Prolyl hydroxylase domain inhibitor for treating hemorrhagic or burn shock
US20250041302A1
Abstract
A majority of military casualties occur during the pre-hospital period. The cause of death is largely associated with massive traumatic bleeding that leads to organ damage due to sustained hypoxia. Currently, therapeutics are lacking at the point of injury to mitigate hypoxic damage and maintain the survivability of severe hemorrhage prior to reaching medical facilities. This invention addresses that by introducing a method of co-administering prolyl hydroxylase domain inhibitor (PHDi, MK-8617), anti-fibrinolytic agent (tranexamic acid), and bradykinin receptor antagonist (icatibant) as anti-hemorrhage agents in combination with resuscitation fluid treatment with colloid solution of 25% human albumin that has an advantage of relatively small volume requirement to maintain blood volume. In addition, a kit comprising anti-hemorrhage agents that can be easily carried to the battlefield is also provided here. The therapeutic application of those agents on or near the point of injury can stabilize hypoxia inducible factor-1 alpha and enhance blood clot formation, which improves the patient's cellular adaptation to hypoxia and reduce hemorrhage, and thus can decrease organ failure and increase the patient's survivability.
Description (excerpt)
STATEMENT AS TO RIGHTS OR INVENTIONS MADE UNDER SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support from the U.S. Army Institute of Surgical Research, a subordinate organization of the United States Army Medical Research and Materiel Command. BACKGROUND Severe trauma with hemorrhage is a leading cause of death in military casualties. Previous studies in both civilian and military trauma epidemiology suggest that the majority of trauma-induced death occurs during the pre-hospital period (1-3). For example, 87.3% of all injury mortality cases from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) combat casualties in 2001 and 2011 occurred prior to arrival at a medical treatment facility (MTF). Among those, 24.3% are due to potentially survivable injury, which is largely associated with hemorrhage (90.9%). Therefore, pre-hospital transport time and treatment capability are both important factors to determine the survivability and outcome of the patient in combat casualty care, and early interventions to impact the outcome of combat casualties with potentially survivable injury should be focused on mitigating bleeding and complications of hemorrhagic shock during pre-hospital care. In addition to early surgical intervention to repair damage and stop bleeding, blood product transfusion to replace blood loss during the pre-hospital period, or even within minutes after injury is crucial to improve the outcome of hemorrhagic shock as it has shown greater association with 24-hour and 30-day survival than delayed transfusion or no transfusion (4). However, blood products including whole blood and blood components are rarely available prior to treatment at a medical facility. Since Jun. 15, 2009, a new mandate for prehospital transportation in 60 minutes from call to arrival at the facility of treatment has been enforced for US military casualties with critical injuries (5). Although the current short transportation time is aligned with the Golden Hour policy and facilitates medical treatment including resuscitation with blood products within an hour from injury, this only benefits those who survive at 60 min from injury, and will not be possible if air superiority is not achieved. A study retrospectively comparing the outcome before and after the mandate shows that reduction in KIA mortality (killed in action, died before arrival at treatment facility) is not accompanied by a proportional change in DOW mortality (died of wounds, died after arrival at treatment facility), suggesting that rapid evacuation combined with current en-route and facility-based care resulted in survival, but still carries risk for attendant morbidity or DOW mortality status (6) because there is currently no applicable pre-hospital intervention besides limited blood supplies that is able to maintain life by counteracting the pathophysiologic damage caused by trauma/hemorrhagic shock. For future conflicts, the time for receiving surgical procedures and blood product is expected to prolong and exceed the Golden Hour; it is therefore even more important to have certain interventions during the prehospital timeframe prior to evacuation and transportation to a medical treatment facility, which are able to extend survivability and mitigate morbidity during prolonged hemorrhagic shock. However, there is currently no applicable pre-hospital intervention besides limited resuscitation fluid and blood products. Stabilization of the organ function under hemorrhagic shock will minimize the side effect and improve outcomes of resuscitation with blood products, and surgical interventions. Current “Golden Hour” policy intends to reduce the time between combat injury and receiving definitive care to 60 min or less, and is associated with reduced combat trauma related mortality and morbidity. In addition to hemorrhagic shock, burn shock is the potentially lethal cardiovascular collapse that occurs after severe burn—it is the leading cause of death following thermal injury. Given the potential for increases in both the number and severity of thermal injuries in coming conflicts, improving the outcomes of burn shock resuscitation is another desired objective. However, for both military and civilian trauma systems, pre-hospital treatment capability for those with severe hemorrhagic and/or burn shock at the point of injury needs to be further developed in order to maintain the survivability prior to receiving definitive care including resuscitation of blood products. SUMMARY Currently, there are no known medical devices or therapeutics that can be implemented at the point of injury to extend the survivability of preventable injury related death prior to access to definitive care and blood products. The current disclosure provides pre-hospital interventions that can be applied at or near the point of injury to reduce mortality and morbidity prior to evacuation and transport to MTF, prior to which the forward surgical team and bl
Filing details
- Inventors
- Evan Ross
- Assignee
- The Government Of The United States, As Represented By The Secretary Of The …
- Filed
- Aug 14, 2024
- Granted
- Application pending
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