Compositions and methods for restoring or increasing tissue

Abstract

To provide a safe and inert composition that greatly improves oxygen transfer to the tissues of a patient, improves post-resuscitation outcomes, and increases patient survival, and also to provide a method for restoring or increasing tissue perfusion locally or systemically.SOLUTION: A composition comprises: polyethylene glycol (PEG) polymers having a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% w / v; PEG having a molecular weight of 1,000 to 10,00 Da at a concentration of 1 to 30% by weight; and water, wherein the PEG having a molecular weight of 18,000 to 100,000 Da and the PEG having a molecular weight of 1,000 to 10,000 Da are dissolved or dispersed in the water.SELECTED DRAWING: None

Description

Technical Field

[0001] Statement Regarding Federally Sponsored Research or Development This invention was made with government support under award number W81XWH-16-2-0040, awarded by the Army (MRMC). The government has certain rights in this invention. This invention generally relates to compositions containing high molecular weight and low molecular weight polymers useful for restoring or increasing oxygen delivery to the microcirculation in ischemic tissue.

Background Art

[0002] The resuscitation of patients in trauma and shock states with whole blood or blood products is considered to have fluid resuscitation as an absolute criterion. However, there is a mechanism of cell and tissue damage during shock that severely limits the effectiveness of any solution used to resuscitate shocked patients. Whole blood may be the best option when compared to other IV solutions such as lactated Ringer's solution, but it is very disadvantageously affected by the no-reflow phenomenon that occurs when reperfusing ischemic tissue.

[0003] Improved compositions and methods for reducing this mechanism of tissue damage enable whole blood in living organs and tissues to easily pass through the capillary network, thereby reducing and reversing the metabolic effects of shock and causing the oxygen transfer necessary for this.

Summary of the Invention

[0004] This disclosure provides, for example, a safe and inert solution for use in resuscitating patients in trauma or shock states in a hospital or emergency medical setting. This solution significantly improves oxygen transfer to the patient's tissues, improves post-resuscitation outcomes, and increases patient survival. Administering the solution prior to transfusion reduces the amount of blood required for fluid infusion.

[0005] One aspect of the present disclosure provides a composition comprising a polyethylene glycol polymer (PEG) having a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% w / v; a PEG having a molecular weight of 1,000 to 10,000 Da at a concentration of 1 to 30% w / v; and water, wherein the PEG having a molecular weight of 18,000 to 100,000 Da and the PEG having a molecular weight of 1,000 to 10,000 Da are dissolved or dispersed in water. In some embodiments, the total volume of the composition is 1000 ml or less, for example 100 to 1000 ml. In some embodiments, the total volume is 136 to 680 ml.

[0006] In some embodiments, the composition comprises a PEG having a molecular weight of 20,000 Da at a concentration of 10% w / v. In some embodiments, the composition comprises a PEG having a molecular weight of 1,000 Da at a concentration of 15% w / v. In some embodiments, the water is deionized water. In some embodiments, the composition further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.

[0007] Another aspect of the present disclosure provides an intravenous injection product comprising a bag configured to deliver an infusion intravenously and the composition described herein within the bag.

[0008] Another aspect of the present disclosure provides a method for restoring or increasing local or extensive tissue perfusion in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein. In some embodiments, the composition is administered intravenously. In some embodiments, the subject has reduced extensive or local tissue perfusion due to cardiogenic or non-cardiogenic shock.

[0009] In some embodiments, the method includes the step of simultaneously or sequentially administering a cellular or acellular oxygen carrier solution. In some embodiments, the acellular oxygen carrier solution is a hemoglobin-based oxygen carrier (HBOC). In some embodiments, the cellular oxygen carrier solution is whole blood or packed red blood cells. In some embodiments, the amount of the cellular oxygen carrier solution to be administered is 50% or less of the estimated blood volume required in the absence of the composition. In some embodiments, the cellular or acellular oxygen carrier solution is administered within 12 hours of administration of the composition.

Brief Description of the Drawings

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BRIEF DESCRIPTION OF THE INVENTION

[0011] Embodiments of the present disclosure provide solutions that restore or increase oxygen delivery to the microcirculation in ischemic tissue. Ischemia can result from non-cardiogenic (e.g., hypovolemic, obstructive, septic, anaphylactic, or neurogenic) shock or cardiogenic shock. The compositions described herein target a novel mechanism of action that is a major causative factor in poor tissue perfusion that occurs during ischemia and after reperfusion resuscitation, specifically after metabolic cell swelling and secondary microcirculation compression.

[0012] Cell ischemia that occurs during shock results in a loss of ATP concentration required to drive the Na / K ATPase in the basolateral cell membrane. This slows the rate of the sodium pump, increases the influx of sodium into the cell, and causes metabolic cell swelling by subsequent movement of infiltrating water (Figure 1A). As parenchymal cells in the tissue, the microcirculation that supplies oxygen to the tissue is compressed, slowing or stopping capillary flow and convective movement of oxygen. Similarly, metabolic swelling of endothelial cells reduces the diameter of the capillary lumen, further restricting flow (Figure 1B). This can be prevented or reversed by filling the extracellular space with impermeable cells, which are inert molecules that escape from the capillary space but cannot enter the cell. They accumulate extracellularly and osmotically prevent or reverse the inward movement of water, thereby preventing tissue edema and decompressing the microcirculation. This allows for efficient capillary perfusion and oxygen transfer to the tissue even in a low-volume state.

[0013] Polyethylene glycol (PEG) polymers with molecular weights of approximately 18,000 to 100,000 Da are most effective for two phenomena: 1) they are impermeable molecules with partial colloidal osmotic pressure properties, and 2) they are highly hydrophilic and attract water molecules. Tracer studies suggest that the osmotic reflection coefficient (σd) of PEG-20k molecules is approximately 0.5, which means that for every two PEG-20k molecules remaining in the capillary space, one molecule exits and enters the interstitial space. Being impermeable, they do not enter the cells. This creates an osmotic gradient, establishing the non-energy movement of isotonic water into the extracellular and intravascular compartments (see Figure 2). This water transport replenishes the volume to increase the driving pressure of capillary flow while promoting capillary decompression and reducing resistance to flow. PEG polymers are very hydrophilic and attract a clean shell of water around the molecule. This enhances the drawing in of water by the osmotic gradient alone.

[0014] Low-flow states and pre-inflammatory states that occur in shock, trauma, critical illness, and tissue injury always cause slow flow (poor perfusion) by constantly reducing the number of capillaries in the tissue. One mechanism for this involves the rouleaux formation of red blood cells (RBCs), which is the aggregated deposition of multiple rows of RBCs in the microcirculation. These RBC rouleaux are trapped in the capillaries, physically obstructing the flow, increasing local blood viscosity, and cross-linking with other inflammatory cells attached to the damaged vascular endothelium due to the disruption of the glycocalyx in shock. Therapeutic PEG polymers (20 - 100k) are likely to increase RBC aggregation and promote rouleaux formation in shock and low-flow states. This acts contrary to the protective effect produced by therapeutic PEG polymers to restore capillary flow and perfusion by limiting the swelling of metabolic cells and tissues.

[0015] The present disclosure provides a composition comprising a therapeutic PEG polymer combined with a small amount of a low molecular weight blocking agent, which enhances the therapeutic effect on local capillary perfusion by restricting thrombus formation. Accordingly, embodiments of the present disclosure provide a composition comprising PEG having a molecular weight of 18,000 to 100,000 Da, such as 18,000 to 40,000 Da, such as 20,000 to 35,000 Da, such as 18,000 Da, 20,000 Da, 25,000 Da, 30,000 Da, 35,000 Da, 40,000 Da, at a concentration of 5 to 30 wt%, such as 5 to 20%, 10 to 30%, or 10 to 20% w / v, g / L of the total solution. The composition further comprises PEG having a molecular weight of 1,000 to 10,000 Da, such as 2,000 to 8,000 Da, such as 2,000 Da, 3,000 Da, 4,000 Da, 5,000 Da, 6,000 Da, 7,000 Da, or 8,000 Da, such as 6,000 Da, at a concentration of 1 to 30 wt%, such as 1 to 20%, 1 to 10% w / v, g / L of the total solution.

[0016] Most PEGs contain molecules with a molecular weight distribution (i.e., are polydisperse). This particle size distribution can be statistically characterized by the weight average molecular weight (Mw) and the number average molecular weight (Mn), and the ratio is called the polydispersity index (Mw / Mn). In some embodiments, the polydispersity index is less than about 5, such as less than 4, 3, 2, 1.5, or 1.2.

[0017] Small polymers provide two important functions: 1) they attenuate the rate of enhancement of large PEG molecules with respect to erythrocyte sedimentation, either in vivo when administered separately from whole blood or blood products, or in vitro when provided as a composite blood product, making administration of the preparation easier, and 2) they provide short-term immunological camouflage of the active components of the cellular immune system after resuscitation, thereby preventing part of the early inflammatory response after resuscitation. The immunological camouflage is achieved by non-specific surface stabilization of blood cells by the polymer. This polymer covers surface receptors activated for cell-cell interaction, thereby "coding" white blood cells by covering or camouflaging them from activation by damaged tissue, further protecting against secondary inflammatory damage after resuscitation.

[0018] High molecular weight PEG and low molecular weight PEG are dissolved or dispersed in water, such as deionized water. In some embodiments, the composition is a physiological saline or lactated Ringer's solution and contains one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.

[0019] In some embodiments, the total volume of the composition is 1000 ml or less, such as 500 ml, 250 ml, or 150 ml or less, such as 100 - 1000 ml. In some embodiments, the total volume ranges from about 136 - 680 ml based on a dose of 6.8 ml / kg body weight for a 20 - 100 kg patient.

[0020] The solution may be a single-phase solution, dispersion, emulsion, or any other form physically suitable for delivery to the subject. The solution is "physiologically acceptable" in that it is suitable for injection into the subject without causing undue harmful effects. The solution can contain autologous blood or substitute blood. In some embodiments, the solution contains additional cell-impermeable agents or swelling agents.

[0021] Referring to FIG. 7, a further embodiment of the present disclosure provides an intravenous infusion product comprising a bag 10 configured to deliver fluid intravenously and the composition described herein within the bag. Suitable IV infusion bags, such as Viaflex® bags, are well known in the art.

[0022] A further embodiment of the present disclosure provides the composition described herein mixed with a cell or cell-free oxygen carrier solution. Cell-free oxygen carrier solutions include, for example, hemoglobin-based oxygen carriers (HBOC) such as hemature® (registered trademark), emulsions of perfluorochemical liquids (PEC emulsions), and lipid encapsulation of any of these oxygen carriers. Cell oxygen carriers include whole blood and are administered, for example, via transfusion or packed red blood cells. Thus, the composition described herein may be a sterile additive for whole blood or blood products, or another oxygen carrier solution used to resuscitate patients with metabolic extremes due to trauma, hypovolemia, shock, or poor perfusion. The additive may be combined with one unit of whole blood or added to the donor bag at the time of whole blood collection. For example, 50 - 150 ml of the composition may be filter sterilized and mixed with 400 - 600 ml of whole blood treated with acid-citrate-dextrose (ACD). The mixed product dramatically increases the effectiveness of whole blood resuscitation and increases outcomes and survival in patients.

[0023] Further embodiments provide a method for restoring or increasing local or widespread tissue perfusion in a subject in need thereof, including administering a therapeutically effective amount of the compositions described herein to a subject, such as a trauma or shock patient. The composition can be added simultaneously with, or prior to, administration of the cell or acellular oxygen carrier solution. In some embodiments, the cell or acellular oxygen carrier solution is administered within 12 hours of administration of the composition, such as within 10, 8, 6, 4, 2, or 1 hour. In some embodiments, the amount of the cell oxygen carrier solution administered is 50% or less, such as 40%, 30%, 20%, 10%, or 5% or less, of the estimated blood volume required in the absence of the composition.

[0024] Further embodiments provide a method for cardiac resuscitation in a subject in need thereof, including administering a therapeutically effective amount of the compositions described herein to a subject, such as a trauma or shock patient. The composition can be added simultaneously with, or prior to, administration of the cell or acellular oxygen carrier solution. In some embodiments, the cell or acellular oxygen carrier solution is administered within 12 hours of administration of the composition, such as within 10, 8, 6, 4, 2, or 1 hour. In some embodiments, the amount of the cell oxygen carrier solution administered is 50% or less, such as 40%, 30%, 20%, 10%, or 5% or less, of the estimated blood volume required in the absence of the composition.

[0025] The solutions described herein can be administered by any suitable means, such as by an intra-arterial, intravenous, intraosseous, or intracardiac route.

[0026] The terms "subject" or "patient" generally refer to any mammal, typically a human. The solutions and methods described herein also have veterinary applications, including, but not limited to, companion animals and livestock animals.

[0027] As used herein, the terms "effective amount" or "therapeutically effective amount" mean an amount of a drug that is non-toxic but sufficient to provide the desired biological result. This result can be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or other desired modifications of a biological system such as a reduction or inhibition of the swelling of metabolizing cells and tissues during resuscitation.

[0028] The compositions described herein enable blood to easily pass through capillary networks in living organs and tissues, so that the necessary oxygen transfer occurs, and the metabolic effects of shock can be alleviated and reversed. The compositions described herein can be administered to critically ill patients having a wide range of oxygen debt (plasma lactate of 2.5 mm or more). The compositions of the present invention improve the performance of whole blood or blood products administered simultaneously or sequentially with respect to oxygen delivery to and transfer of oxygen to hypoxic tissues by providing protection against excessive cellular inflammation as secondary injury. The compositions of the present invention improve the outcome and survival as compared to the same amount of whole blood or blood products without using the composition.

[0029] The compositions described herein solve the problem of "no reflow" associated with infusion resuscitation, which is much more important than previously recognized. When blood cannot reach the capillary exchange vessels (capillary no reflow), the administration of whole blood to a shocked patient is not good. The solution of no reflow enables the oxygen-carrying whole blood to move into the capillary space and affect the many necessary oxygen transfers to ischemic tissues. This reduces lactate, returns the generated oxygen debt, and dramatically increases survival.

[0030] The compositions described herein are useful for hospital transfusions for patients having metabolic and cardiovascular dysfunction (e.g., as indicated by plasma lactate greater than 2.5 mM). Other uses include use in critically ill patients in surgical or medical ICUs, burn patients, trauma patients at risk of compartment syndrome, transplant patients receiving grafts, organ donors with cardiovascular collapse, operating rooms for treating acute blood loss, and for transport in cases of blood loss or cardiovascular collapse. The product may also be used in forward field hospitals within military conflict zones, in ground and air transport vehicles, or anywhere there is a need for whole blood in patients suffering from any form of oxygen deprivation resulting from cardiovascular collapse, shock, trauma, or disease.

[0031] Before describing exemplary embodiments of the invention in more detail, it should be understood that the invention is, of course, not limited to such specific embodiments. The terms used herein are for the purpose of describing only particular embodiments and it should also be understood that they are not intended to limit the scope of the invention, which is defined only by the appended claims and is not intended to limit the scope of the invention.

[0032] Where a range of values is provided, each value intervening between the upper and lower limits of that range, to one tenth of the unit of the lower limit unless the context clearly dictates otherwise, and other recited values or intervening values within the recited range are included in the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded boundaries within the range, and are also included within the scope of the disclosure. Where the recited range includes one or both of the boundaries, ranges excluding either or both of those included boundaries are also included in the disclosure.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, representative and exemplary methods and materials are described.

[0034] All publications and patents cited herein are incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, and are incorporated herein to disclose and describe the methods and / or materials associated with the cited publications. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention has no right to antedate such publication by virtue of prior invention. Also, the dates of the provided publications need to be independently verified and may differ from the actual publication dates.

[0035] As used in this specification and the appended claims, it should be noted that the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Further, it should be noted that the claims may be drafted to exclude any element. Thus, this description serves as a basis for the use of exclusive terms such as "solely", "only", etc., or the use of "negative" limitations in relation to the recitation of claim elements.

[0036] As will be apparent to those of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with any of the features of some other embodiments without departing from the scope or spirit of the present invention. The described methods can be performed in the order of the described events or in any other order that is logically possible.

[0037] The present invention will be further described by the following non-limiting examples, which are not intended to further describe the present invention and are not to be construed as limiting the scope of the present invention.

[0038] Example 1 Size of PEG polymers for hemorrhagic shock resuscitation Initial studies in a well-established rodent model of lethal hemorrhagic shock and low-volume resuscitation (LVR) showed that typical impermeant molecules were very effective, doubling the low-volume resuscitation (LVR) time, which is an indicator of shock tolerance. Other cardiovascular and metabolic outcomes were also improved two-fold relative to the saline volume control group. To optimize the effect, the inventors searched for impermeant molecules with an osmotic reflection coefficient less than 1 (a pure expander such as albumin that remains within the capillary space) and greater than 0 (a pure non-permeant such as gluconic acid that freely equilibrates between the capillary and interstitial spaces). The inventors found that PEG polymers greater than 10k but less than 100k were attractive candidates. Sizing studies were performed in the shocked state, and the results are presented as LVR time, arterial pressure after resuscitation, and plasma lactate accumulation after resuscitation as indicators of oxygen debt. These studies are summarized in Figure 3.

[0039] The results showed that PEG-8k produced a 2- to 3-fold increase in shock tolerance, which was similar to gluconic acid and consistent with its molecular reflection coefficient. PEG polymers between 20-35k had the highest LVR time, the highest peripheral mean arterial pressure, and the lowest final lactate value, and thus produced optimal results in a rodent shock model. In fact, PEG-20k and -35k decreased lactate from 10 mM to near baseline (1.2 mM) during resuscitation, indicating repayment of the oxygen debt over 24 hours. Low-volume resuscitation with PEG-100k yielded good results based on LVR fold, but the rats' MAP was very low (about 40 mmHg 4 hours after resuscitation), and lactate increased to near 10 mM, indicating re-accumulation of oxygen debt and the rats began to deteriorate. Thus, a 20-35 kDa PEG polymer size seems optimal for resuscitation after lethal shock.

[0040] Example 2 PEG Dosage for Hemorrhagic Shock Resuscitation The current recommended dosage for shock resuscitation is a volume equal to 10% of the estimated blood volume or a single low-volume IV bolus injection of 6.8 ml / kg. The solution used is a 10% solution of polyethylene glycol 20,000 (PEG-20k). The dosage is administered over 5 minutes by syringe or by gravity feed into the venous access line. This specific dosage was determined experimentally from repeated experiments in a well-known rodent model of lethal shock that has been shown to correlate with a preclinical pig model. These dosage response data are shown in Figure 4. These data indicate the optimal dosage of the PEG-20k IV solution based on both the results of the LVR time and the final plasma lactate value. Specifically, the most effective resuscitation results are those with the longest LVR time and the lowest lactate value (shown in mM / L below each bar). Using these criteria in this test model, administration of PEG-20k as a 10% solution at a volume dosage of 10% of the estimated blood volume (6.8 ml / kg) most clearly showed optimal results.

[0041] Reducing the concentration to 5% (10% EBV dose), or administering up to 5% EBV in a 10% solution, resulted in low outcomes. Similarly, delivering the same mass of PEG-20k but in half the volume (20% solution delivered at a 5% EBV dose) was inferior, although the same effective mass of PEG-20k suggested the need for a minimal amount of isotonic vehicle (Ringer's lactate components). This is understood from the mechanism of moving the isotonic solution outside the cell and refilling the capillary space. A minimum fluid volume of 10% EBV (6.8 ml / kg) is required. This is still within the upper limit of what can be considered a low-volume resuscitation volume. The 10% PEG-20k solution yielded optimal results, although there is doubt as to whether its concentration was more effective, and the final lactate concentration was not very beneficial as it was slightly higher at the end of the 240-minute LVR period (1.2 mM for 10% PEG-20k vs. 2.5 mM for 20% PEG-20k, respectively). The optimal PEG-20k dose was also compared to the performance of other known crystalloid solutions (saline, Hextend, albumin) that can be used as LVR solutions in shock resuscitation methods. In other studies, resuscitation with a solution containing 7.5% PEG-20k was not significantly different from the 10% solution.

[0042] Example 3 Formulation Optimization: ESR Effect High molecular weight PEGs that have these beneficial effects when resuscitating after severe shock also cause a dramatic increase in the erythrocyte sedimentation rate (ESR) when mixed with whole blood. Polyethylene glycol polymers can bind non-specifically to biological and non-biological substances. Furthermore, polymers with a molecular radius greater than 4 nM can bind to and crosslink cells such as red blood cells, while polymers less than 4 nm do not bind. This is explained as a molecular weight cut-off between 10 - 20 kDa, where PEG-20k is large enough to interact with RBCs and is not sufficient when smaller than PEG-10k. In a preclinical model of shock, one of the first observations when acting in vivo with a 10% PEG-20k IV solution was the ability to rapidly sediment RBCs in whole blood samples taken after a single intravenous administration of PEG-20k (the right side of Figure 5 contains a 10% solution of PEG-20k. This image shows the degree of erythrocyte sedimentation after 10 minutes). This effect was quantified for the PEG-20k ESR effect using the classical Western ESR quantification method in ex vivo human blood. Sedimentation in normal blood at 60 minutes is approximately 2 - 6 mm. It increased to 60 mm when the blood was diluted 1:9 with 10% PEG-20k, simulating the dilution after LVR during shock.

[0043] Next, the ESR rate was measured using a standard Western ESR assay and attempts were made to block or attenuate the sedimentation effect by adding different concentrations of a family of small PEG polymers that act as competitive inhibitors of the binding sites on RBCs. Without being bound by theory, our hypothesis is that large PEG polymers bind non-specifically to the charged surface of RBCs. When multiple RBCs attach to each large polymer, crosslinking occurs, increasing the blood particle density and thereby rapidly sedimenting them out of solution. Small polymers have the same affinity for the surface of RBCs but are hypothesized not to accept multiple RBC bindings and thus not allow crosslinking.

[0044] To test this hypothesis, the inventors conducted a systematic study of polymeric blocks. To competitively interfere with PEG crosslinking and ESR sedimentation, small PEG polymers with a molecular radius of less than 4 nm (molecular weight of less than 10 kDa) were added to PEG-treated whole blood. Three commercially available PEG polymers (PEG-20k, PEG-35k, and PEG-100k) against known therapeutic range shock were tested. The results are shown in FIGS. 6a-6c. Very strong ESR effects (2x) with therapeutic concentrations of PEG-35k (FIG. 6b) and PEG-100k (FIG. 6c) are shown. The ability of these small PEG polymers (PEG-lk-PEG-10k) to suppress these ESR effects is blunted as the molecular weight of the therapeutic PEG increases. Generally, they require higher concentrations of blocker PEG polymers to produce a more suppressed effect compared to that seen using PEG-20k.

[0045] Another advantage of using small PEG polymers is the immune camouflage effect they have on activated inflammatory cells. This helps to inhibit and limit secondary resuscitation and reperfusion injury.

[0046] Although the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be modified and practiced within the spirit and scope of the appended claims. Accordingly, the invention should not be limited to the embodiments described above, but further includes all modifications and equivalents within the spirit and scope of the description provided herein.

Claims

1. Polyethylene glycol polymers (PEG) having a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% w / v; PEG with a molecular weight between 1,000 and 10,000 Da at a concentration of 1-30% w / v; and A composition comprising water, A composition, wherein the PEG having a molecular weight of 18,000 to 100,000 Da and the PEG having a molecular weight of 1,000 to 10,000 Da are dissolved or dispersed in the water.

2. 2. The composition of claim 1, wherein the total volume of the composition is from 100 to 1000 ml.

3. 3. The composition of claim 2, wherein the total volume is in the range of 136 to 680 ml.

4. The composition of claim 1, wherein the PEG having a molecular weight of 18,000 to 100,000 Da is a PEG having a molecular weight of 20,000 Da.

5. The composition of claim 4, wherein the PEG having a molecular weight of 20,000 Da is at a concentration of 10% w / v.

6. The composition of claim 1 , wherein the water is deionized water.

7. 10. The composition of claim 1, wherein the composition further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.

8. 1. An intravenous infusion product comprising a bag configured to deliver a fluid intravenously and a composition within the bag, the composition comprising: a polyethylene glycol polymer (PEG) having a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% w / v; PEG having a molecular weight of 1,000 to 10,000 Da at a concentration of 1 to 20% w / v; and water, The PEG having a molecular weight of 18,000 to 100,000 Da and the PEG having a molecular weight of 1,000 to 10,000 Da and PEG having a molecular weight of about 1,000 to about 1,000;

9. 9. The intravenous infusion product of claim 8, wherein the total volume of the composition is between 100 and 1000 ml.

10. 10. The intravenous infusion product of claim 9, having a total overall volume in the range of 136 to 680 ml.

11. 9. The intravenous infusion product of claim 8, wherein said PEG having a molecular weight of 18,000 to 35,000 Da is a PEG having a molecular weight of 20,000 Da.

12. 12. The intravenous infusion product of claim 11, wherein the PEG having a molecular weight of 20,000 Da is at a concentration of 10% w / v.

13. 9. The intravenous infusion product of claim 8, wherein the water is deionized water.

14. 9. The intravenous infusion product of claim 8, wherein the composition further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride and magnesium chloride.

15. 1. A method of restoring or increasing tissue perfusion locally or globally in a subject in need thereof, comprising: A method comprising administering to the subject a therapeutically effective amount of the composition of claim 1.

16. 16. The method of claim 15, wherein the composition is administered intravenously.

17. The method of claim 15, wherein the amount of the composition is from 100 to 1000 ml.

18. 16. The method of claim 15, wherein the amount of the composition is 136-680 ml.

19. 16. The method of claim 15, wherein the subject has global or localized reduced tissue perfusion due to cardiogenic or non-cardiogenic shock.

20. 16. The method of claim 15, further comprising the step of simultaneously or sequentially administering cells or an acellular oxygen carrier solution.

21. 21. The method of claim 20, wherein the acellular oxygen carrier solution is a hemoglobin-based oxygen carrier (HBOC).

22. 21. The method of claim 20, wherein the cellular oxygen carrier solution is whole blood or packed red blood cells.

23. 21. The method of claim 20, wherein the amount of cellular oxygen carrier solution administered is no more than 50% of the estimated blood volume required in the absence of the composition.

24. 21. The method of claim 20, wherein the cells or acellular oxygen carrier solution is administered within 12 hours of administration of the composition.

25. 1. A method of cardiac resuscitation in a subject in need thereof, comprising: A method comprising administering to the subject a therapeutically effective amount of the composition of claim 1.

26. 26. The method of claim 25, wherein the composition is administered intravenously.

27. 26. The method of claim 25, wherein the amount of the composition is between 100 and 1000 ml.

28. 26. The method of claim 25, wherein the amount of the composition is in the range of 136 to 680 ml.

29. 26. The method of claim 25, wherein the subject is suffering from cardiogenic or non-cardiogenic shock.

30. 26. The method of claim 25, further comprising the step of simultaneously or sequentially administering cells or an acellular oxygen carrier solution.

31. 31. The method of claim 30, wherein the acellular oxygen carrier solution is a hemoglobin-based oxygen carrier (HBOC).

32. 31. The method of claim 30, wherein the cellular oxygen carrier solution is whole blood or packed red blood cells.

33. 31. The method of claim 30, wherein the amount of cellular oxygen carrier solution administered is no more than 50% of the estimated blood volume required in the absence of the composition.

34. 31. The method of claim 30, wherein the cells or acellular oxygen carrier solution is administered within 12 hours of administration of the composition.

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