Emergency preservation and resuscitation in exsanguination cardiac arrest: science fiction to future reality?

Summary

Non-compressible torso hemorrhage (NCTH), leading to exsanguination cardiac arrest, remains the primary cause of preventable death in combat trauma. As the future operational environment shifts toward large-scale combat operations (LSCO) with delayed evacuations and increased casualty volumes, existing damage control strategies may prove inadequate due to limited resources and delayed evacuation. In 1984, US Army Colonel Ronald Bellamy challenged military medicine to develop new interventions for hemorrhagic shock, emphasizing the need for technologies that could ‘buy time’ for evacuation and surgical intervention. Decades later, Emergency Preservation and Resuscitation (EPR), which induces a hypometabolic state through profound hypothermia, offers a potential solution to this problem. This review summarizes the historical evolution of the EPR concept, from early military observations to modern preclinical and clinical advancements in EPR. We explore emerging technologies, such as portable extracorporeal life support systems (eg, MobyBox and CARL), organ perfusion platforms (BrainEx and OrganEx) and adjunctive pharmacologic agents (eg, Frunexian, PEG-20K, TAT-PHLPP9c and mitochondrial transplantation), that can enhance the efficacy of EPR, leading to optimized organ recovery. These innovations provide a foundation for developing resource-expedient EPR capabilities tailored for future battlefields. By synthesizing current evidence and examining the military context of prolonged casualty care, this paper outlines how EPR could meet Bellamy’s challenge and serve as a next-generation tool for combat casualty care. As military medicine prepares for future conflicts, EPR may provide a critical capability to reduce mortality from NCTH and revolutionize combat trauma management in LSCO scenarios.

Introduction

‘We need to be able to slow the casualty’s biological clock…to decrease the casualty’s metabolic rate to a tiny fraction of normal without damaging organs and constituent cells. Cardiopulmonary function could then be suspended until it became possible to institute definitive treatment. Is it foolish to expect that practitioners of combat casualty care in the 21st century will employ techniques for inducing a state of suspended animation?’¹

—COL Ronald Bellamy, MD, MC, USA, 1984

Non-compressible torso hemorrhage (NCTH) remains an unresolved challenge in combat casualty care. NCTH is defined as hemorrhage within the thoracic, abdominal or pelvic cavities that cannot be controlled with external pressure or tourniquets.² NCTH from combat trauma results in rapid exsanguination cardiac arrest (ECA) when surgical intervention is delayed.³

Despite significant advancements in damage control resuscitation, whole blood transfusion and endovascular hemorrhage control techniques such as resuscitative endovascular balloon occlusion of the aorta (REBOA), NCTH continues to be the primary cause of battlefield mortality.⁴ Data from the Wars in Iraq and Afghanistan reveal that 91% of potentially survivable battlefield deaths resulted from hemorrhage, with 67% attributed explicitly to NCTH.⁵ These figures underscore the urgent need for novel resuscitation strategies capable of extending survival beyond conventional limits.

However, the challenge of truncal hemorrhage control in combat trauma is not new. Historical analyses of past conflicts have consistently demonstrated that uncontrolled bleeding is the dominant cause of battlefield mortality. During the Vietnam War, hemorrhage accounted for 50% of all battlefield deaths, with a substantial proportion attributed to injuries of the heart, great vessels (aorta and inferior vena cava), liver and major abdominal organs. A landmark study examining 500 consecutive autopsies of US casualties in Vietnam found that one-third of these fatalities were potentially survivable if earlier surgical intervention had been available.⁶

Furthermore, as military medicine prepares for future large-scale combat operations (LSCO) against near-peer or peer adversaries, the challenges associated with NCTH will become increasingly apparent. LSCO will likely result in delayed medical evacuation and large casualty volumes.⁷ Prolonged casualty care will also be a concern, as wounded personnel may require extended resuscitative interventions before reaching definitive surgical care. Current paradigms that rely on rapid evacuation to surgical facilities within the ‘golden hour’ will no longer be viable in this environment.⁸ Thus, new strategies are needed to extend survivability in patients with NCTH, particularly when surgical intervention is delayed by hours or even days.

Unlike traditional resuscitation strategies that focus on immediate restoration of circulation, the concept of Emergency Preservation and Resuscitation (EPR), or ‘suspended animation’, represents a different approach to managing ECA, offering a potential breakthrough in NCTH survival. EPR involves the induction of profound hypothermia to reduce oxygen consumption and preserve cellular viability. This hypometabolic state halts the progression of ischemic injury and delays irreversible cell death, affording surgeons a critical window for definitive surgical repair in combat trauma.

Given the persistent lethality of NCTH and the anticipated challenges of future warfare, EPR may represent the next frontier in combat casualty care. This narrative review explores the history of ‘suspended animation’ and EPR, the development of novel technologies and adjuncts for EPR, and its potential application as a resource-expedient life-saving strategy in combat trauma care on the future battlefield.

Historical review of ‘suspended animation’

The conceptual groundwork leading to EPR can be traced back to US Army Colonel Ronald Bellamy’s seminal observations on combat trauma mortality during World War II and the Vietnam War, where exsanguination was identified as the leading cause of preventable battlefield deaths.¹ In 1984, Bellamy issued what has since been termed the ‘Bellamy Challenge’, calling on military medicine to develop new management interventions for hemorrhagic shock.⁹ From this, Bellamy hypothesized that interrupting metabolic processes to ‘slow the biological clock’, reducing a casualty’s metabolic rate to a fraction of normal, organ viability could be preserved long enough to allow for delayed but definitive surgical care. Bellamy defined this ‘suspended animation’ as ‘the protection and preservation of the whole organism during prolonged clinical death, for transport and repair (resuscitative surgery) without a pulse, followed by delayed resuscitation to complete recovery’.¹⁰ His concept was further supported by evidence from accidental hypothermic circulatory arrest (AHCA) as well as research into therapeutic hypothermia in cardiac surgery, where induced cooling demonstrated neuroprotective effects during periods of circulatory arrest.¹¹ Building on these discoveries, Bellamy, in collaboration with Peter Safar and Samuel Tisherman, pioneered EPR to ‘buy time’ for critically injured patients. This section provides a historical overview of key ‘suspended animation’ concepts, including AHCA, deep hypothermic circulatory arrest (DHCA) under controlled conditions, preclinical studies of EPR and ongoing clinical investigations of EPR.

Accidental hypothermic circulatory arrest

Hypothermia-induced cardiac arrest (CA) offers a unique perspective for prolonged resuscitation due to the protective effects of cold temperatures on metabolic processes, particularly in the brain. In extreme cases, patients can survive extended periods of circulatory arrest, as case reports of successful resuscitation without long-term sequelae have been observed. Two patients, a 31-year-old man and a 65-year-old woman, survived prolonged hypothermic CA (8+ hours) with full or near-full recovery using mechanical cardiopulmonary resuscitation (CPR) and extracorporeal rewarming methods, marking the most extended documented cases of successful resuscitation.^{12 13} These cases demonstrate that the utility of hypothermia to extend the resuscitation window is not without precedent, with extracorporeal rewarming enabling recovery even after prolonged arrest.

Likewise, according to the International Hypothermia Registry (IHR), which documented 201 cases between 2010 and 2020, the majority of accidental hypothermic cardiac arrest (ACHA) involved young military-aged patients (median age 38 years, 74% male) with severe accidental hypothermia caused by mountain activities (66%), cold water immersion (15%), or urban exposure (19%). Among these, extracorporeal life support (ECLS) was used in 62% of HCA cases where data were available, achieving a survival rate of 40% and a rewarming rate of 3.1 °C/hour.^{14 15} Other studies demonstrate that AHCA has survival rates of 37%–42% when treated with ECLS, with approximately 84% of survivors achieving favorable neurological outcomes.¹⁶ The HOPE score, incorporating factors like age, temperature, and CPR duration, determines survival prediction and guides ECLS use in AHCA cases.^{17 18 19}

DHCA under planned conditions

DHCA under planned conditions is utilized in cardiothoracic procedures, including aortic arch surgery, pulmonary thromboendarterectomy, and pediatric cardiac surgery to suppress metabolic demand and protect the brain and vital organs during circulatory arrest.²⁰ Typical target temperatures range from 18°C to 20°C, enabling safe arrest durations of 30–40 min, beyond which neurologic risks increase exponentially.20,22 DHCA under planned conditions demonstrates its feasibility and potential use in trauma.²³

Building on Bellamy’s seminal analysis of combat trauma and evidence from ACHA, in the late 1980s, researchers at the University of Pittsburgh, led by Tisherman and Safar, developed a canine model of hemorrhagic shock to explore the role of induced hypothermia and cardiopulmonary bypass (CPB) in extending survival.²⁴ Their initial work in EPR demonstrated that profound hypothermia (5–10 °C) could be induced after an hour of normothermic hemorrhagic shock and then safely reversed without neurologic or histological brain damage.²⁵ Furthermore, to address the logistical challenges and complexity of formal CPB, they developed a modified system utilizing intra-aortic retrograde flushing with ice-cold saline via a femoral artery cannula, coupled with venous drainage through a right atrial cannula placed via the internal jugular vein.

Subsequent studies by Woods et al optimized this technique by delivering a 500 mL bolus of 4 °C saline directly into the descending thoracic aorta, rapidly inducing neuroprotective hypothermia and enabling up to 15 min of circulatory arrest, which bought time to initiate formal CPB.²⁶ Unfortunately, early experiments were limited by spinal cord ischemia and hind limb weakness beyond 15 min of arrest. However, further refinements allowed for larger flush volumes directed to the distal abdominal aorta.²⁷ This improved technique achieved brain temperatures as low as 10 °C and extended safe arrest times to 120 min with acceptable neurological outcomes.²⁸

Advancing the hemorrhagic shock models pioneered by Tisherman and Safar, Rhee et al at the Uniformed Services University (USU) developed a swine model of EPR based on the Eastern Association For The Surgery of Trauma (EAST) guidelines for resuscitative thoracotomy (RT).²⁹ Using RT for rapid aortic access, the descending thoracic aorta was able to be clamped and cannulated, initiating cold perfusion with Hypothermosol, a specialized preservation solution, followed by formal aortic root and atrial cannulation for CPB. This method facilitated intracranial cooling to below 10 °C within 12 min, followed by up to 90 min of hypothermic low-flow CPB and successful repair of the descending aorta. In this model, all experimental animals survived, with only one exhibiting detectable neurologic injury.³⁰

Further work by Alam et al systematically refined the cooling and rewarming protocols, identifying optimal parameters.^{31 32} They found that a target tympanic membrane temperature of 10 °C, rapid cooling at 2 °C/min, and controlled rewarming at 0.5 °C/min directly impacted outcomes, preventing ischemic damage in vital organs and improving survival.^{33 34} A later study confirmed these findings and demonstrated that delaying cooling by even a few minutes resulted in a marked decrease in survival, underscoring the necessity of rapid intervention.³⁵

After optimizing EPR parameters, Alam et al showed that hypothermic arrest durations of up to 60 min could preserve postoperative learning and memory.³⁶ When applied in a porcine model featuring complex abdominal and vascular injuries, these parameters resulted in over 75% 6 week survival with intact neurologic function.³⁷ Ultimately, these pre-clinical studies established EPR as a promising strategy to extend survival windows in traumatic arrest, forming the scientific basis to move into clinical investigation.

Clinical investigations of EPR

With the success of EPR in pre-clinical studies, the approach was advanced beyond animal models to a feasibility human clinical trial at the University of Maryland’s R Adams Cowley Shock Trauma Center and the University of Pittsburgh Medical Center, which has now been terminated due to enrollment.^{38 39} The EPR for Cardiac Arrest from Trauma (EPR-CAT) trial, funded by the

Department of Defense (DoD), aimed to evaluate the feasibility, safety, and effectiveness of EPR in patients suffering traumatic CA from exsanguinating hemorrhage.⁴⁰

Eligible patients were adults aged 18 to 65 who suffer penetrating trauma and lose vital signs within 5 min of emergency department (ED) or operating room (OR) arrival.⁴⁰ Patients without immediate pulse return after emergency thoracotomy are considered for EPR, provided no contraindications exist (eg, non-survivable injuries or electrical asystole). Trained trauma surgeons initiate EPR following clamshell thoracotomy and aortic cross-clamping or REBOA placement. A large-bore arterial cannula is placed into the descending aorta, and ice-cold saline is rapidly infused, reducing core and brain temperatures to approximately 10 °C. This profound hypothermia induces metabolic suppression, allowing up to 60 min for hemorrhage control and damage control surgery. After hemorrhage control, CPB is established, followed by slow, controlled rewarming (~0.5 °C per minute) to minimize reperfusion injury. Mild hypothermia is maintained for 12–24 hours post-procedure, with temperature regulation continued up to 72 hours. The overall conceptual workflow of EPR is illustrated in figure 1.

Figure 1. Conceptual timeline of EPR. CPR, cardiopulmonary resuscitation; EPR, Emergency Preservation and Resuscitation; NCTH, non-compressible torso hemorrhage.

The objective is for EPR to improve survival compared with RT, which historically yields less than a 5–7% survival rate in traumatic CA.⁴¹ The goal of enrollment for the trial was 20 patients (10 EPR, 10 control who undergo standard-of-care resuscitation by non-EPR-trained surgeons), with the potential for then refining the selection criteria or technique for another 20 patients. The primary endpoint was survival to hospital discharge without significant neurological sequelae. The secondary endpoints were 28-day survival, neurologic function outcome at 6 and 12 months, organ failure, and any complications related to EPR.

Key challenges remain in EPR as profound hypothermia significantly exacerbates coagulopathy, complicating surgical repair and necessitating aggressive blood product resuscitation during reperfusion and rewarming.⁴² Managing this balance between ongoing bleeding and clot formation is a critical limitation. Additionally, the requirement for anticoagulation during extracorporeal circulation to prevent membrane and circuit thrombosis further amplifies this concern. Recent efforts exploring regional anticoagulation strategies designed to limit clotting within the oxygenator while avoiding systemic anticoagulation show promise but are still being investigated.⁴³ Additionally, rewarming poses the risk of reperfusion injury, which can trigger systemic inflammation, oxidative stress, and multi-organ dysfunction, which may particularly affect neurologic outcomes. Other barriers include the logistical and technical complexities of establishing cardiopulmonary bypass in time-sensitive environments, the need for highly trained personnel, and challenges in deploying EPR outside of advanced trauma centers.

Novel technologies and emerging adjuncts for EPR

Recent advances in extracorporeal life support and pharmacologic therapies have enhanced the feasibility and broadened the capabilities of EPR, addressing many of its inherent challenges and limitations. Emerging technologies in circulation support and drug interventions may enable the optimization of the technique and its application across civilian and austere military environments. This section highlights the novel innovations driving the future of EPR and their role in improving outcomes for critically injured combat trauma patients and is summarized in table 1.

Table 1. Adjunctive therapies and their potential role in Emergency Preservation and Resuscitation.

Category	Therapy	Mechanism/proposed features
Extracorporeal life support systems	Extracorporeal membrane oxygenation (ECMO)	Provides extracorporeal oxygenation and circulatory support via venovenous (VV) or venoarterial (VA) circuits
	MobyBox	Compact portable pneumatically driven ECMO system requiring no external power
	Controlled automated reperfusion of the whole body (CARL)	Goal-directed reperfusion system with pulsatile flow, real-time metabolic monitoring and controlled perfusion parameters
Organ perfusion platforms	BrainEx	Acellular hemoglobin-based perfusate restores cerebral microcirculation, cellular metabolism and structural integrity after prolonged ischemia
	OrganEx	Whole-body perfusion platform restoring systemic circulation, cellular metabolism and multi-organ viability
Pharmacological adjuncts	Frunexian	Selective factor Xia inhibitor reducing pathologic thrombosis while preserving physiologic hemostasis
	Polyethylene glycol-20,000 (PEG-20K)	Cell impermeant polymer restoring microcirculatory perfusion and reducing cellular edema
	TAC-PHLPP9c	Activates AKT survival pathway, preserves ATP production and enhances metabolic recovery
	Mitochondrial transplantation	Restores oxidative phosphorylation and reduces reactive oxygen species through organelle replacement

AKT: protein kinase B (PKB), a serine/threonine kinase that mediates PI3K-dependent cell survival and metabolic signaling.

ATP, Adenosine Triphosphate.

Extracorporeal life support systems

Extracorporeal membrane oxygenation

The role of extracorporeal membrane oxygenation (ECMO) in trauma care has significantly expanded in the last two decades.⁴⁴ Both venovenous (VV) and venoarterial (VA) extracorporeal support are now used to treat the acutely injured casualty, as well as the sequelae of massive resuscitation such as acute respiratory distress syndrome (ARDS).45,47 While the original circuits were designed to be implemented in the operating room, trauma centers have found equivalent success in deploying portable circuits in the emergency room and throughout their facilities.^{48 49 50} This expansion to the trauma bay has led to the successful use of ECMO for massive thoracoabdominal injury and the development of extracorporeal CPR (ECPR) for traumatic arrest.^{48 51} Though cases of ECLS have been utilized in austere military environments, challenges remain in the ability to deploy these interventions forward in the field past the damage control surgery and field hospital settings.51,53 To do this, these systems designed for deployment in the military prehospital setting must consider portability, power requirements, consumables and minimal user intervention to ensure functionality in resource-limited environments.⁴

The MobyBox, a fully pneumatically driven ECMO device weighing 2 kg, provides a compact, potential field-deployable solution. In animal studies with sheep, this device operated safely for 7 days without needing extra power, and it did not cause any clotting or hemolysis complications. The MobyBox has been utilized in Venovenous-ECMO in a small case series of seven patients with severe COVID-19-related ARDS, five of whom were able to be weaned off ECMO and survived until discharge.⁵⁴

Controlled automated reperfusion of the whole body

Controlled automated reperfusion of the whole body (CARL) is an advanced extracorporeal resuscitation strategy designed to mitigate ischemia-reperfusion injury (IRI) and improve survival following prolonged CA.⁵⁵ Developed over the past two decades, CARL expands on conventional ECPR by introducing a goal-directed approach to reperfusion tailored to the patient’s specific physiologic needs.⁵⁶ Unlike traditional ECMO circuits, which provide non-pulsatile flow and limited metabolic control, CARL delivers pulsatile perfusion, precise hemodynamic regulation and real-time biochemical monitoring.⁵⁷

CARL directly addresses the challenge of global IRI, particularly in the brain and other critical organs during prolonged ischemia. Standard CPR and ECPR, while restoring circulation, often exacerbate reperfusion injury due to uncontrolled flow dynamics and the absence of biochemical regulation. CARL overcomes this limitation by modulating key reperfusion parameters such as arterial blood pressure, oxygen and carbon dioxide levels, temperature, calcium concentration and osmolarity.⁵⁶ The system incorporates a mobile perfusion unit equipped with dual pumps to generate pulsatile flow, integrated arterial pressure sensors, real-time blood gas analysis, and controlled hypothermia capability.

Preclinical studies have shown that CARL significantly improves survival and neurological outcomes following prolonged circulatory arrest. In porcine models, CARL achieved high survival rates with preserved brain morphology after 20 min of normothermic arrest, outperforming standard CPR and ECPR protocols.⁵⁸ Early clinical application of CARL has demonstrated promising results, including survival after prolonged CA with good neurological recovery, even in cases with over 120 min of continuous CPR.⁵⁹ Several questions remain though, such as optimal reperfusion protocols, defining indications, evaluating feasibility and clarifying its translation into trauma.

Organ perfusion platforms

BrainEx and OrganEx

BrainEx and OrganEx are perfusion platforms developed to restore cellular function following prolonged ischemia. Both systems leverage hemoglobin-based, acellular and non-coagulopathic perfusates delivered via advanced extracorporeal circulation systems capable of generating physiologic pulsatile flow to optimize microvascular perfusion and mitigate IRI.^{60 61}

BrainEx was originally designed as an ex vivo perfusion system for isolated brain resuscitation, demonstrating that neural tissue can maintain structural and functional viability hours after cessation of circulation. Using a cytoprotective perfusate, BrainEx restored microvascular circulation, reversed ionic imbalances and preserved cytoarchitecture in porcine brains following up to 4 hours of warm ischemia. Markers of neural integrity, such as NeuN and MAP2, were preserved, while apoptosis and neuroinflammation, measured by caspase-3 activation and microglial activation, were significantly reduced.⁶⁰

Building on BrainEx, OrganEx was engineered to expand perfusion capabilities from a single organ to the whole body. In a porcine model, OrganEx successfully restored systemic circulation and multiorgan viability after 1 hour of warm ischemia caused by CA. Histologic assessments demonstrated preserved cellular integrity and reduced cytotoxic edema across critical organs, including the brain, heart, liver and kidneys. OrganEx attenuated ischemia-induced cell death through multiple pathways, reducing apoptotic (caspase-3), pyroptotic (IL-1β), necroptotic (RIPK3) and ferroptotic (GPX4) signaling compared with ECMO. It also more effectively corrected metabolic derangements, including hyperkalemia and acidosis, and improved cellular glucose uptake.⁶¹ Despite their promise, the translation path for both BrainEx and OrganEx remains uncertain. Key gaps include elucidating the composition and mechanism of their perfusates, evaluating safety and immunological compatibility, and determining feasibility outside of controlled laboratory settings. The opacity of these perfusate formulations underscores the need for targeted pharmacological adjuncts capable of reproducing key cytoprotective effects.

Pharmacological adjuncts

Frunexian

Frunexian is a potent, selective small molecule inhibitor of activated factor XIa (FXIa) with significant implications for trauma-related coagulopathy management.⁶¹ Unlike traditional anticoagulants that broadly impair hemostasis, frunexian leverages the differential role of FXIa, which is critical for pathological thrombus propagation but less essential for physiological hemostasis. By selectively inhibiting FXIa, frunexian minimizes thromboembolic risk while preserving sufficient clotting capacity, reducing the likelihood of catastrophic bleeding in trauma settings.^{62 63}

Recent pharmacokinetic and pharmacodynamic studies of frunexian have demonstrated its favorable profile. In phase I clinical trials, frunexian exhibited a dose-proportional increase in plasma concentration and a rapid onset of action, with steady-state concentrations achieved within 1 to 1.5 hours. Notably, the agent was well-tolerated, with no serious bleeding events reported even at higher infusion rates (up to 2.25 mg/kg/h) over continuous 5-day administration in healthy volunteers.⁶⁴

Frunexian’s mechanism of action is particularly suited for integration into EPR protocols. Reducing thrombin generation through intrinsic pathway inhibition helps prevent trauma-induced coagulopathy-associated thromboembolic events, such as deep vein thrombosis and pulmonary embolism, while mitigating the excessive bleeding that typically accompanies conventional anticoagulants or reversal agents.

Polyethylene glycol—20 000

Polyethylene glycol—20 000 (PEG-20K) is a cell-impermeant polymer solution demonstrating unique capabilities in managing hemorrhagic shock. PEG-20K acts at the microcirculatory level, targeting ischemia-induced cellular swelling and restoring capillary perfusion, making it particularly suited for low-volume resuscitation in trauma.⁶⁵

PEG-20K exerts a hybrid oncotic and osmotic effect, facilitating fluid shifts from intracellular and interstitial compartments back into the intravascular space, thereby decompressing the microcirculation and optimizing tissue oxygen delivery. Preclinical studies have shown that PEG-20K administration significantly improves tolerance to severe hypovolemia and promotes oxygen debt repayment even in the absence of red blood cell transfusion. In a porcine model of lethal hemorrhagic shock, PEG-20K resuscitation achieved a 100% 24-hour survival rate with full neurological recovery, outperforming both whole blood and Hextend resuscitation strategies.⁶⁶

Furthermore, PEG-20K has been shown to enhance cerebral microcirculation and reduce brain edema in models of CA and resuscitation. By preserving blood–brain barrier integrity and reducing markers of neuronal injury (eg, S-100β, neuron-specific enolase), PEG-20K mitigates postresuscitation cerebral dysfunction.⁶⁷

PEG-20K’s resuscitative benefits may extend beyond microcirculatory support. Thromboelastographic analyses indicate that while PEG-20K transiently reduces platelet-mediated clot strength due to hemodilution, it does not exacerbate coagulopathy to a clinically significant extent when used appropriately in low-volume resuscitation in trauma settings.⁶⁸ These characteristics have particular relevance for EPR where microvascular collapse and coagulopathy complicate induction before extracorporeal perfusion. By helping restore capillary flow without anticoagulation, PEG-20K may function as a physiologic bridge to stabilize patients before cannulation.

TAT-PHLPP9c

TAT-PHLPP9c is a cell-permeable peptide designed to enhance the protein kinase B (AKT) survival signaling pathway by selectively inhibiting the phosphatase PHLPP1.⁶⁹ This targeted action promotes metabolic recovery and cytoprotection in ischemic tissues without deep hypothermia. Mechanistically, TAT-PHLPP9c augments AKT phosphorylation, reduces pyruvate dehydrogenase inhibition, limits sorbitol production and increases ATP generation in cardiac and cerebral tissues.⁷⁰

In preclinical murine and swine models of CA, intravenous administration of TAT-PHLPP9c during CPR significantly improved return of spontaneous circulation, cerebral blood flow, cardiac output and neurologically intact survival rates.^{69 71} The peptide distributes rapidly to vital organs within minutes, making it highly suited for emergent settings.⁷² In a swine ventricular fibrillation model, TAT-PHLPP9c improved 24-hour survival from 0% to 83%, with most treated animals demonstrating full neurological recovery.⁶⁹

Mitochondrial transplantation

Mitochondrial transplantation (MT) is an emerging biologic therapy aimed at restoring cellular bioenergetics and limiting ischemia–reperfusion injury through direct organelle replacement.73,75 This strategy involves delivering viable, respiration-competent mitochondria to ischemic tissues to reestablish oxidative phosphorylation and maintain ATP generation.⁷⁶ Mechanistically, MT replenishes electron transport chain function, stabilizes mitochondrial membrane potential, reduces cytochrome-c release and suppresses reactive oxygen species (ROS) production, which are key drivers of metabolic collapse after ischemia.

In preclinical rodent and swine models of CA and limb ischemia, intravenous or intramyocardial administration of exogenous mitochondria during reperfusion markedly improved survival, cardiac output and neurological recovery, while reducing tissue necrosis and systemic inflammation.⁷⁷ Electron microscopy and functional assays confirmed mitochondrial uptake and integration into host cardiomyocytes, neurons and endothelial cells within minutes.⁷⁸ Additionally, MT modulates postischemic immune responses by attenuating DAMP release, neutrophil activation and cytokine storm, further mitigating secondary injury.⁷⁹ Conceptually, MT could complement EPR by addressing the mitochondrial dysfunction and ROS injury during rewarming and reperfusion.

Collectively, this non-exhaustive collection of emerging pharmacologic technologies illustrates a rapidly expanding kit for mitigating ischemia reperfusion injury, but substantial translational barriers remain. Future progress will require the development of simplified techniques and equipment that can be safely deployed outside of high-resource settings and adapted for use in austere environments.

EPR application to improve survivability from combat trauma on the future battlefield

NCTH continues to be one of the leading causes of preventable death in combat, particularly in the context of LSCO. As Bellamy highlighted in his landmark 1984 study, most fatalities from battlefield injuries occur before a casualty can reach surgical care, with NCTH specifically causing loss of pulses in less than 5 min after injury.¹ This narrow window underscores the critical need to ‘buy biological time’, especially when prolonged evacuation times are anticipated. Modern battlefield realities are revalidating Bellamy’s original conclusions, as medical planners now face the challenges of peer-to-peer conflict environments that mirror the intensity and attrition rates of World War II.⁸⁰

The shift from the counterinsurgency operations of the Global War on Terror to the anticipated LSCO environment presents a radically different casualty care scenario. During the former, the US military’s ability to maintain air superiority enabled the rapid evacuation of casualties within the so-called ‘Golden Hour’, significantly improving survivability.⁸¹ Surgical teams could be dispersed across smaller bases with assured air medical evacuation to higher roles of care within minutes to hours.⁸² However, future battlefields will likely include denied or contested airspace, logistical bottlenecks and increased casualty volumes, as seen in the Russo-Ukrainian war.⁸³ Without reliable air evacuation and with ground-based transport vulnerable to long-range fires and complex terrain, medical personnel will be forced to operate within prolonged casualty care environments where definitive surgical intervention may be delayed by hours or even days.

While interventions such as RT and REBOA have been advancing care for patients with NCTH, these procedures carry significant drawbacks. Both techniques, though lifesaving in the short term, precipitate downstream complications, including end-organ ischemia, acidosis and multiorgan failure, especially when evacuation times are extended.⁸⁴

EPR emerges as a transformative capability for the LSCO environment. In contrast to REBOA and ERT, which seek to restore perfusion at the risk of IRI, EPR’s core advantage lies in the ability to suspend biological processes and delay cellular death. This technique buys biological time, allowing medics and austere surgical teams the time required to stabilize and transport casualties across the vast and contested LSCO battlespace.

To meet the evolving demands of LSCO and maximize the life-saving potential of EPR, the Military Health System and the DoD must invest in the development of resource-expedient EPR (REEPR) capabilities. Unlike conventional EPR platforms, which rely heavily on robust infrastructure and specialized teams, REEPR must be designed for field-forward use in resource-constrained and contested environments.

Achieving this capability will require integrating next-generation technologies that enable suspended animation and cellular protection closer to the point of injury. Systems such as MobyBox ECMO for portable extracorporeal life support, CARL and BrainEx/OrganEx for controlled reperfusion following prolonged ischemia, and novel pharmacologic adjuncts, including Frunexian, PEG-20K and TAT-PHLPP9c, can create a layered preservation strategy. These tools can mitigate IRI, extend viability during evacuation delays and significantly enhance survivability in scenarios where conventional evacuation timelines are exceeded.

Additionally, on-hand supplies of blood products may be insufficient to meet demand when aggressive resuscitation is required, such as patients requiring EPR.⁸⁵ Limited availability in the Russo-Ukraine war highlights this challenge, and current strategies, such as walking blood banks, might not always be feasible depending on the operational environment. Thus, novel resuscitation approaches, such as deceased donor blood or hemoglobin-based oxygen carriers, could eventually be considered for critical supplement to traditional blood products within REEPR strategy.86,88^,

The ideal REEPR system must be purpose-built to address the operational realities of LSCO and irregular warfare. Specifically, it should be lightweight and compact enough for a medic or surgical team to carry in addition to their standard load, capable of autonomous operation without external power for up to 12 hours and designed to minimize the need for consumable supplies. Additionally, REEPR systems must integrate intelligent automation, enabling dynamic adjustment of critical life-support parameters with minimal human input, freeing medical personnel to manage multiple casualties or continue mission objectives.^{89 90}

In future combat environments with increased casualty volumes and delayed medical evacuation, identifying suitable candidates for REEPR is critical to maximizing its life-saving potential while conserving limited resources. Ideal candidates are those who suffer traumatic CA secondary to NCTH and lose vital signs within minutes of injury, particularly in austere environments where surgical care is not immediately available. Selection could prioritize young, previously healthy individuals with a high potential for neurologic recovery if timely intervention is achieved. Simple tools like vital signs, injury patterns, and trauma-specific scores could further refine REEPR triage protocols.

When combined with advancements in prolonged casualty care training and doctrine, REEPR technologies will constitute a next-generation solution to reduce mortality from NCTH and other critical injuries common in LSCO and austere environments. This approach will significantly expand the operational reach of medics and austere surgical teams, supporting the shift toward distributed and decentralized medical operations in high-intensity conflict.

Conclusion

ECA from NCTH remains a critical driver of preventable battlefield deaths, a challenge that will intensify in LSCO, where evacuation delays are inevitable. Conventional interventions like REBOA and ERT offer limited utility when surgical care is hours away. EPR, by inducing profound hypothermia, provides a novel means to extend cellular viability and ‘buy time’ for life-saving surgery in austere settings. Coupled with advances in portable extracorporeal systems and adjunctive pharmacologics, EPR has the potential to significantly improve combat casualty survival. As Bellamy envisioned, EPR is shifting from science fiction to a future reality, with the means to revolutionize combat casualty care and reduce NCTH mortality on future battlefields.