作者: Liebrecht, Loren K ; Eldering, Gerard ; Li, Ru ; Deitch, Rebecca ; Khoraki, Jad ; Bane, John ; Mangino, Martin J ; Broadway, Michael ; Archambault, Caitlin

Trauma is a leading cause of death in the United States. Advancements in shock resuscitation have been disappointing because the correct upstream mechanisms of injury are not being targeted. Recently, significant advancements have been shown using new cell-impermeant molecules that work by transferring metabolic water from swollen ischemic cells to the capillary, which restores tissue perfusion by microcirculatory decompression. The rapid normalization of oxygen transfer improves resuscitation outcomes. Since poor resuscitation and perfusion of trauma patients also causes critical illness and sepsis and can be mimicked by ischemia-reperfusion of splanchnic tissues, we hypothesized that inadequate oxygenation of the gut during trauma drives development of later shock and critical illness. We further hypothesized that this is caused by ischemia-induced water shifts causing compression no-reflow. To test this, the superior mesenteric artery of juvenile anesthetized swine was occluded for 30 minutes followed by 8 hours of reperfusion to induce mild splanchnic artery occlusion (SAO) shock. One group received the impermeant polyethylene glycol 20,000 Da (PEG-20k) that prevents metabolic cell swelling, and the other received a lactated Ringer's vehicle. Survival doubled in PEG-20k-treated swine along with improved macrohemodynamics and intestinal mucosal perfusion. Villus morphometry and plasma inflammatory cytokines normalized with impermeants. Plasma endotoxin rose over time after reperfusion, and impermeants abolished the rise. Inert osmotically active cell impermeants like PEG-20k improve intestinal reperfusion injury, SAO shock, and early signs of sepsis, which may be due to early restoration of mucosal perfusion and preservation of the septic barrier by reversal of ischemic compression no-reflow. SIGNIFICANCE STATEMENT: Significant advancements in treating shock and ischemia have been disappointing because the correct upstream causes have not been targeted. This study supports that poor tissue perfusion after intestinal ischemia from shock is caused by capillary compression no-reflow secondary to metabolic cell and tissue swelling since selectively targeting this issue with novel polyethylene glycol 20,000 Da-based cell-impermeant intravenous solutions reduces splanchnic artery occlusion shock, doubles survival time, restores tissue microperfusion, and preserves gut barrier function.

2023-09-01·Current Opinion in Biomedical Engineering

Engineered intravenous therapies for trauma

Article

作者: Pun, Suzie H ; Pichon, Trey J ; White, Nathan J

Trauma leading to severe hemorrhage and shock on average kills patients within 3 to 6 hours after injury. With average prehospital transport times reaching 1-6 hours in low- to middle-income countries, stopping the bleeding and reversing hemorrhagic shock is vital. First-generation intravenous hemostats rely on traditional drug delivery platforms, such as self-assembling systems, fabricated nanoparticles, and soluble polymers due to their active targeting, biodistribution, and safety. We discuss some challenges translating these therapies to patients, as very few have successfully made it through preclinical evaluation in large-animals, and none have translated to the clinic. Finally, we discuss the physiology of hemorrhagic shock, highlight a new low volume resuscitant (LVR) PEG-20k, and end with considerations for the rational design of LVRs.

2022-05-01·Annals of Surgery1区 · 医学

Superior Survival Outcomes of a Polyethylene Glycol-20k Based Resuscitation Solution in a Preclinical Porcine Model of Lethal Hemorrhagic Shock

1区 · 医学

Article

作者: Xu, Haoxuan ; Khoraki, Jad ; Kang, Hae Sung ; Aboutanos, Michel ; Wickramaratne, Niluka ; Archambault, Caitlin ; Blocher, Charles ; Li, Ru ; Mangino, Martin J ; Liebrecht, Loren

Objective:To compare early outcomes and 24-hour survival after LVR with the novel polyethylene glycol-20k-based crystalloid (PEG-20k), WB, or hextend in a preclinical model of lethal HS.Background:Posttraumatic HS is a major cause of preventable death. current resuscitation strategies focus on restoring oxygen-carrying capacity (OCC) and coagulation with blood products. Our lab shows that PEG-20k is an effective non-sanguineous, LVR solution in acute models of HS through mechanisms targeting cell swelling-induced microcirculatory failure.Methods:Male pigs underwent splenectomy followed by controlled hemorrhage until lactate reached 7.5–8.5 mmol/L. They were randomized to receive LVR with PEG-20k, WB, or Hextend. Surviving animals were recovered 4 hours post-LVR. Outcomes included 24-hour survival rates, mean arterial pressure, lactate, hemoglobin, and estimated intravascular volume changes.Results:Twenty-four-hour survival rates were 100%, 16.7%, and 0% in the PEG-20k, WB, and Hextend groups, respectively (P= 0.001). PEG-20k significantly restored mean arterial press, intravascular volume, and capillary perfusion to baseline, compared to other groups. This caused complete lactate clearance despite decreased OCC. Neurological function was normal after next-day recovery in PEG-20k resuscitated pigs.Conclusion:Superior early and 24-hour outcomes were observed with PEG-20k LVR compared to WB and Hextend in a preclinical porcine model of lethal HS, despite decreased OCC from substantial volume-expansion. These findings demonstrate the importance of enhancing microcirculatory perfusion in early resuscitation strategies.

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适应症	最高研发状态	国家/地区	公司	日期
心肌梗塞	临床2期	美国	-	-
心肌梗塞	临床2期	-	Thrombogenics, Inc.	-
心肌梗塞	临床2期	-	Katholieke Universiteit Leuven	-
心肌梗塞	临床2期	-	Bharat Biotech International Ltd.	-
心肌梗塞	临床2期	欧洲	-	-