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Background Ischemia from organ preservation or donation causes cells and tissues to swell owing to loss of energy-dependent mechanisms of control of cell volume. These volume changes cause substantial preservation injury, because preventing these changes by adding cell impermeants to preservation solutions decreases preservation injury. The objective of this study was to assess if this effect could be realized early in uncontrolled donation after cardiac death (DCD) livers by systemically loading donors with gluconate immediately after death to prevent accelerated swelling injury during the warm ischemia period before liver retrieval. Methods Uncontrolled DCD rat livers were cold-stored in University of Wisconsin solution for 24 hours and reperfused on an isolated perfused liver (IPL) device for 2 hours or transplanted into a rat as an allograft for 7 days. Donors were pretreated with a solution of the impermeant gluconate or a saline control immediately after cardiac death. Livers were retrieved after 30 minutes. Results In vivo, gluconate infusion in donors immediately before or after cardiac death prevented DCD-induced increases in total tissue water, decreased vascular resistance, increased oxygen consumption and synthesis of adenosine triphosphate, increased bile production, decreased lactate dehydrogenase release, and decreased histology injury scores after reperfusion on the IPL relative to saline-treated DCD controls. In the transplant model, donor gluconate pretreatment significantly decreased both alanine aminotransferase the first day after transplantation and total bilirubin the seventh day after transplantation. Conclusion Cell and tissue swelling plays a key role in preservation injury of uncontrolled DCD livers, which can be mitigated by early administration of gluconate solutions to the donor immediately after death.

Hypovolemic shock reduces oxygen delivery and compromises energy-dependent cell volume control. Consequent cell swelling compromises microcirculatory flow, which reduces oxygen exchange further. The importance of this mechanism is highlighted by the effectiveness of cell impermeants in low-volume resuscitation (LVR) solutions in acute studies. The objectives of this study were to assess impermeants in survival models and to compare them with commonly used crystalloid solutions.Adult rats were hemorrhaged to a pressure of 30 mm Hg to 35 mm Hg, held there until the plasma lactate reached 10 mM, and given an LVR solution (5-10% blood volume) with saline alone (control) and saline with various concentrations of polyethylene glycol-20k (PEG-20k), Hextend, or albumin. When lactate again reached 10 mM following LVR, full resuscitation was started with crystalloid and red blood cells. Rats were either euthanized (acute) or allowed to recover (survival). The LVR time, which is the time from the start of the LVR solution until the start of full resuscitation, was measured as was survival and diagnostic laboratory values. In some studies, the capillary oncotic reflection coefficient was determined for PEG-20k to determine its relative impermeant and oncotic effects.PEG-20k (10%) significantly increased LVR times relative to saline (eightfold), Hextend, and albumin. Lower amounts of PEG-20k (5%) were also effective but less so than 10% doses. PEG-20k maintained normal arterial pressure during the low-volume state. Survival of a 180-minute LVR time challenge was 0% in saline controls and 100% in rats given PEG-20k as the LVR solution. Surviving rats had normal laboratory values 24 hours later. PEG-20k had an oncotic reflection coefficient of 0.65, which indicates that the molecule is a hybrid cell impermeant with significant oncotic properties.PEG-20k-based LVR solutions are highly effective for inducing tolerance to the low-volume state and for improving survival.

INTRODUCTION Polyethylene glycol-20k (PEG-20k) is highly effective for low-volume resuscitation (LVR) by increasing tolerance to the low-volume state. In our rodent shock model, PEG-20k increased survival and expanded the "golden hour" 16-fold compared to saline. The molecular mechanism is largely attributed to normalizations in cell and tissue fluid shifts after low-flow ischemia resulting in efficient microvascular exchange. The objective of this study was to evaluate PEG-20k as an LVR solution for hemorrhagic shock in a preclinical model. METHODS Anesthetized male Yorkshire pigs (30-40 kg) were hemorrhaged to a mean arterial pressure (MAP) of 35 to 40 mm Hg. Once lactate reached 7 mmol/L, either saline (n = 5) or 10% PEG-20k (n = 5) was rapidly infused at 10% calculated blood volume. The primary outcome was LVR time, defined by the time from LVR administration to the time when lactate again reached 7 mmol/L. Other outcomes measured included MAP, heart rate, cardiac output, mixed venous oxygen saturation, splanchnic blood flow, and hemoglobin. RESULTS Relative to saline, PEG-20k given after controlled hemorrhage increased LVR time by 16-fold, a conservative estimate given that the lactate never rose after LVR in the PEG-20k group. Survival was 80% for PEG-20k LVR compared to 0% for the saline controls (p < 0.05). Polyethylene glycol-20k also significantly decreased heart rate after hemorrhage and increased cardiac output, MAP, splanchnic flow, and mixed venous oxygen saturation. Falling hemoglobin concentrations suggested sizable hemodilution from fluid shifts into the intravascular compartment. CONCLUSIONS In a preclinical model of controlled hemorrhagic shock, PEG-20k-based LVR solution increased tolerance to the shock state 16-fold compared to saline. Polyethylene glycol-20k is a superior crystalloid for LVR that may increase safe transport times in the prehospital setting and find use in hospital emergency departments and operating rooms for patients awaiting volume replacement or normalization of cell, tissue, and compartment fluid volumes.