Compositions and methods for priming a heart-lung bypass machine

Abstract

A composition useful for priming a heart-lung bypass machine is provided. The composition contains polyethylene glycol polymers (PEG) with a molecular weight of 18,000-100,000 Da at a concentration of 5-30% w / v; and water, wherein the PEG with a molecular weight of 18,000-100,000 Da is dissolved or dispersed in said water. The composition may further include PEG with a molecular weight of 1,000-10,000 Da at a concentration of 1-30% w / v dissolved or dispersed in said water. Methods for priming a heart-lung bypass machine and treating cardiopulmonary bypass injury are also provided.

Description

-7-ascending aorta and arch. Membrane oxygenators comprise hollow microporous polypropylene fibers (100-200 pm internal diameter). Blood flows outside the fiber while gases pass inside the fiber, thus separating the blood and gas phases. They have lesser propensity for air embolism and give greater accuracy in blood gas control. Some embodiments have an integrated filter to manage emboli, thus making additional arterial filters unnecessary. A heat exchanger is integrated with the oxygenator and placed proximal to it to reduce the release of gaseous emboli due to alterations in the temperature of saturated blood. The tubing is generally made of PVC, due to PVC's durability and acceptable haemolysis rate. The reservoir collects the blood drained from the heart. Open reservoirs are more commonly used. They allow passive removal of entrained venous air along with the option of applying vacuum to assist drainage. They integrate a separate cardiotomy, and defoaming circuit to process suctioned blood. When they are used, a safe level of blood in the reservoir is maintained to avoid air entry into the arterial circuit. Closed reservoirs have a limited volume capacity, but offer a smaller area of blood contact with artificial surfaces. This produces less inflammatory activation, better sterility and reduces post-operative transfusion. They, however, require a separate circuit for processing suctioned blood. Other circuit components include the gas line and blender, which delivers fresh gas to the oxygenator in a controlled mixture. The set FiO2 determines PaO2 while total flow determines PaCO2 on the bypass. The arterial line filter is present distal to the pump and removes particulate matter more than 20-40 pm in size. Depending on the pre-bypass haemoglobin and priming volume, addition of external blood may be required to maintain a target haematocrit on bypass (21%-24% in adults and 28%-30% in children). The following equations are used: Total circulating volume (TCV) = Patient's blood volume + priming volume Target haematocrit (Het) on CPB = Patient's blood volume (PBV) x Hct / TCV Blood required on prime = (Target Het x TCV) - (Pt. Het x PBV) / Hct of donor blood Cardiac index of a 70 kg adult with normal metabolism at 37°C is 2.2-2.4 L / m2 / min. For each 1°C decrease in temperature, the required cardiac output reduces by 7%, and the pump flow can be reduced by an equivalent factor. Knowing the body surface area (BSA) of -8-the patient, the required pump flow is as follows: Pump flow rate = BSA x Cardiac index For a bypass procedure, a surgeon will place a cannula in the right atrium, vena cava, or femoral vein to withdraw blood from the body. The cannula used to return oxygenated blood is usually inserted in the ascending aorta, but there is a possibility that it is inserted in the femoral artery, axillary artery, or brachiocephalic artery according to the demand of the surgery. After the cannula is inserted, venous blood is drained from the body by the cannula into a reservoir. This blood is then filtered, cooled, or warmed, and oxygenated before it returns to the body through a mechanical pump. The bypass circuit must be primed with fluid and all air expunged from the arterial line / cannula before connection to the patient. In embodiments of the present disclosure, the circuit is primed with a priming fluid as described herein. Operations requiring the opening of the chambers of the heart, for example mitral valve repair or replacement, requires the use of CPB. This is to avoid engulfing air systemically, and to provide a bloodless field to increase visibility for the surgeon. The machine pumps the blood and, using an oxygenator, allows red blood cells to pick up oxygen, as well as allowing carbon dioxide levels to decrease. This mimics the function of the heart and the lungs, respectively. ECMO is a simplified version of a CPB circuit that includes a centrifugal pump and an oxygenator to temporarily take over the function of heart and / or the lungs. ECMO is useful for post-cardiac surgery patients with cardiac or pulmonary dysfunction, patients with acute pulmonary failure, massive pulmonary embolisms, lung trauma from infections, and a range of other problems that impair cardiac or pulmonary function. During bypass, there are a number of associated physiologic problems induced by the interactions of the machine’s artificial surfaces and the patient’s blood and tissues that can worsen outcomes, extend hospital stays, and even lead to death. Specific categories of derangements have both independent and inter-related mechanisms of action, which complicates care of the patient. The priming fluid described herein may be used to prevent or treat any one or more of the following conditions. 1. Inflammation: Both the blood cell components (i.e. red blood cells, platelets, and white blood cells) and the non-cellular humoral components of blood (i.e. antibodies, -9- complement) interact with the artificial surfaces of the bypass machine to trigger an acute inflammatory response via multiple mechanisms / pathways. The activation, generation, and expression of thrombin, complement, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators produce systemic inflammation that is amplified by redundant cascades and contribute to other physiological derangements. Activation of surface receptors on mononuclear and polymorphonuclear inflammatory cells cause production of local inflammatory mediators such as cytokines, chemokines, and lipids. These mediators activate inflammation and spill into the general circulation to produce systemic inflammatory response syndrome (SIRS) that can have effects on the cardiovascular and other organ systems manifesting as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency (AKI), and neurocognitive decline. Inflammatory mediators also induce capillary leakage of fluid into the interstitial spaces leading to volume loss and local tissue swelling. Local platelet activation and red blood cell rouleaux formation along with activation of clotting can cause regional decreases in capillary flow followed by tissue and cell ischemia, which leads to metabolic cell swelling and compression of capillary flow in a self-amplifying cycle. Finally, cytokines in the circulation can cause the heart to beat less strongly because many inflammatory mediators alter cardiac contractility. This further compromises the circulation. 2. Coagulopathy: Dysregulated coagulation can be induced by initiation of coagulation cascades with both pro- and anti-coagulant proteins, leading to platelet activation and dysfunction as well as depletion of circulating clotting factors. Activation of coagulation and inflammation are closely linked through proteases like tissue factor, which is expressed on mononuclear cells and mediates host defense, and thrombin, which activates endothelial cells and has direct chemoattractant activity for polymorphonuclear leukocytes and monocytes. 3. Capillary leak, fluid shifts, and perfusion: Leaky capillaries and mediators produced by cellular inflammation cause water and electrolytes to egress the capillary spaces and load outside the cell where they cause the blood volume and pressure to fall. Fluid leak produces unfavorable effects on tissue perfusion and oxygen transfer due to hemodynamic and microcirculatory changes as well as the newly formed water fluid layer that serves to limit diffusion of oxygen from the capillary space to the cell mitochondria. Conversely, the opposite occurs in the lungs where an extravasated water barrier limits diffusion of oxygen from the lung alveoli into the red cell in the pulmonary capillary space. This limits oxygenation and can lead to desaturation of hemoglobin. This third spacing of fluid can be severe and progress -10-for days after the CPB period. The presence and amount of accumulated third space fluid is directly related to post-pump morbidity and mortality. As little as 500 ml of extracellular fluid accumulating in the tissues after bypass can cause significantly poorer outcomes in the recovery period. As hemodynamic changes occur from fluid shifts and capillary derecruitment through these shifts and from inflammation, the perfusion of vital organs and tissues decreases and can remain low for 24 hours after discontinuation of CPB. The fall in tissue perfusion is serious since this limits oxygen transfer to tissues, which is the primary goal of the cardiovascular and respiratory systems. This causes regions of tissue ischemia and metabolic derangements that worsen patient outcomes. 4. Acute kidney injury: Acute kidney injury (AKI) is a common complication after cardiopulmonary bypass assisted cardiac surgery. The incidence of post-CPB AKI is about 25% with 5% being serious enough to require dialysis. Milder forms of non-dialysis dependent AKI that present with mild elevations in plasma creatinine and BUN are independent risk factors for serious complications after surgery, including death. CPB leads to 20% decreased renal oxygen delivery to the renal capillaries, which worsens after removal from bypass. This results in tubular ischemia and release of tubular injury biomarkers. Together, the effects of CPB alone on kidney function are enough to put the patient at risk of poor outcomes, higher morbidity, and increased mortality. Combined with the other non-renal effects it has on third spacing, poor tissue perfusion in all organs, and inflammation, bypass patients face longer hospital stays with both non-life-threatening and life-threatening complications, which drives up health care costs. Further embodiments provide a method for treating cardiopulmonary bypass injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PEG composition as described herein. The PEG polymers rapidly transfer water out of swollen ischemic cells and leaky interstitial compartments into the vascular capillary space due to its unique size and hydrophilic properties. The therapeutic PEG polymers force water redistribution using multiple osmotic gradients across the microcirculation because the biophysical behavior of this size polymer causes unequal distributions in the capillary band interstitial spaces (Figure 1). This water transfer property is used in CPB to prevent water from leaving the vascular spaces, which is a major problem causing CPB injury and perfusion problems after recovery from bypass. -11- This PEG composition described herein can prevent or attenuate the development of cardiopulmonary bypass injury and / or treat cardiopulmonary bypass injury. CPB may result in various injuries including SIRS, ischemia-reperfusion injury, lung injury (e.g. ALI or ARDS), neurological / brain injury, myocardial disfunction, kidney injury, pancreatitis, and other organ damage. Lung injury is associated with low arterial oxygen tension or high carbon dioxide tension. Some embodiments include a step of detecting or diagnosing a CPB injury prior to administering the PEG composition. Administration of the PEG composition (e.g. intravenously) as a rescue therapy to subjects already showing pump bypass injury can correct their perfusion defects and inflammation, independent of prior priming with the PEG composition. The PEG composition may be administered in an amount of 100-2000 ml, e.g. 200-1500 ml, e.g. 250-1000 ml. The composition may be administered over a time period of 5-120 minutes, e.g. 10-90 minutes, e.g. 15-60 minutes. The composition may be administered immediately after the bypass or within 24 hours of the bypass, e.g. within 1-12 hours of the bypass. The composition may be added simultaneously with or prior to administration of a cellular or acellular oxygen carrier solution. In some embodiments, the cellular or acellular oxygen carrier solution is administered within 12 hours, e.g. within 10, 8, 6, 4, 2, or 1 hour, of administering the composition. In some embodiments, the amount of the cellular oxygen carrier solution administered is 50% or less, e.g. 40%, 30%, 20%, 10%, or 5% or less, of the estimated blood volume that would otherwise be needed in the absence of the composition. The solution described herein may be administered by any suitable means such as via intra-arterial, intravenous, intraosseous, or intracardiac routes. The term “subject” or “patient” generally refers to any mammal, typically humans. The solutions and methods described herein also have veterinary applications including, but not limited to, companion animals and farm animals. As used herein, the terms “effective amount,” or “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease or injury, or any other desired alteration of a biological system, such as the reduction or inhibition of metabolic cell and tissue swelling. Before exemplary embodiments of the present invention are described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as -12-such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, 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 any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference 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. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features -13- which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLE 1. Cellular Inflammation Studies It is contemplated that concentration-dependent passivation of Peripheral Blood Mononuclear Leukocytes (PBMNL) occurs with a PEG priming fluid as described herein, which abrogates the proliferative and cytokine response to antigen presentation. Rationale Activation of inflammation in CPB is complex, involving complement, endotoxin, and ischemia through acute- and delayed-phase responses that require cell-to-cell communication and migration using signaling molecules and surface receptors. Cellular camouflage is a phenomenon where large molecules can bind (specifically or non-specifically) to cell surfaces to cover and mask activation sites. Since a significant pathophysiological mechanism of CPB involves nonspecific immunological activation and cytokine release, it may be possible to use immuno-camouflage to short-circuit cell activation and mediator release during CPB to curb post-bypass injury. Polymers of polyethylene glycol (PEG) have been demonstrated to have immune-camouflage potential, and a new anti-shock solution (PM-208) comprising PEG-20k and PEG-8k as active pharmacological agents may have similar effects. Thus, the objective of this study is to determine if PM-208 IV solution can cause immunological passivation and camouflage in mononuclear cell proliferation assays as proof-of-concept for using PM-208 as a novel polymer-based crystalloid pump prime solution in CBP and ECMO. If we can demonstrate a parallel interruption in communication and inflammation in a similar model using delayed type hypersensitivity responses in PBMNL cultures in-vitro, then the same likely happens in CPB patients in-vivo using the same concentrations of polymers. Outcomes Cell proliferation indices and cytokine synthesis in both the mitogen proliferation assay and the two-way mixed lymphocyte reaction assay. -14- Design and Methods Mitogen proliferation Assays: Peripheral Blood Mononuclear Lymphocytes (PBMNL) are obtained from healthy human volunteers in accordance with the local IRB protocol. Peripheral venous blood (40-ml) is drawn into citrated anticoagulated tubes. After centrifugation for 20 minutes at 400 x g, the buffy coat is removed from platelets and RBCs. After washing, PBMNLs are purified by isopycnic gradient centrifugation over a cushion of 54% Percoll at 500 x g for 30 minutes. The cells present at the Percoll-plasma interface are washed in PBS and reconstituted in DMEM media and used in the Con-A proliferation assays and the 2-way MLR. Briefly, in Con-A proliferation assays, 106 mononuclear cells per ml of DMEM are plated in 96-well round-bottom microtiter trays in triplicate at 200,000 cells / well. Some cells are stimulated with Con-A (20 ug / ml) with or without PM-208 (10-0.1 mg / ml PEG-20k component). The plates are incubated for 48 h at 37°C in an 8% C02 humidified atmosphere. After 48 h, 1 pCi of tritiated thymidine [3H]TdR is added to each well and allowed to incubate an additional 18 h. Cells are then deposited on glass filters using a Tomtec® manual cell harvester and [3H]TdR uptake is measured by scintillation spectroscopy and used as an index of cell proliferation (expressed as cpm of [3H] uptake). Mixed Lymphocyte Reaction Assays: Two-way MLR cultures established with isolated mononuclear cells from two different volunteers are used. Cells from each of two different individuals (stimulator and responder cells) are combined at a 1: 1 ratio (total 10' cells / ml). These cells are plated in triplicate wells per condition (at 200,000 cells / well) in 96-well microtiter plates using complete DMEM media. MLR cultures are incubated at 37 °C in an 8% CO2 humidified atmosphere for 6 days. One pCi [3H]TdR is then added to each well for 18 h. Cells are then harvested and [3H] uptake determined by scintillation spectroscopy. Alloantigen-induced cell proliferation is expressed as the stimulation index or the percent increase in proliferation induced by allogeneic stimulators, relative to the changes in proliferation observed with auto stimulator controls. Auto stimulator control cultures contain syngeneic stimulators and syngeneic responder cells at a 1:1 ratio. Cytokine Assays: Conditioned media from the proliferation assays described above are assayed for IL-1, IL-2, TNFa, and INFg by ELISA. Results are normalized to cell numbers. Table 1. Experimental Design and Groups Experiment PM-208 (mg / ml) Con-A 0 0.1 1 2 5 10 -15- MLR 0 0.1 1 2 5 10 CON-A = Concavalin-A (plant mitogen stimulus), MLR = Mixed Lymphocyte Reaction (Alloantigen stimulus). PM-208 is polyethylene glycol 20,000 IV solution in its commercial form. Each experiment is repeated in four independent cell isolation protocols using peripheral blood mononuclear leukocytes isolated from peripheral human blood donors. Analysis The antigen presentation assays will be analyzed by comparing the proliferation index between untreated (control) and cells treated with increasing doses of PM-208. The concentration ranges of PM-208 are selected based on known peak blood levels of the active polymers when a single dose is administered to trauma patients. Similar concentrations and doses will be seen in CPB patients using the same loading dose of PM-208. The proliferation index is calculated as the tritiated thymidine uptake in the stimulated cells (either with Con-A or with alloantigen) divided by the tritiated thymidine uptake observed in naive cells without antigen stimulation. The anticipated outcomes in this experiment are that PM-208 dose dependently attenuates or prevents the mononuclear cell proliferation index stimulated by both plant mitogens and alloantigen stimulation. EXAMPLE 2. ECMO Studies It is contemplated that priming ECMO (CPB) circuits with PM-208, relative to standard of care (Plasma-Lyte®), prevents time-dependent decreases in tissue perfusion and early signs of acute kidney injury associated with ECMO use. Rationale The use of CPB and ECMO is known to cause significant derangements in tissue perfusion from third spacing and from capillary no-reflow. While this is likely due to activation of inflammatory reactions from the interactions of the cellular immune and coagulation components of the blood with the artificial reactive surfaces on the inner tubing and membrane oxygenator, the end result of poor tissue perfusion causes most of the pump bypass sickness. The objective of the study is to determine whether PM-208, utilized as a prime solution, can prevent changes in tissue perfusion from developing and be used as a rescue solution in cases where perfusion changes in the tissue have already occurred. Outcomes Tissue perfusion data from direct visualization of capillary flow (Orthogonal -16-polarization spectral imaging, OPSI) and biochemical data (plasma lactate), hemodynamic data including plasma volume expansion measurements, and early indicators of Acute Kidney Injury (AKI). Inflammatory mediators and cytokines and coagulation and platelet function (TEG) of the blood are measured as secondary outcomes. Design and Methods Experiments are conducted in juvenile (20 kg, 3-4 months old) Yorkshire swine of either sex. All studies are acute in nature. After anesthesia with ketamine / xylazine for induction, the pigs are intubated and maintained in a state of surgical anesthesia using inhalation isoflurane gas (0.5-3%). Vascular catheters are placed in the femoral artery for blood pressure monitoring and chemistry analysis and in the carotid artery and external jugular vein for arterial and venous access for A-V ECMO. ECMO studies are used for simplicity but similar or worse pump bypass injury effects are expected for cardiopulmonary bypass, which has larger surface areas and more complicated vascular access. The swine are ventilated until start of ECMO when the ventilator is largely turned off except for 2-3 breath every minute to prevent atelectasis in the lungs. An affinity Pixie™ Pediatric Membrane Oxygenator circuit with a venous reservoir (Medtronic) is used for ECMO, run at a flow rate of 2 liters per minute for 10 hours with 100% oxygen sweep of about 1 liter per minute. Global changes in perfusion are monitored hourly by plasma lactate numbers while capillary bed and perfusion imaging of the ileal mucosa and sublingual mucosa is monitored every 120 minutes after ECMO with baseline values taken before ECMO bypass. Arterial blood gases are measured hourly to monitor and maintain adequate oxygenation and CO2 removal. Systemic heparinization (loading with 600 u / lg) is used to prevent serious coagulation of the circuit during use. Heparin is administered as needed to maintain the blood ACT value between 180-220 seconds. A bedside ACT machine is used to measure ACT values while on bypass at least every hour. The design of the study is shown in detail in Table 2. Generally, a control goup using Plasma-Lyte® as the system prime solution establishes the time-dependent perfusion defects while a PM-208 priming group will demonstrate mitigation of these effects. Finally, a group primed with Plasma-Lyte® will run for 8 hours to establish documented perfusion changes followed by IV administration of PM-208 to show a reversal of those perfusion changes toward normal values (Rescue therapy). Table 2. Experimental Design for ECMO Study in juvenile swine Treatment Group ECMO Treatment Time Data n -17- Duration Collection 1. Control-Plasma-Lyte® Prime 10 hrs Start of ECMO (prime) Hourly 5 2. PM-208 Prime 10 hrs Start of ECMO (prime) Hourly 5 3. Plasma-Lyte® Prime PM-208 Rescue 10 hrs Start of ECMO (prime) 8 hrs after ECMO (rescue) Hourly 5 PM-208 (Perfusion Medical, Inc) is a 10% solution of polyethylene glycol 20,000 and 1% polyethylene glycol 8,000 in lactated Ringers solution. Plasma-Lyte® is a balanced electrolyte solution most used for priming bypass circuits in the US. ECMO = Extracorporeal Membrane Oxygenation is used to demonstrate injury induced by both ECMO and Cardiopulmonary Bypass (CPB) Analysis In the ECMO studies in pigs, we will use the first group to establish a perfusion defect from the values obtained before the start of ECMO. We anticipate a time dependent drop in tissue perfusion starting about 4 hours after the start of ECMO. This control defect will be used to benchmark the effects of changing the prime solution to PM-208. It is anticipated that PM-208 will abolish these perfusion defects seen with a standard of care prime solution (Plasma-Lyte®). Finally, we will induce tissue perfusion abnormalities as in the control group but we will rescue those changes after 8 hours of ECMO by administering an IV infusion of PM-208 equivalent to about the same volume used to prime the circuits. This is done in the last experimental group. We anticipate that a rescue treatment will also normalize tissue perfusion in the 2 hours after it is administered. Statistical Analysis Descriptive statistics are first calculated along with sample distribution analysis. With few exceptions, parametric data analysis are done by using a parametric ANOVA followed by a Bonferroni correction. Nonparametric data (transformed values such as indices) are analyzed by the Kruskal-Walis test. Linear regression analysis is used for standard curves used in chemical assays. A P value of less than or equal to 0.05 is considered statistically significant. Each group may include 6 volunteer donors or donor sets. -18- While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above, but should further include all modifications 5 and equivalents thereof within the spirit and scope of the description provided herein.

Claims

1. A method for priming a heart-lung bypass machine, comprising:flowing a priming fluid through the heart-lung bypass machine, wherein the priming fluid comprisespolyethylene glycol polymers (PEG) with a molecular weight of 18,000-100,000 Da at a concentration of 5-30% w / v; andwater, wherein said PEG with a molecular weight of 18,000-100,000 Da is dissolved or dispersed in said water.

2. The method of claim 1, wherein the priming fluid further comprises PEG with a molecular weight of 1,000-10,000 Da at a concentration of 1-30% w / v dissolved or dispersed in said water.

2. The method of claim 1, wherein the heart-lung bypass machine is a cardiopulmonary bypass (CPB) machine.

3. The method of claim 1, wherein the heart-lung bypass machine is an extracorporeal membrane oxygenation (ECMO) machine.

4. The method of claim 1, wherein a total volume of the priming fluid flowed through the heart-lung bypass machine is 100-1000 ml.

5. The method of claim 1, wherein the PEG with the molecular weight of 18,000-100,000 Da is PEG with a molecular weight of 20,000 Da.

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

7. The method of claim 1, wherein the priming fluid further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.-208. A heart-lung bypass machine comprising:a priming fluid contained within one or more components of the heart-lung bypass machine, wherein the priming fluid comprisespolyethylene glycol polymers (PEG) with a molecular weight of 18,000-100,000 Da at a concentration of 5-30% w / v; andwater, wherein said PEG with a molecular weight of 18,000-100,000 Da is dissolved or dispersed in said water.

9. The heart-lung bypass machine of claim 8, wherein the priming fluid further comprises PEG with a molecular weight of 1,000-10,000 Da at a concentration of 1-30% w / v dissolved or dispersed in said water.

10. The heart-lung bypass machine of claim 8, wherein the heart-lung bypass machine is a cardiopulmonary bypass (CPB) machine.

11. The heart-lung bypass machine of claim 8, wherein the heart-lung bypass machine is an extracorporeal membrane oxygenation (ECMO) machine.

12. The heart-lung bypass machine of claim 8, wherein a total volume of the priming fluid contained within one or more components of the heart-lung bypass machine is 100-2000 ml.

13. The heart-lung bypass machine of claim 8, wherein the PEG with the molecular weight of 18,000-100,000 Da is PEG with a molecular weight of 20,000 Da.

14. The heart-lung bypass machine of claim 8, wherein the water is deionized water.

15. The heart-lung bypass machine of claim 8, wherein the priming fluid further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.

16. A method for treating cardiopulmonary bypass injury in a subject in need thereof,-21-comprising:administering to the subject a therapeutically effective amount of a composition comprising polyethylene glycol polymers (PEG) with a molecular weight of 18,000-100,000 Da at a concentration of 5-30% w / v; andwater, wherein said PEG with a molecular weight of 18,000-100,000 Da is dissolved or dispersed in said water.

17. The method of claim 16, wherein the composition is administered intraveneously.

18. The method of claim 16, wherein the composition further comprises PEG with a molecular weight of 1,000-10,000 Da at a concentration of 1-30% w / v dissolved or dispersed in said water.

19. The method of claim 16, wherein the PEG with the molecular weight of 18,000-100,000 Da is PEG with a molecular weight of 20,000 Da.

20. The method of claim 16, wherein the water is deionized water.

21. The method of claim 16, wherein the composition further comprises one or more of sodium chloride, sodium lactate, potassium chloride, calcium chloride, and magnesium chloride.

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