Compositions and methods for repairing or augmenting tissue - Patents.com

Abstract

A composition for restoring or increasing tissue perfusion is provided, which comprises a polyethylene glycol polymer (PEG) having a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% by weight, a PEG having a molecular weight of 1,000 to 10,000 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.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was developed with Government support under Grant No. W81XWH-16-2-0040 awarded by the Army (MRMC). The Government has certain rights in this invention. The present invention relates generally to compositions comprising high and low molecular weight polymers that are useful for restoring or increasing oxygen delivery to the microcirculation in ischemic tissues. [Background technology]

[0002] Resuscitation of traumatic and shock patients with whole blood or blood products is considered the gold standard for fluid resuscitation. However, there are certain mechanisms of cellular and tissue damage during shock that greatly limit 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 also at a great disadvantage due to the no-reflow phenomenon that occurs when reperfusing ischemic tissue.

[0003] Improved compositions and methods for mitigating this mechanism of tissue damage would allow whole blood to easily pass through the capillary network in vital organs and tissues, thereby providing the oxygen transfer necessary to mitigate and reverse the metabolic effects of shock. Summary of the Invention

[0004] The present disclosure provides a safe, inert solution for use in, for example, hospital or emergency care, to resuscitate patients suffering from trauma or shock. The solution significantly improves oxygen transfer to the patient's tissues, improving post-resuscitation outcomes and increasing patient survival. Administration of the solution prior to transfusion reduces the amount of blood required for transfusion.

[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 the 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 PEG having a molecular weight of 20,000 Da at a concentration of 10% w / v. In some embodiments, the composition comprises 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 infusion product comprising a bag configured to deliver fluids intravenously and a composition described herein within the bag.

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

[0009] In some embodiments, the method includes administering cells or acellular oxygen carrier solution simultaneously or sequentially. 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 cellular oxygen carrier solution administered is 50% or less of the estimated blood volume that would be required in the absence of the composition. In some embodiments, the cells or acellular oxygen carrier solution is administered within 12 hours of administration of the composition. [Brief description of the drawings]

[0010] [Figure 1] (A) Diagram of osmotic water movement and metabolic cell swelling during shock. (B) Illustration of metabolic cell swelling of endothelial cells and associated capillary compression. [Diagram 2] Diagram of the osmotic gradient that causes the non-energy movement of isotonic water out of cells and into capillaries. [Diagram 3] (A) LVR time, (B) final lactate, and (C) final MAP after administration of different LVR solutions. [Figure 4] Dose-response data in a rodent model of lethal shock [Diagram 5] Diagram showing erythrocyte sedimentation after addition of 10% PEG-20k to whole human blood. [Figure 6] Western ESR analysis data showing the effect of small molecule PEG polymers over larger polymers (A) PEG-20k, (B) PEG-35k, and (C) PEG-100k in improving ESR sedimentation rate in whole blood. [Figure 7] Intravenous infusion products according to some embodiments of the present disclosure DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The embodiments of the present disclosure provide a solution that restores or increases oxygen delivery to the microcirculation in ischemic tissue.Ischemia can result from non-cardiogenic (e.g., hypovolemic, obstructive, septic, anafilariasis, 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 during ischemia and after reperfusion resuscitation, specifically following metabolic cell expansion and secondary microcirculatory compression.

[0012] Cellular ischemia occurring during shock results in a loss of ATP concentration required to drive Na / K ATPase in the basolateral cell membrane. This slows the rate of sodium pumping, increasing sodium entry into the cell and subsequent osmotic water movement resulting in metabolic cell swelling (Figure 1A). As parenchymal cells in tissues compress, the microcirculation that supplies oxygen to the tissues slows or stops capillary flow and convective transfer 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, inert molecules that escape the capillary space but cannot enter the cell. They accumulate outside the cells and osmotically block or reverse the inward water movement, thereby preventing tissue edema and depressurizing the microcirculation. This allows for efficient capillary perfusion and oxygen transfer to the tissues, even in low-volume conditions.

[0013] Polyethylene glycol (PEG) polymers, with molecular weights of approximately 18,000-100,000 Da, are the most effective due to two phenomena: 1) they are impermeable molecules with partial oncotic properties, and 2) they are highly hydrophilic, attracting water molecules. Tracer studies suggest that the osmotic reflection coefficient (σd) of PEG-20k molecules is approximately 0.5, meaning that for every two molecules of PEG-20k that stay within the capillary space, one molecule exits and enters the interstitial space. Being impermeable, it never enters the cell. This creates an osmotic gradient, establishing a non-energy transfer of isotonic water out of the cell and into the capillary (see Figure 2). This transfer of water promotes capillary decompression to decrease resistance to flow while replenishing volume to increase the driving pressure of capillary flow. PEG polymers are highly hydrophilic, attracting a shell of water neatly around the molecule. This enhances the pull of water by the osmotic gradient alone.

[0014] Hypo-flow and pro-inflammatory states, as occurs in shock, trauma, critical illness, and tissue injury, cause sluggish flow (poor perfusion) by constantly reducing the number of capillaries in tissues. One mechanism for this involves the formation of red blood cell (RBC) rouleaux, which are the accumulation of rows of RBCs in the microcirculation. These RBC rouleaux become trapped within capillaries, impeding flow through physical obstruction, increasing local blood viscosity, and bridging with other inflammatory cells attached to damaged vascular endothelium due to disruption of the glycocalyx in shock. Therapeutic PEG polymers (20-100k) likely increase RBC aggregation, promoting rouleaux formation in shock and hypo-flow conditions. This works against the protective effect exerted by therapeutic PEG polymers to restore capillary flow and perfusion by limiting metabolic cell and tissue swelling.

[0015] The present disclosure provides compositions comprising a therapeutic PEG polymer in combination with a small amount of a low molecular weight blocking agent to enhance the therapeutic effect on local capillary perfusion by limiting rouleaux formation. Accordingly, embodiments of the present disclosure provide compositions comprising PEG having a molecular weight of 18,000-100,000 Da, e.g., 18,000-40,000 Da, e.g., 20,000-35,000 Da, e.g., 18,000 Da, 20,000 Da, 25,000 Da, 30,000 Da, 35,000 Da, 40,000 Da, at a concentration of 5-30% by weight, e.g., 5-20%, 10-30%, or 10-20% w / v, g / L of total solution. The composition further comprises PEG having a molecular weight of 1,000-10,000 Da, for example 2,000-8,000 Da, for example 2,000 Da, 3,000 Da, 4,000 Da, 5,000 Da, 6,000 Da, 7,000 Da or 8,000 Da, for example 6,000 Da, in a concentration of 1-30%, for example 1-20%, 1-10% w / v, g / L of the total solution.

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

[0017] The small polymers provide two important actions: 1) they attenuate the enhanced rate of erythrocyte sedimentation of larger PEG molecules, either in vivo when administered separately from whole blood or blood products, or in vitro when provided as a combined blood product, making the product easier to administer, and 2) they provide short-term immune camouflage of the active components of the cellular immune system after resuscitation, thereby blocking some of the early inflammatory response after resuscitation. Immune camouflage is achieved by non-specific surface stabilization of blood cells by the polymer. The polymer "codes" the leukocyte by covering activated surface receptors for cell-cell interactions, thereby covering or camouflaging it from activation by damaged tissue, further protecting against secondary inflammatory damage after resuscitation.

[0018] The high molecular weight PEG and the low molecular weight PEG are dissolved or dispersed in water, for example deionized water. In some embodiments, the composition is saline or lactated Ringer's solution and includes 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, e.g., 500 ml, 250 ml, or 150 ml or less, e.g., 100-1000 ml. In some embodiments, the total volume is in the range of 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 a subject. The solution is "physiologically acceptable" in that it is suitable for injection into a subject without causing undue deleterious effects. The solution may include autologous blood or a blood substitute. In some embodiments, the solution includes an additional cell impermeable agent or a bulking agent.

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

[0022] Further embodiments of the present disclosure provide compositions described herein mixed with a cellular or acellular oxygen carrier solution. Acellular oxygen carrier solutions include hemoglobin-based oxygen carriers (HBOCs), such as hemature®, perfluorochemical emulsions (PEC emulsions), and lipid encapsulation of any of these oxygen carriers. Cellular oxygen carriers include whole blood, administered, for example, via transfusion or packed red blood cells. Thus, the compositions described herein may be a sterile additive for whole blood or blood products, or other oxygen carrier solutions used to resuscitate patients with metabolic extremities due to trauma, hypovolemia, shock, or poor perfusion. The additive may be combined with a 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 acid-citrate-dextrose (ACD) treated whole blood. The combined product dramatically increases the effectiveness of whole blood resuscitation, increasing patient outcomes and survival.

[0023] Further embodiments provide a method for restoring or increasing local or global tissue perfusion in a subject in need thereof, comprising administering to the subject, e.g., a trauma or shock patient, a therapeutically effective amount of a composition described herein. The composition can be added simultaneously with or prior to administration of the cells or acellular oxygen carrier solution. In some embodiments, the cells or acellular oxygen carrier solution is administered within 12 hours, e.g., within 10, 8, 6, 4, 2, or 1 hour, of administration of the composition. In some embodiments, the amount of the cells-oxygen carrier solution administered is 50% or less, e.g., 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, comprising administering a therapeutically effective amount of the composition described herein to the subject, e.g., a trauma or shock patient. The composition can be added simultaneously with or prior to administration of the cells or acellular oxygen carrier solution. In some embodiments, the cells or acellular oxygen carrier solution is administered within 12 hours, e.g., within 10, 8, 6, 4, 2, or 1 hour, of administration of the composition. In some embodiments, the amount of the cells oxygen carrier solution administered is 50% or less, e.g., 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 intra-arterial, intravenous, intraosseous, or intracardiac routes.

[0026] The term "subject" or "patient" generally refers 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 term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of an agent to provide a desired biological result, which may be the reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of a biological system, such as the reduction or inhibition of metabolic cell and tissue expansion during resuscitation.

[0028] The compositions described herein allow blood to easily pass through capillary networks in vital organs and tissues, allowing necessary oxygen transfer to occur and mitigating and reversing the metabolic effects of shock. The compositions described herein can be administered to critically ill patients with extensive oxygen debt (2.5 mm or greater plasma lactate). The compositions of the present invention improve the performance of whole blood or blood products administered simultaneously or sequentially in terms of oxygen delivery and oxygen transfer to hypoxic tissues by conferring protection against excessive cellular inflammation as a secondary injury. The compositions of the present invention improve outcomes and survival compared to the same volume of whole blood or blood products without the use of the compositions.

[0029] The compositions described herein solve the "no reflow" problem associated with fluid resuscitation, which is much more significant than previously recognized. Administration of whole blood to a shocked patient is not successful if blood cannot reach the capillary exchange vessels (capillary no reflow). The no reflow solution allows oxygen-carrying whole blood to migrate into the capillary space, where it can affect much needed oxygen transfer to ischemic tissues. This reduces lactate, reverses the accrued oxygen debt, and dramatically increases survival.

[0030] The compositions described herein are useful for hospital blood transfusion for patients with metabolic and cardiovascular dysfunction (e.g., as indicated by plasma lactate greater than 2.5 mM).Other applications include 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 when there is blood loss or cardiovascular collapse.The product may also be used in forward field hospitals in military conflict zones, in ground and airborne 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 present invention in more detail, it should be understood that the present invention is, of course, not limited to such specific embodiments. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims.

[0032] When a range of values ​​is provided, it is understood that each intervening value 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 any other stated or intervening value within that stated range, is included in the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the scope of the disclosure, subject to any specifically excluded boundary within that range. When the stated 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 illustrative methods and materials are described.

[0034] All publications and patents cited herein are incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated herein to disclose and describe the methods and / or materials in connection with which the publications are cited. 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 is not entitled to antedate such publication by virtue of prior invention. Additionally, dates of publications provided may need to be independently confirmed and may differ from the actual publication dates.

[0035] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be written to exclude any element. As such, this statement is intended to serve as a predicate for the use of specialized terminology such as "sole," "only," and the like, or the use of "negative" limitations in connection with the recitation of claim elements.

[0036] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. The methods described may be carried out in the order of events described or in any other order which is logically possible.

[0037] The present invention is further illustrated by the following non-limiting examples which further describe the invention and are not intended, nor should they be construed, as limiting the scope of the invention.

[0038] Example 1 Sizing of PEG polymers for hemorrhagic shock resuscitation Early studies in a robust rodent model of lethal hemorrhagic shock and low-volume resuscitation (LVR) showed that a typical impermeable molecule was highly effective, doubling the low-volume resuscitation (LVR) time, an indicator of resistance to shock. Other cardiovascular and metabolic outcomes were also improved two-fold versus saline volume control groups. To optimize efficacy, we searched for impermeable molecules with an osmotic reflection coefficient less than 1 (pure swelling agents such as albumin that remain in the capillary space) and greater than 0 (pure non-permeable agents such as gluconic acid that are free to equilibrate between the capillaries and interstitial spaces). We found that PEG polymers greater than 10k but less than 100k were attractive candidates. Sizing studies in shock conditions were performed, with results shown in LVR time, post-resuscitation arterial pressure, and post-resuscitation plasma lactate accumulation as indicators of oxygen debt. These studies are summarized in Figure 3.

[0039] Results showed that PEG-8k produced a 2-3 fold increase in shock resistance, similar to gluconic acid and consistent with its molecular reflectance coefficient. PEG polymers between 20-35k produced optimal results in the rodent shock model, as they had the highest LVR times, highest peripheral mean arterial pressures, and lowest final lactate values. In fact, PEG-20k and -35k reduced lactate from 10 mM to near baseline (1.2 mM) in resuscitation, indicating repayment of oxygen debt at 24 hours. Low-volume resuscitation with PEG-100k produced good results based on LVR fold, but the rats' MAP was very low (approximately 40 mmHg 4 hours after resuscitation) and lactate rose to near 10 mM, indicating reaccumulation of oxygen debt, and the rats began to deteriorate. Thus, PEG polymer sizes between 20-35 kDa appear to be optimal for resuscitation after lethal shock.

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

[0041] Decreasing the concentration to 5% (10% EBV dose) or administering up to 5% EBV in a 10% solution produced poor results. Similarly, delivering the same mass of PEG-20k but half the volume (20% solution delivered in a 5% EBV dose) was inferior, suggesting that the same effective mass of PEG-20k requires a minimum amount of isotonic vehicle (lactated Ringer's solution components). This is understood from the mechanism of moving isotonic solution out of the cells and refilling the capillary space. A minimum fluid volume of 10% EBV (6.8ml / kg) is required. This is still within the upper limit of what would be considered a low-volume resuscitation volume. The 10% PEG-20k solution yielded optimal results, but it is doubtful that that concentration would be more effective, and the final lactate concentration was slightly higher at the end of the 240-minute LVR period, which was less beneficial (1.2mM vs. 2.5mM for 10% PEG-20k compared to 20% PEG-20k, respectively). The optimal PEG-20k dose is also compared to the performance of other known crystalloids (saline, Hextend, albumin) that may be used as LVR solutions in shock resuscitation. In another study, resuscitation with a solution containing 7.5% PEG-20k was not significantly different from a 10% solution.

[0042] Example 3 Formulation Optimization: ESR Effect High molecular weight PEGs, which have these beneficial effects in resuscitation after severe shock, also dramatically increase the erythrocyte sedimentation rate (ESR) when mixed with whole blood. Polyethylene glycol polymers can nonspecifically bind to biological and nonbiological substances. Furthermore, polymers with a molecular radius greater than 4 nM can bind and crosslink cells such as red blood cells, while polymers smaller than 4 nm do not. This is explained as a molecular weight cutoff between 10-20 kDa, where PEG-20k is large enough to interact with RBCs and smaller sizes than PEG-10k are not sufficient. One of the first observations working with a 10% PEG-20k IV solution in vivo in a preclinical model of shock showed the ability to rapidly sediment RBCs in whole blood samples taken after a single intravenous dose of PEG-20k (Figure 5-right side contains a 10% solution of PEG-20k. This image shows the extent of erythrocyte sedimentation after 10 minutes). This effect was quantified using classical Western ESR quantification in ex vivo human blood to determine the PEG-20k ESR effect. Sedimentation in normal blood at 60 minutes is approximately 2-6mm. This increases to 60mm when blood is diluted 1:9 with 10% PEG-20k, simulating dilution after LVR during shock.

[0043] We then measured the ESR rate using a standard Western ESR assay and attempted to block or attenuate the sedimentation effect by adding different concentrations of a family of small PEG polymers that act as competitive inhibitors of binding sites on the RBCs. Without being bound by theory, our hypothesis is that the large PEG polymers bind non-specifically to the RBC charged surface. When multiple RBCs attach to each large polymer, cross-linking occurs, increasing blood particle density and thereby causing them to rapidly sediment out of solution. We hypothesized that the smaller polymers have the same affinity for the surface of RBCs, but cannot accommodate multiple RBC binding and therefore do not tolerate cross-linking.

[0044] To test this hypothesis, we performed a systematic polymer block study. Small PEG polymers with molecular radii of less than 4 nm (molecular weight less than 10 kDa) were added to PEG-treated whole blood to competitively interfere with PEG cross-linking and ESR precipitation. Three commercially available PEG polymers (PEG-20k, PEG-35k, and PEG-lOOk) were tested for known therapeutic range shock. The results are shown in Figures 6a-c. We show very strong ESR effects (2x) with therapeutic concentrations of PEG-35k (Figure 6b) and PEG-100k (Figure 6c). The ability to suppress these ESR effects using small PEG polymers (PEG-lk-PEG-10k) is blunted as the molecular weight of the therapeutic PEG increases. In general, they require higher concentrations of blocker PEG polymers to produce a more suppressive effect compared to those seen using PEG-20k.

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

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

Claims

1. 1. A composition for restoring or increasing tissue perfusion in a subject in need of localized or widespread tissue perfusion, said composition comprising: 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 Contains 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 according to any one of claims 1 to 3, 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 any one of claims 1 to 5, wherein the water is deionized water.

7. The composition of any one of claims 1 to 6, 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: Polyethylene glycol polymer (PEG) with a molecular weight of 18,000 to 100,000 Da at a concentration of 5 to 20% w / v; PEG with a molecular weight of 1,000 to 10,000 Da at a concentration of 1 to 30% w / v and water, An intravenous infusion product, wherein said PEG having a molecular weight of 18,000 to 100,000 Da and said PEG having a molecular weight of 1,000 to 10,000 Da are dissolved or dispersed in said water.

9. A composition for restoring or increasing tissue perfusion in a subject in need of localized or widespread tissue perfusion according to any one of claims 1 to 7, comprising: A composition comprising a therapeutically effective amount of said composition.

10. The composition according to any one of claims 1 to 7 and 9, A composition for intravenous administration.

11. The composition according to any one of claims 1 to 7, 9 and 10, The composition, wherein the subject is a subject suffering from global or localized reduced tissue perfusion due to cardiogenic or non-cardiogenic shock.

12. The composition according to any one of claims 1 to 7 and 9 to 11, Compositions for use in conjunction with the simultaneous or sequential administration of cells or acellular oxygen carrier solutions.

13. 13. The composition of claim 12, The composition, wherein the acellular oxygen carrier solution is a hemoglobin-based oxygen carrier (HBOC) or the cellular oxygen carrier solution is whole blood or packed red blood cells.

14. 14. The composition according to claim 12 or 13, A composition, wherein the amount of said cellular oxygen carrier solution is no more than 50% of the estimated blood volume required in the absence of said composition.

15. The composition according to any one of claims 12 to 14, The cell or acellular oxygen carrier solution is administered within 12 hours of administration of the composition.

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