Low-Volume Resuscitation for Hemorrhagic Shock: Understanding the Mechanism of PEG-20k

Abstract

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.

Thromboelastographic analysis of novel polyethylene glycol based low volume resuscitation solutions

“…Recently, polyethylene glycol (PEG) polymers of specific molecular weight ranges have been used in crystalloid solutions to act as highly effective Low volume Resuscitation (LVR) solutions [ 2 , 8 – 10 ]. These polymers non-energetically move isotonic fluid from intracellular and interstitial spaces into the capillary space by osmotic flow mechanics in response to metabolic cell swelling that occurs in shocked and ischemic tissues.…”

“…PEG-20k molecules are impermeant to cells and selectively partition in the capillary and interstitial spaces in a ratio of 2:1, respectively [ 2 , 10 ]. This pulls isotonic fluid out of swollen cells and tissues.…”

“…This pulls isotonic fluid out of swollen cells and tissues. As water flow moves from the interstitial spaces to the capillaries, the capillary exchange in the tissues dramatically improves under very low volume conditions because the microcirculation is decompressed, lowering the resistance to flow, while the capillary spaces are re-loaded with volume and pressure for driving flow [ 10 ]. This causes rapid clearance of lactate, increased blood pressure, and tolerance to the low volume state [ 8 ].…”

Physician Awareness of Immune Responses to Polyethylene Glycol‐Drug Conjugates

“…PEGylation has become a mainstay in biopharmaceutical production: a search of http://www.clinicaltrials.gov for studies of interventions with the keyword “PEG” revealed that there are currently 75 active (finished recruiting) trials involving a PEGylated therapeutic, and an additional 219 open studies (not yet recruiting, recruiting, or available for expanded access). Unmodified PEG alone is also under development for intravenous administration as a low‐volume resuscitation solution for hemorrhagic shock …”

“…Unmodified PEG alone is also under development for intravenous administration as a low-volume resuscitation solution for hemorrhagic shock. 3,4 Surprisingly, animal and human studies have shown that some PEG-modified therapeutics can induce antibodies that specifically bind PEG, leading to rapid elimination, loss of efficacy, and a marked increase in risk of serious adverse events. 1,[5][6][7][8] For example, in 2016 a phase III study (NCT01848106) of a PEGylated RNA aptamer (pegnivacogin) for inhibition of coagulation factor IXa was halted following serious adverse events (SAEs) linked to anti-PEG antibody (APA) responses.…”