Background Hypovolemic shock reduces oxygen delivery and compromises energy dependent cell volume control. Consequent cell swelling compromises microcirculatory flow, which reducing 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 objective of this study was to assess impermeants in survival models and compare them to commonly used crystalloid solutions. Methods Adult rats were hemorrhaged to a pressure of 30–35 mm Hg, held there until the plasma lactate reached 10 mM, and given an LVR solution (5–10% blood volume) with saline alone (control), 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 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 labs. In some studies, the capillary oncotic reflection coefficient was determined for PEG-20k to determine its relative impermeant and oncotic effects. Results PEG-20k (10%) significantly increased LVR times relative to saline (8 fold), 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 labs 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. Conclusions PEG-20k based LVR solutions are highly effective for inducing tolerance to the low volume state and for improving survival.

Hemorrhagic shock leads to cell and tissue swelling and no reflow from compressed capillaries. Cell impermeants, including polyethylene glycol-20,000 (PEG-20k), reverse ischemia-induced cell swelling, extend low-volume resuscitation (LVR) time after shock, and increase tolerance to the low-volume state. The purpose of this study was to explore the mechanisms of action of PEG-20k containing LVR solutions. We hypothesized that PEG-20k acts as both an oncotic agent and an impermeant in the microcirculation, which moves water out of the space and into the capillaries to affect peripheral capillary filling and enhanced perfusion during the low-volume state. Rats were hemorrhaged until arterial lactate reached 9-10 mM/liter. Then, saline-based LVR solutions containing various impermeant materials were administered (10% blood volume). The LVR times for these solutions were determined by measuring the amount of time required for plasma lactate to climb back to 9 to 10 mM after LVR administration (low-volume tolerance). Capillary blood flow was measured by colored microspheres, and blood volume was measured by fluorescein isothiocyanate-labeled albumin dilution. Gluconate (impermeant), albumin (colloid), and PEG-20k (hybrid) increased LVR time over saline by 4-, 3-, and 8-fold, respectively. The combination of impermeant + albumin produced a biologic effect that was similar to PEG-20k alone. Capillary blood flow and plasma volume were decreased after shock with saline LVR but increased with PEG-20k, relative to saline. These data are consistent with the hypothesis that PEG-20k may act by establishing multiple osmotic gradients in the microcirculation to drive cell-to-capillary water transfer during hypovolemic shock.

Objective To determine the role of cell swelling in severe hemorrhagic shock and resuscitation injury. Summary Background Data Circulatory shock induces the loss of energy dependent volume control mechanisms. As water enters ischemic cells, they swell, die, and compress nearby vascular structures, which further aggravates ischemia by reducing local microcirculatory flow and oxygenation. Loading the interstitial space with cell impermeant molecules prevents water movement into the cell by passive biophysical osmotic effects, which prevents swelling injury and no-reflow. Methods Adult rats were hemorrhaged to a pressure of 30–35 mm Hg, held there until the plasma lactate reached 10 mM, and given a low volume resuscitation (LVR) (10–20% blood volume) with saline or various cell impermeants (sorbitol, raffinose, trehalose, gluconate, and Polyethylene glycol-20k (PEG-20k). When lactate again reached 10 mM following LVR, full resuscitation was started with crystalloid and red cells. One hour after full resuscitation, the rats were euthanized. Capillary blood flow was measured by the colored microsphere technique. Results Impermeants prevented ischemia-induced cell swelling in liver tissue and dramatically improved LVR outcomes in shocked rats. Small cell impermeants and PEG-20k in LVR solutions increased tolerance to the low flow state by 2 and 5 fold, respectively, normalized arterial pressure during LVR, and lowered plasma lactate after full resuscitation, relative to saline. This was accompanied by higher capillary blood flow with cell impermeants. Conclusions Ischemia-induced lethal cell swelling during hemorrhagic shock is a key mediator of resuscitation injury, which can be prevented by cell impermeants in low volume resuscitation solutions.