during storage. Methods also provide for providing a hemorrhagic trauma patient with oxygen reduced stored blood that has an oxygen saturation of between <NUM> and <NUM>% prior to and during storage.

Methods also provide for providing oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage for transfusion to a person having hemorrhagic shock. Methods also provide for providing oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage for transfusion to a person having hemorrhagic trauma. Also included are methods comprising transfusing oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage to a patient having an increased risk of trauma due to surgery. Methods providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less include providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less. Methods of providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less. Methods of providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less.

Methods of the present disclosure provide for, and include, providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of <NUM>% or less prior to and during storage for a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of <NUM>% or less after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of <NUM>% or less after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods further provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of <NUM>% or less after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods further provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of <NUM>% or less after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of between <NUM> and <NUM>% after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of between <NUM> and <NUM>% after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of between <NUM> and <NUM>% after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks. Methods also provide for providing oxygen reduced stored blood for the treatment of trauma having an oxygen saturation of between <NUM> and <NUM>% after a storage period of at least one week, at least two weeks, at least <NUM> weeks, at least <NUM> weeks, at least <NUM> weeks, or at least <NUM> weeks.

Methods of the present disclosure provide for, and include, providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, a trauma patient suffers from a head trauma, a penetrating wound, blunt force trauma, injury due to a fall, or injury due to a car accident. In another aspect, a trauma patient is a hemorrhagic trauma patient. In yet another aspect, a trauma patient is hemorrhagic due to surgery, a penetrating wound, blunt force trauma, an injury due to a fall, or an injury due to a car accident.

In an aspect of the present disclosure, a trauma patient or hemorrhagic trauma patient is a subject in need of OR and OCR stored blood. In aspects of the present disclosure, a trauma patient is a hemorrhagic trauma patient in need of one or more units of blood as transfusion therapy. In aspects of the present disclosure, a trauma patient is a hemorrhagic trauma patient in need of two or more units of blood as transfusion therapy. In aspects of the present disclosure, a trauma patient is a hemorrhagic trauma patient in need of three or more units of blood as transfusion therapy.

In an aspect of the present disclosure, a trauma patient is a patient in hemorrhagic shock. In an aspect, a trauma patient is in hemorrhagic shock due to a head trauma, a penetrating wound, blunt force trauma, injury from a fall, or injury from a car accident. In aspects of the present disclosure, a hemorrhagic trauma patient is a patient with a class I hemorrhage. In another aspect, a hemorrhagic trauma patient is a patient with a class II hemorrhage. In another aspect, a hemorrhagic trauma patient is a patient with a class III hemorrhage. In another aspect, a hemorrhagic trauma patient is a patient with a class IV hemorrhage. In an aspect of the present disclosure, a hemorrhagic trauma patient loses up to <NUM>% of blood volume. In another aspect, a hemorrhagic trauma patient loses between <NUM> and <NUM>% of blood volume. In another aspect, a hemorrhagic trauma patient loses between <NUM> and <NUM>% of blood volume. In a further, a hemorrhagic trauma patient loses greater than <NUM>% of blood volume.

The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits one or more signs selected from the group consisting of decreased mean arterial pressure, a decreased hematocrit, increased lactate, increased glucose, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased urine neutrophil gelatinase-associated lipocalin (u-NGAL), increased serum creatinine, and increased blood urea nitrogen. In an aspect of the present disclosure, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having a decreased mean arterial pressure. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits increased aspartate aminotransferase (AST) and increased alanine aminotransferase (ALT). The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits decreased mean arterial pressure and increased lactate. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), and increased blood urea nitrogen. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased serum creatinine, and increased blood urea nitrogen. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits increased lactate and increased glucose. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibiting increased urine neutrophil gelatinase-associated lipocalin (u-NGAL), increased serum creatinine, and increased blood urea nitrogen.

In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having a decreased hematocrit. In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased lactate. In yet another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased glucose. In a further aspect, a hemorrhagic trauma patient having increased in aspartate aminotransferase (AST). In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased alanine aminotransferase (ALT). In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased urine neutrophil gelatinase-associated lipocalin (u-NGAL). In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased serum creatinine. In another aspect, a patient in need of transfusion therapy with OR or OCR RBCs is a hemorrhagic trauma patient having increased blood urea nitrogen.

In an aspect of the present disclosure, the OR and OCR stored blood for use in transfusion therapy of a trauma patient in need thereof has an initial oxygen saturation of <NUM>% or less. In another aspect, OR and OCR stored blood has an initial oxygen saturation of <NUM>% or less. In another aspect, OR and OCR stored blood has an initial oxygen saturation of <NUM>% or less. In another aspect, OR and OCR stored blood has an initial oxygen saturation of <NUM>% or less.

In an aspect of the present disclosure, the OCR stored blood for use in transfusion therapy of a trauma patient in need thereof has an initial pCO<NUM> (at <NUM>) of between <NUM> and <NUM> mmHg. In another aspect, OCR stored blood has an initial pCO<NUM> of between <NUM> and <NUM> mmHg. In another aspect, OCR stored blood has an initial pCO<NUM> of between <NUM> and <NUM> mmHg. In another aspect, OCR stored blood has an initial pCO<NUM> of between <NUM> and <NUM> mmHg. In yet another aspect, OCR stored blood has an initial pCO<NUM> of less than <NUM> mmHg.

In an aspect of the present disclosure, OR and OCR stored blood for use in transfusion therapy of a trauma patient in need thereof has an initial oxygen saturation of <NUM>% or less and is stored for less than <NUM> days. In an aspect, OR and OCR stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, OR and OCR stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, oxygen reduced stored blood for use in transfusion therapy of a trauma patient in need thereof has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of <NUM>% or less is stored for less than <NUM> days. In an aspect of the present disclosure, OR and OCR stored blood has an oxygen saturation of <NUM>% or less during storage.

Suitable blood for use methods according to the present disclosure for use in transfusion therapy of a trauma patient in need thereof comprise oxygen reduced stored blood having an anticoagulant. In an aspect of the present disclosure, oxygen reduced red blood cells is stored for up to <NUM> weeks to produce oxygen reduced stored blood. In another aspect, oxygen reduced stored blood usually further comprise an additive solution. Suitable additive solutions according to the present disclosure include AS-<NUM>, AS-<NUM> (Nutricel®), AS-<NUM>, SAGM, PAGG-SM, PAGG-GM, MAP, AS-<NUM>, ESOL-<NUM>, EAS61, OFAS1, OFAS3, and combinations thereof. In an aspect, the additive solution is added at the time of component separation. In an aspect, the additive solution is AS-<NUM>. In another aspect, the additive solution is AS-<NUM>. In other aspects, the additive solution is SAGM.

Methods of the present disclosure provide for, and include, increasing the mean arterial pressure (MAP) in a hemorrhagic trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the mean arterial pressure is increased by between <NUM> and <NUM>%. In another aspect, the mean arterial pressure is increased by between <NUM> and <NUM>%. In another aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased by between <NUM> and <NUM>%. In yet another aspect, the mean arterial pressure is increased by between <NUM> and <NUM>%. In a further aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased by between <NUM> and <NUM>%. In an aspect, the mean arterial pressure is increased by at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>% more than the mean arterial pressure of a patient transfused with conventionally stored blood.

In an aspect of the present disclosure, the mean arterial pressure is increased by at least <NUM> fold. In another aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased by at least <NUM> fold. In a further aspect, the mean arterial pressure is increased by between <NUM> and <NUM> fold. In an aspect of the present disclosure, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased by at least <NUM> mmHg, at least <NUM> mmHg, at least <NUM> mmHg, at least <NUM> mmHg, at least <NUM> mmHg, or at least <NUM> mmHg. In another aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased by between <NUM> and <NUM> mmHg. In a further aspect, the mean arterial pressure is increased by between <NUM> and <NUM> mmHg.

Methods of the present disclosure provide for, and include, increasing the mean arterial pressure in a trauma patient in need of transfusion therapy to between <NUM> and <NUM> mmHg comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to, and during storage. In another aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased to at least <NUM> mmHg. In another aspect, the mean arterial pressure of a trauma patient receiving transfusion therapy of OR or OCR blood is increased to at least 80mmHg. In yet another aspect, the mean arterial pressure is increased to at least <NUM> mmHg. In a further aspect, the mean arterial pressure is increased to at least <NUM> mmHg. In an aspect of the present disclosure, the mean arterial pressure in a subject in need thereof remains between <NUM> and <NUM> mmHg for at least <NUM> hour after transfusion. In another aspect, the mean arterial pressure remains between <NUM> and <NUM> mmHg for at least <NUM> hours after transfusion. In yet another aspect, the mean arterial pressure remains between <NUM> and <NUM> mmHg for at least <NUM> hours after transfusion. In another aspect, the mean arterial pressure remains between <NUM> and <NUM> mmHg for at least <NUM> hours after transfusion. In another aspect, the mean arterial pressure remains between <NUM> and <NUM> mmHg for at least <NUM> hours after transfusion.

Methods of the present disclosure provide for, and include, increasing the mean arterial pressure in a trauma patient in need of transfusion therapy at a rate faster than the mean arterial pressure of a patient transfused with conventionally stored blood comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the mean arterial pressure of a patient transfused with OR or OCR blood is restored to within normal physiologic parameters in half the time when compared to conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the amount of stored blood needed for transfusion in a hemorrhagic trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In yet another aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In a further aspect, the amount of OR stored blood needed for transfusion is between <NUM> and <NUM>% less than the amount of conventionally stored blood needed.

Methods of the present disclosure provide for, and include, reducing the amount of stored blood needed for transfusion in a hemorrhagic trauma patient in need of transfusion therapy by at least <NUM>% less comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In yet another aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion is at least <NUM>% less than the amount of conventionally stored blood needed. In a further aspect, the amount of OR stored blood needed for transfusion is between about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, about <NUM> and <NUM>%, or about <NUM> and <NUM>% less than the amount of conventionally stored blood needed. In another aspect, the amount of OR stored blood needed for transfusion in a trauma patient in need of transfusion therapy is between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% less than the amount of conventionally stored blood needed.

Lactate clearance is a biomarker for resuscitation from hemorrhagic shock. See <NPL>); <NPL>); and <NPL>) ("Zhang <NUM>"). The clinical value of lactate clearance is useful in predicting the outcome of patients with septic shock and critically ill patients without evident circulatory shock. Elevated lactate is an indicator of adverse clinical outcome, and its rapid clearance is universally associated with improved outcome in heterogeneous ICU or ED patient population. See Zhang <NUM>. Decreased lactate levels in animals resuscitated with OR-RBCs compared to conventionally RBCs support the notion that resuscitation with OR RBCs can significantly improve patients' clinical outcome. See <FIG> and <FIG>.

Methods of the present disclosure provide for, and include, reducing the lactate level in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced (OR) stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the lactate level is reduced by between <NUM> and <NUM>%. In an aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by between <NUM> and <NUM>%. In another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by between <NUM> and <NUM>%. In another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by between <NUM> and <NUM>%. In yet another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by between <NUM> and <NUM>%. In another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>%. In another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by at least <NUM>%. In another aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by at least <NUM>%. In a further aspect, transfusion with OR stored blood reduces the lactate level in a trauma patient in need of transfusion therapy by at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, or at least <NUM>%.

Methods of the present disclosure provide for, and include, reducing elevated lactate levels in a trauma patient in need of transfusion therapy to between about <NUM> and about <NUM> mmol/L comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between about <NUM> and about <NUM> mmol/L. In an aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between about <NUM> and about <NUM> mmol/L. In another aspect, the lactate level in a patient in need of transfusion therapy is reduced to between about <NUM> and about <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between about <NUM> and about <NUM> mmol/L. In yet another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than about <NUM> mmol/L. In a further aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than about <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than about <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than about <NUM> mmol/L. In yet another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between about <NUM> and about <NUM> mmol/L.

Methods of the present disclosure provide for, and include, reducing elevated lactate levels in a trauma patient in need of transfusion therapy to between <NUM> and <NUM> mmol/L comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the lactate level in a patient in need of transfusion therapy is reduced to between <NUM> and <NUM> mmol/L. In an aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between <NUM> and <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between <NUM> and <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between <NUM> and <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to between <NUM> and <NUM> mmol/L.

Methods of the present disclosure provide for, and include, reducing elevated lactate levels in a hemorrhagic trauma patient in need of transfusion therapy to less than <NUM> mmol/L comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than 3mmol/L. In yet another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than <NUM> mmol/L. In another aspect, the lactate level in a patient is reduced to less than <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than <NUM> mmol/L. In another aspect, the lactate level in a trauma patient in need of transfusion therapy is reduced to less than <NUM> mmol/L.

Blood glucose level is also known to be a predictor for outcome in several disease patterns and particularly in trauma patients. Trauma patients are more prone to poor outcome due to hyperglycemia than other critically ill patients. See <NPL>). Studies evaluating the relationship of early hyperglycemia and trauma patients examined early hyperglycemia at three possible cutoffs: glucose ≥ <NUM>/dL, glucose ≥ <NUM>/dL, and glucose ≥ <NUM>/dL. See <NPL>). A glucose level ≥ <NUM>/dL, is associated with significantly higher infection and mortality rates in trauma patients independent of injury characteristics. This was not true at the cutoffs of ≥ <NUM>/dL or ≥<NUM>/dL. Decreased glucose levels in animals resuscitated with OR- and OCR-RBCs compared to conventionally RBCs support the notion that resuscitation with OR-RBCs can significantly improve patients' clinical outcome. See <FIG> and <FIG>.

Methods of the present disclosure provide for, and include, reducing glucose in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced (OR) stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, glucose is reduced by between <NUM> and <NUM>% as compared to transfusion of blood stored under conventional conditions. In an aspect, transfusion with OR stored blood reduces glucose by between <NUM> and <NUM>% as compared to transfusion of blood stored under conventional conditions. In another aspect, transfusion with OR stored blood reduces glucose by between <NUM> and <NUM>% as compared to transfusion of blood stored under conventional conditions. In another aspect, transfusion with OR stored blood reduces glucose by between <NUM> and <NUM>% as compared to transfusion of blood stored under conventional conditions. In yet another aspect, transfusion with OR stored blood reduces glucose by between <NUM> and <NUM>%. In another aspect, transfusion with OR stored blood reduces glucose by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% as compared to transfusion of blood stored under conventional conditions. In another aspect, transfusion with OR stored blood reduces glucose by at least <NUM>% as compared to transfusion of blood stored under conventional conditions. In another aspect, transfusion with OR stored blood reduces glucose by at least <NUM>%. In a further aspect, transfusion with OR stored blood reduces glucose by at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, or at least <NUM>%.

Methods of the present disclosure provide for, and include, reducing glucose levels in a trauma patient in need of transfusion therapy to between about <NUM> and about <NUM>/dL comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, glucose in a patient after transfusion therapy with OR or OCR blood is between about <NUM> and about <NUM>/dL. In another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is between about <NUM> and about <NUM>/dL. In another aspect, glucose in a trauma patient after transfusion therapy with OR or OCR blood is between about <NUM> and about <NUM>/dL. In another aspect, glucose in a trauma patient after transfusion therapy with OR or OCR blood is between about <NUM> and about <NUM>/dL.

Methods of the present disclosure provide for, and include, reducing glucose levels in a trauma patient in need of transfusion therapy to between <NUM> and <NUM>/dL comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, glucose in a patient after transfusion therapy with OR or OCR blood is between <NUM> and <NUM>/dL. In another aspect, glucose in a patient is between <NUM> and <NUM>/dL. In another aspect, glucose in a patient is between <NUM> and <NUM>/dL. In another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is between <NUM> and <NUM>/dL.

Methods of the present disclosure provide for, and include, reducing glucose levels in a trauma patient in need of transfusion therapy to less than <NUM>/dL comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In a further aspect, glucose in a patient after transfusion therapy with OR or OCR blood is less than <NUM> mmol/L. In yet another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is less than <NUM>/dL. In another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is less than <NUM>/dL. In another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is less than <NUM>/dL. In another aspect, glucose in a patient after transfusion therapy with OR or OCR blood is less than <NUM>/dL.

In an aspect of the present disclosure, a trauma patient is at increased risk of complications from transfusion therapies based on a pre-existing or underlying condition. In an aspect, a trauma patient has a pre-existing or underlying condition selected from the group consisting of a diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, chronic pulmonary obstructive disease such as systemic inflammation due to infection, a coagulopathy disorder, and autoimmune diseases. In another aspect, a trauma patient has one or more pre-existing or underlying conditions selected from the group consisting of a diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, and chronic pulmonary obstructive disease such as systemic inflammation due to infection, a coagulopathy disorder, and autoimmune diseases. In another aspect, a trauma patient has two or more pre-existing or underlying conditions selected from the group consisting of a diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, chronic pulmonary obstructive disease such as systemic inflammation due to infection, a coagulopathy disorder, and autoimmune diseases. In another aspect, a trauma patient has three or more pre-existing or underlying conditions selected from the group consisting of a diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, chronic pulmonary obstructive disease such as systemic inflammation due to infection, a coagulopathy disorder, and autoimmune diseases.

During hemorrhagic shock, patients experience an adverse event including liver damage or failure, kidney damage or failure, lung damage or failure, or a combination thereof. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits one or more adverse event selected from the group consisting of liver damage or failure, kidney damage or failure, or lung damage or failure. The present disclosure provides for, and includes, a patient in need of transfusion therapy with OR or OCR RBCs exhibits two or more adverse event selected from the group consisting of liver damage or failure, kidney damage or failure, or lung damage or failure.

Methods of the present disclosure provide for, and include, reducing an adverse event in a trauma patient comprising providing a trauma patient in need of transfusion therapy with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event is reduced by at least <NUM>%. In another aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by at least <NUM>%. In another aspect, the adverse event is reduced by at least <NUM>%. In a further aspect, the adverse event after transfusion therapy with OR or OCR blood is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>%. In an aspect, the adverse event after transfusion therapy with OR or OCR blood is liver injury or damage. In another aspect, the adverse event is lung injury or damage. In yet another aspect, the adverse event is kidney injury or damage. In a further aspect, an adverse event is liver injury, lung injury, kidney injury, or a combination thereof.

Elevated levels of liver enzymes, including but not limited to aspartate aminotransferase (AST) and alanine aminotransferase (ALT), signify some form of liver damage, shock, or injury. Methods of the present disclosure provide for, and include, reducing elevated levels of liver enzymes in a trauma patient comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage.

Methods of the present disclosure provide for, and include, reducing AST levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM>%. In another aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM>%. In another aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In yet another aspect, the AST level is reduced by at least <NUM>%. In a further aspect, the AST level is reduced by at least <NUM>% relative to the AST level of a patient transfused with conventionally stored blood. In a further aspect, the AST level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the AST level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing AST levels in a trauma patient in need of transfusion therapy by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the AST level is reduced by between <NUM> and <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by between <NUM> and <NUM> fold. In another aspect, the AST level is reduced by between <NUM> and <NUM> fold. In another aspect, the AST level is reduced by between <NUM> and <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In a further aspect, the AST level is reduced by between <NUM> and <NUM> fold. In another aspect, the AST level is reduced by between <NUM> and <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing AST levels in a trauma patient in need of transfusion therapy by at least <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In a further aspect, the AST level is reduced by at least <NUM> fold. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM> fold. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In a further aspect, the AST level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing ALT levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the AS ALT T level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In yet another aspect, the ALT level is reduced by at least <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood. In a further aspect, the ALT level is reduced by at least <NUM>%. In a further aspect, the ALT level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the ALT level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing ALT levels in a trauma patient in need of transfusion therapy by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the ALT level is reduced by between <NUM> and <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by between <NUM> and <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by between <NUM> and <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by between <NUM> and <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In a further aspect, the ALT level is reduced by between <NUM> and <NUM> fold. In another aspect, the ALT level is reduced by between <NUM> and <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing ALT levels in a trauma patient in need of transfusion therapy by at least <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In a further aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In another aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood. In a further aspect, the ALT level is reduced by at least <NUM> fold relative to the ALT level of a patient transfused with conventionally stored blood.

Markers of kidney function during and after hemorrhagic trauma include urine neutrophil gelatinase-associated lipocalin (u-NGAL), serum creatinine, and blood urea nitrogen (BUN). See <NPL>). Gene expression analyses reported in greater than <NUM> distinct studies performed in AKI models from several species ranging from rodents to humans have consistently revealed the NGAL gene to be one of the most dramatically upregulated genes in the kidney soon after an ischemic or a nephrotoxic insult. See <NPL>). Similarly serum creatinine levels can vary depending on age, race and body size, however, rising creatinine levels are indicative of kidney damage. Creatinine levels of greater than <NUM> for women and greater than <NUM> for men may be an early sign of kidney damage. Increased blood urea nitrogen (BUN) is seen associated with kidney disease or failure, as well as, congestive heart failure, shock and bleeding in the digestive tract. If the BUN level is higher than <NUM>/dL it points to severe kidney damage. Decreased levels of BUN are also a concern and can point to fluid excess, trauma, surgery, opioids, malnutrition, and anabolic steroid use. See <NPL>); and <NPL>). Decreased u-NGAL (<FIG> and <FIG>) serum creatinine (<FIG> and <FIG>), and BUN (<FIG> and <FIG>) levels in animals resuscitated with OR- and OCR-RBCs compared to conventionally RBCs, as provided by the present disclosure, show that resuscitation with OR-RBCs can significantly improve patients' clinical outcome.

Methods of the present disclosure provide for, and include, reducing urinary neutrophil gelatinase-associated lipocalin (u-NGAL) levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>%. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In yet another aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In a further aspect, the u-NGAL level is reduced by at least <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood. In a further aspect, the u-NGAL level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the u-NGAL level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing urinary neutrophil gelatinase-associated lipocalin (u-NGAL) levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient by between <NUM> and <NUM> fold with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the u-NGAL level is reduced by between <NUM> and <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by between <NUM> and <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by between <NUM> and <NUM> folds. In another aspect, the u-NGAL level is reduced by between <NUM> and <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In a further aspect, the u-NGAL level is reduced by between <NUM> and <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by between <NUM> and <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing urinary neutrophil gelatinase-associated lipocalin (u-NGAL) levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient by at least <NUM> fold with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In a further aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold relative to the u-NGAL level of a patient transfused with conventionally stored blood. In another aspect, the u-NGAL level is reduced by at least <NUM> fold. In another aspect, the u-NGAL level is reduced by at least <NUM> fold. In a further aspect, the u-NGAL level is reduced by at least <NUM> fold.

Methods of the present disclosure provide for, and include, reducing serum creatinine levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In yet another aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In a further aspect, the serum creatinine level is reduced by at least <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood. In a further aspect, the serum creatinine level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the serum creatinine level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing serum creatinine levels in a trauma patient in need of transfusion therapy by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In a further aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by between <NUM> and <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing serum creatinine levels in a trauma patient in need of transfusion therapy by at least <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the AST level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold. In a further aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced by at least <NUM> fold relative to the serum creatinine level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing serum creatinine levels in a trauma patient in need of transfusion therapy to between <NUM> and <NUM>/dL comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the serum creatinine level is reduced to between <NUM> and <NUM>/dL relative to the serum creatinine level of a patient transfused with conventionally stored blood. In an aspect, the serum creatinine level is reduced to between <NUM> and <NUM>/dL relative to the serum creatinine level of a patient transfused with conventionally stored blood. In another aspect, the serum creatinine level is reduced to between <NUM> and <NUM>/dL relative to the serum creatinine level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing serum creatinine levels in a trauma patient in need of transfusion therapy to less than <NUM>/dL comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the serum creatinine level is reduced to less than <NUM>/dL relative to the serum creatinine level of a patient transfused with conventionally stored blood. In an aspect, the serum creatinine level is reduced to less than <NUM>/dL. In another aspect, the serum creatinine level is reduced to less than <NUM>/dL relative to the serum creatinine level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing BUN levels in a trauma patient comprising providing a trauma patient in need of transfusion therapy with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In yet another aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In a further aspect, the BUN level is reduced by at least <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood. In a further aspect, the BUN level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the BUN level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing BUN levels in a trauma patient by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the BUN level is reduced by between <NUM> and <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by between <NUM> and <NUM> folds. In another aspect, the BUN level is reduced by between <NUM> and <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by between <NUM> and <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In a further aspect, the BUN level is reduced by between <NUM> and <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by between <NUM> and <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing BUN levels in a trauma patient by at least <NUM> fold comprising providing a trauma patient in need of transfusion therapy with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In a further aspect, the BUN level is reduced by at least <NUM> fold. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood. In another aspect, the BUN level is reduced by at least <NUM> fold relative to the BUN level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the percentage of CD45+ neutrophils in a trauma patient comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In yet another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In a further aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In a further aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the percentage of CD45+ neutrophils in a trauma patient in need of transfusion therapy by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In a further aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by between <NUM> and <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the percentage of CD45+ neutrophils in a trauma patient in need of transfusion therapy by at least <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In a further aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood. In another aspect, the percentage of CD45+ neutrophils is reduced by at least <NUM> fold relative to the CD45+ neutrophil level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the CXCL1 levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In yet another aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In a further aspect, the CXCL1 level is reduced by at least <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood. In a further aspect, the CXCL1 level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the CXCL1 level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the CXCL1 levels in a trauma patient by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In a further aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by between <NUM> and <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the CXCL1 levels in a trauma patient by at least <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In a further aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood. In another aspect, the CXCL1 level is reduced by at least <NUM> fold relative to the CXCL1 level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the IL-<NUM> levels in a trauma patient in need of transfusion therapy comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>%. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In yet another aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In a further aspect, the IL-<NUM> level is reduced by at least <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In a further aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, <NUM> and <NUM>%, or <NUM> and <NUM>% relative to the IL-<NUM> level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the IL-<NUM> levels in a trauma patient by between <NUM> and <NUM> fold comprising providing a trauma patient with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> folds. In another aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In a further aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by between <NUM> and <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood.

Methods of the present disclosure provide for, and include, reducing the IL-<NUM> levels in a trauma patient by at least <NUM> fold comprising providing a trauma patient in need of transfusion therapy with oxygen reduced stored blood that has an oxygen saturation of <NUM>% or less prior to and during storage. In an aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold. In a further aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood. In another aspect, the IL-<NUM> level is reduced by at least <NUM> fold relative to the IL-<NUM> level of a patient transfused with conventionally stored blood.

As used herein, the terms "higher", "greater" or "increased" means that the measured values of oxygen reduced and anaerobically stored blood, when compared to the measured values of otherwise equivalently treated conventionally stored blood, are at least <NUM> standard deviation greater, with a sample size of at least <NUM> for each compared measured condition.

As used herein, the terms "reduce", "reduced", "lower", "decreased" or "less" means that the measured values of oxygen reduced and anaerobically stored blood when compared to the measured values of otherwise equivalently treated normoxic or hyperoxic conventionally stored blood RBCs, are at least <NUM> standard deviation lower, with a sample size of at least <NUM> for each compared measured condition.

As used herein the term "less than" refers to a smaller amount and an amount greater than zero.

The terms "comprises," "comprising," "includes," "including," "having," and their conjugates mean "including but not limited to.

The term "consisting of" means "including and limited to.

The term "consisting essentially of" means that the composition, method or structure can include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" can include a plurality of compounds, including mixtures thereof.

As used herein, the term "blood" refers to whole blood, leukoreduced RBCs, platelet reduced RBCs, and leukocyte and platelet reduced RBCs. The term blood further includes packed red blood cells, platelet reduced packed red blood cells, leukocyte reduced packed red blood cells, and leukocyte and platelet reduced packed red blood cells. The temperature of blood can vary depending on the stage of the collection process, starting at the normal body temperature of <NUM> at the time and point of collection, but decreasing rapidly to about <NUM> as soon as the blood leaves the patient's body and further thereafter to room temperature in about <NUM> hours when untreated, and ultimately being refrigerated at between about <NUM> and <NUM>. Human red blood cells in vivo are in a dynamic state. The red blood cells contain hemoglobin, the iron-containing protein that carries oxygen throughout the body and gives red blood its color. The percentage of blood volume composed of red blood cells is called the hematocrit. As used herein, unless otherwise limited, RBCs also includes packed red blood cells (pRBCs). Packed red blood cells are prepared from whole blood using centrifugation techniques commonly known in the art. As used herein, unless otherwise indicated, the hematocrit of pRBCs is about <NUM>%. As used herein, oxygen reduced stored RBCs can include oxygen and carbon dioxide reduced stored RBCs. As used herein, oxygen reduced (OR) blood can include oxygen and carbon dioxide (OCR) reduced blood.

As used herein the terms "patient" and "subject" is used interchangeably to mean a person or animal in need of transfusion.

As used herein the term "trauma" includes exsanguination, hemorrhagic trauma.

As used herein the term "hemorrhagic shock" is shock brought on by a loss of circulating blood volume and/or oxygen carrying capacity. Hemorrhagic shock results from any condition associated with blood loss, internal (e.g., gastrointestinal bleeding) or external hemorrhage, and trauma (e.g., penetrating or blunt trauma), among others.

As used herein the term "adverse event" includes an event resulting from hemorrhagic shock in a hemorrhagic trauma patient.

As used herein the terms "injury", "damage", and "failure" refer to an organ not functioning properly or not functioning as is expected in a person or animal without disease or injury.

As used herein, a "unit" of blood is about <NUM>-<NUM> including anticoagulant. Suitable anticoagulants include CPD, CPDA1, ACD, and ACD-A.

Throughout this application, various aspects of this disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. For example, description of a range such as "from <NUM> to <NUM>" should be considered to have specifically disclosed subranges such as "from <NUM> to <NUM>," "from <NUM> to <NUM>," "from <NUM> to <NUM>," "from <NUM> to <NUM>," "from <NUM> to <NUM>," "from <NUM> to <NUM>," etc., as well as individual numbers within that range, for example, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>.

The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals there between.

As used herein the term "method" refers to manners, means, techniques, and procedures for accomplishing a given task including, but not limited to, providing a human patient in need of a blood transfusion with oxygen reduced stored blood having an initial oxygen saturation of <NUM>% or less and stored for at least <NUM> days.

While the present disclosure has been described with reference to particular embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from the scope of the present disclosure.

Therefore, it is intended that the present disclosure not be limited to the particular embodiments disclosed as the best mode contemplated for carrying out the present disclosure, but that the present disclosure will include all embodiments falling within the scope of the appended claims.

Each pool of red blood cells are collected from a total of <NUM>-<NUM> rats in CP2D anticoagulant. The pooled blood is leukoreduced using neonatal leukoreduction filter, component separated and RBCs are stored in AS-<NUM> additive solution. Total of two pools of RBCs are collected. Each pool is split four ways: Unprocessed control (C), sham control (SC), oxygen-reduced (OR) and oxygen and carbon dioxide reduced (OCR). For C, SC, OR and OCR units, RBC subunit is processed by transferring into <NUM> PVC blood transfer bag and final RBC products are made by gas exchange process. The RBC bags except for C are filled with <NUM>% N<NUM> (for OR), or <NUM>% N<NUM> / <NUM>% CO<NUM> (for OCR) or air (SC) through sterile filter and gently rotated on its long side at <NUM>-<NUM> RPM (except for C). For OR and OCR units, after <NUM> minutes, gas is removed through the filter and fresh gas is introduced for subsequent gas exchange process. This process is repeated <NUM>-<NUM> times until target %SO2 of <NUM>-<NUM>% as measured by ABL-<NUM> cooximeter (Radiometer Copenhagen) is achieved. SC unit is rotated without any gas exchange for <NUM> minutes. OR and OCR units are stored anaerobically in a N<NUM>-filled canister, while C and SC units are stored in ambient air. All units are stored for <NUM> weeks at <NUM> and sampled at days <NUM> or <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. Two pools were prepared and stored.

On days <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, ATP, <NUM>,<NUM>-DPG, and hemolysis analysis are performed. As shown in <FIG>, ATP levels are higher in OR-blood at day <NUM> and OCR-blood at days <NUM>, <NUM>, <NUM>, and <NUM> compared to conventionally stored blood (control). OR-blood also has higher levels of <NUM>-DPG at days <NUM>, <NUM>, and <NUM>, compared to control. OCR-blood also shows a higher level of <NUM>,<NUM>-DPG on days <NUM>, <NUM>, and <NUM> compared to control.

A small volume (less than <NUM>µL) of Control, OR-, and OCR-blood stored for <NUM> weeks is labeled with techniteum-<NUM>. Animals are transfused with labeled RBC (less than 200uL) and circulating radioactivity is measured periodically up to <NUM> hours in order to estimate fraction of transfused RBC surviving <NUM> hours after transfusion. As shown in <FIG>, significantly more OR- and OCR-RBCs are recovered compared to control RBCs when RBCs were stored for three weeks.

Collection of blood and sample preparation: Each pool of red blood cells are collected from a total of <NUM>-<NUM> rats in CP2D anticoagulant. The pooled blood is leukoreduced using neonatal leukoreduction filter, component separated and RBCs are stored in AS-<NUM> additive solution. Total of six pools of RBCs are collected. Two pools are prepared for conventional storage (control). Two pools are depleted of oxygen (oxygen reduced; OR), and the remaining two pools of blood are depleted of oxygen and carbon dioxide (oxygen and carbon dioxide reduced; OCR). Each of the four pools to be reduced is processed by transferring RBCs into <NUM> PVC blood transfer bag and final RBC products are made by gas exchange process. The RBC bag is filled with <NUM>% N<NUM> (for OR), or <NUM>% N<NUM> / <NUM>% CO<NUM> (for OCR) through sterile filter and gently rotated on its long side at <NUM>-<NUM> RPM. After <NUM> minutes, gas is removed through the filter and fresh gas is introduced for subsequent gas exchange process. This process is repeated <NUM>-<NUM> times until target %SO2 of <NUM>-<NUM>% as measured by ABL-<NUM> cooximeter (Radiometer Copenhagen) is achieved. OR and OCR blood is stored anaerobically in a N<NUM>-filled canister.

Studies are performed in Sprague-Dawley rats (Charles River Laboratories, Boston, MA) weighing <NUM>-<NUM> grams (g). Briefly, animals are anesthetized by administering <NUM>/kg of sodium pentobarbital intraperitoneally. Animals are placed in the supine position on a heating pad to maintain core body temperature at <NUM> C. Animals are prepared with: (i) a left jugular vein and left femoral artery catheterization, (ii) tracheotomy (polyethylene-<NUM> tube), and (iii) left ventricle (LV) conductance catheter introduction through the right carotid artery. Animals are mechanically ventilated (TOPO ventilator, Kent Scientific, Torrington, CT) using room air, with a respiration rate of <NUM>-<NUM> breaths per min and a peak inspiratory pressure of <NUM>-<NUM> cmH2O. After instrumentation, volatile anesthesia (<NUM>%/vol Isoflurane, Dragerwerk AG, Laubeck, Germany) is administered using a vaporizer connected to the ventilator. Depth of anesthesia is continually verified via toe pinch, as needed, isoflurane was increased by <NUM>%/vol to prevent animal discomfort.

Anesthetized animals are hemorrhaged by withdrawing <NUM>% of the animal's blood volume (BV; estimated <NUM>% of body weight) via the femoral artery catheter within <NUM>, placing the animals in a hypovolemic shock condition. The hypovolemic shock condition is maintained for <NUM>. Resuscitation is implemented by infusion of previously stored RBCs at <NUM> microliters per min (µL/min) via the femoral artery until Mean arterial pressure (MAP) is stabilized at <NUM>% of the baseline during <NUM> minutes resuscitation period. At <NUM>, <NUM>, <NUM>, <NUM> and <NUM> minutes during this period, MAP and heart rate (HR) are obtained from a femoral artery catheter (PowerLab, AD Instruments, Colorado Springs, CO). After <NUM> mins, hematocrit (Hct) is measured via centrifugation of heparinized capillary tubes. Hemoglobin (Hb), lactate, glucose, K+, Na+, pH, arterial blood gas are determined by ABL90 cooximeter (Radiometer, Copenhagen). Indices of cardiac function and systemic values (MAP, HR, Hct, Hb, and blood gases) are monitored at baseline (BL), during shock, and <NUM> (Early R), <NUM>, <NUM>, <NUM>, and <NUM> (Late R) mins post resuscitation. Animals are euthanized at the end of the experiment.

Hematocrit (Hct) is reduced by approximately <NUM> to <NUM>% after hypovolemic shock is induced. Providing conventionally, OR, or OCR blood stored for <NUM> week is capable of restoring hematocrit to normal levels. However, as shown in <FIG>, OR-blood stored for one week show an increased percent hematocrit compared to control and OCR-blood after <NUM> mins of resuscitation (Early R). The percent hematocrit of OR-blood remains improved compared to control after <NUM> mins (Late R) of resuscitation.

Mean arterial pressure (MAP) is obtained from the femoral artery catheter (PowerLab, AD Instruments, Colorado Springs, CO). As shown in <FIG>, baseline MAP is between <NUM> and <NUM> mmHg. MAP is reduced to between <NUM> and <NUM> mmHg during hemorrhagic shock. Resuscitation of animals with OR and OCR blood stored for one week increases the MAP to approximately <NUM> and <NUM> mmHg, respectively. As shown in <FIG>, resuscitation with OR blood, after <NUM> mins, is able to restore MAP to normal range compared to control. Control and OCR stored blood is able to restore MAP to a normal range after <NUM> mins of resuscitation. The amount of blood required to resuscitate and preserve hemodynamics with conventionally stored RBCs (control) was greater than OR and OCR RBCs required. See <FIG> and <FIG>.

Hemorrhagic shock in animals increases the lactate level from about <NUM> mmol/L to between about <NUM> and <NUM> mmol/L. Resuscitation with OR and OCR RBCs stored for one week reduces lactate levels to near normal levels after just <NUM> mins of resuscitation. Lactate levels of animals resuscitated with control blood are similar to lactate levels of animals in hemorrhagic shock. Animals treated with control, OR and OCR RBCs for <NUM> mins show similar lactate levels. As shown, in <FIG>, OR RBCs stored for <NUM> weeks are also able to reduce lactate levels compared to control after <NUM> mins of resuscitation. However, after <NUM> mins of resuscitation OCR RBCs restored lactate levels to a normal range. Control and OR RBCs were able to reduce lactate levels but not to the normal range of <NUM> to <NUM> mmol/L. Analysis of glucose levels show that the normal range of about <NUM>/dL to about <NUM>/dL glucose is increased to a range of about <NUM> to about <NUM>/dL in animals under hemorrhagic shock. <FIG> and <FIG>. Both OR and OCR RBCs stored for one week decrease glucose levels compared to control after <NUM> mins of resuscitation. All three samples restored glucose levels to the normal range after <NUM> mins of resuscitation. As shown in <FIG>, OR and OCR RBCs stored for three weeks are also able to decrease glucose levels compared to control after <NUM> mins of resuscitation. Unlike the RBCs stored for one week, only OR and OCR RBCs were able to restore glucose within the normal range. Thus, both lactate and glucose levels are reduced faster in OR and OCR RBCs compared to control RBCs.

Animals are analyzed for organ injury and inflammation after experiencing hemorrhagic shock and resuscitation. Elevated levels of liver enzymes signify some form of liver damage or injury. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were analyzed to determine liver damage. Resuscitation with OR and OCR RBCs previously stored for one week (<FIG> and <FIG>) and three weeks (<FIG> and <FIG>) reduced AST and ALT levels compared control RBCs stored for the same period of time. Serum creatinine and blood urea nitrogen (BUN) levels were analyzed to determine kidney function. OR and OCR RBCs stored for one week reduced serum creatinine levels greater than <NUM>% compared to control RBCs (<FIG>). After three weeks of storage serum creatinine levels of animals treated with control, OR, and OCR RBCs overlap (<FIG>). BUN levels are decreased by greater than <NUM>% in animals treated with OCR RBCs stored for one week compared to control (<FIG>). BUN levels also decreased by greater than <NUM>% in animals treated with OR RBCs stored for three weeks compared to control (<FIG>). Overall, vital organ function was preserved with OR and OCR RBCs compared to control RBCs.

Claim 1:
Oxygen reduced stored blood for use in a method of treating hemorrhagic trauma in a patient in need thereof, wherein the oxygen reduced stored blood comprises an initial oxygen saturation of <NUM>% or less and is maintained at an oxygen saturation of <NUM>% or less for a storage period, wherein the hemorrhagic trauma patient in need thereof is in hemorrhagic shock prior to administration of the oxygen reduced stored blood, and wherein the hemorrhagic shock is reversed after administration of the oxygen reduced stored blood, wherein the method comprises transfusion therapy.