(A-30) Emergency Resuscitation of Hemorrhaging Patients with Next-Generation Oncotic Polymers

Introduction:: Hemorrhagic shock is the leading cause of death across civilian and military populations, with 150,000 trauma-related deaths annually in the United States alone^1,2. Patient rescue is achieved by resuscitation, which reintroduces fluid into the bloodstream to prevent hypovolemia and to recover blood pressure and tissue oxygenation³. Traditional resuscitants operate on the principle of aggressive fluid replacement, a strategy which can interfere with coagulation, is impractical in the prehospital setting, and makes no therapeutic effort to seal endothelial barriers and prevent further bleeding⁴. However, recent efforts have demonstrated the powerful oncotic resuscitation profiles of high molecular weight, hydrophilic polymers such as PEG-20k⁵.

We are developing a suite of novel oncotic polymers for emergency resuscitation applications and investigating the effects of polymer molecular weight, composition, and architecture upon oncotic profiles. Our research aims to develop next-generation low-volume resuscitants for the treatment of traumatic injury. To maximize the efficiency of patient rescue, we have developed a strategy for specifically targeting damaged endothelium to provide resuscitation directly at the site of vascular injury. This novel targeted approach achieves highly efficient site-specific fluid recovery for resuscitation, which may also prevent the development of edema in recovering patients.


Materials and Methods:: Our oncotic polymers are prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization. The molecular weight and architecture/size of polymers are characterized by gel permeation chromatography (GPC). The resuscitative profiles of our polymers are assessed for their ability to recover mean arterial pressure (MAP) and achieve survival in an in vivo rat catheter hemorrhage model. To ensure that patient coagulation will not be affected by resuscitation, each of our polymers is evaluated through in vitro clot contraction assays including rotational thromboelastometry (ROTEM), rheometric clot firmness assays, and thrombin generation assays. Flow cytometry assays with human umbilical vein endothelial cells (HUVECs) are used to confirm binding between fluorescently labeled oncotic polymer and damaged endothelium.

Results, Conclusions, and Discussions:: Through analysis of our suite of oncotic polymers, we are now able to understand the relationship between polymer architecture/composition and desirable oncotic properties for resuscitation. Through our in vivo model, we have demonstrated that a 10% blood volume dose of oncotic polymer recovers MAP and achieves resuscitation and survival after severe hemorrhages in which 60-70% blood volume was lost (Figure 1a). Our oncotic polymers are competitive with PEG-20k, meaning that resuscitation is achieved with dramatic improvement over the current standard of care. Furthermore, we demonstrate for the first time an oncotic polymer capable of achieving resuscitation without interfering with coagulation, an imperative but historically ignored criterion for trauma therapies⁵ (Figure 1B). This uniquely site-specific approach to resuscitation presents a long overdue improvement in the treatment of hemorrhagic shock.

Acknowledgements (Optional): :

References (Optional): : 1. Rahbar, E. et al. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J. Transl. Med. 13, 117 (2015).

2. US Department of Health & Human Services. Traumatic Brain Injury in the United States - A Report to Congress. (1999).

3. Revell, M., Greaves, I. & Porter, K. Endpoints for Fluid Resuscitation in Hemorrhagic Shock. J. Trauma Acute Care Surg. 54, (1992).

4. Mangino, M. J., Liebrecht, L., Plant, V. & Limkemann, A. Crystalloid and Colloid Resuscitation: Hypertonic Saline, Starches, Polymers, and Gelatins. in Crystalloid and Colloid Resuscitation (2018).

5. Mangino, M. J. Polyethylene glycol polymers in low volume resuscitation. (2020).