Re-evaluating the role of arginine vasopressin (AVP) in damage control resuscitation for combat casualties in hemorrhagic shock

1 INTRODUCTION

Trauma is a leading cause of hemorrhagic shock and death.¹ It disproportionately affects the young (people under 45 years old), similar to the demographics of the military population.² Early analysis of military data obtained from the Wars in Iraq and Afghanistan demonstrated that 90.9% of acute mortality from traumatic injury was associated with hemorrhage.³ Kotwal et al. determined that the early use of blood products reduced mortality by 80%, twice the effect of decreased evacuation time on mortality.^{4, 5} In the absence of timely evacuation and definitive surgery on the battlefield, the rapid transfusion of blood can be a life-prolonging intervention in patients with hemorrhagic shock.⁶ Due to potentially limited supply of blood, other adjuncts, including vasopressors, may be used to stabilize hemorrhaging casualties.⁷

Early vasopressor use in trauma-related hemorrhagic shock remains controversial due to potential deleterious consequences.⁶ Some studies suggest norepinephrine supplementation does not affect mortality adversely, while others report a significant association between vasopressor use and higher mortality rates.^{6, 7} Current European guidelines on the management of major bleeding recommend the use of norepinephrine when fluids fail to achieve the target arterial pressure.⁸ However, due to inconclusive evidence and concerns about potential harm, North American Trauma Centers have generally avoided early vasopressor initiation in hemorrhagic shock.⁹

Recent literature suggests that arginine vasopressin (AVP) therapy in hemorrhagic shock does not increase complications or mortality but instead decreases the overall volume of transfused blood products.¹⁰ AVP is an endogenous neurohypophyseal hormone that is associated with improved platelet function and clot formation.¹¹ Additionally, it redistributes blood flow from the skin, splanchnic, and skeletal areas to vital organs such as the heart and brain.⁹ In cases of intra-abdominal trauma, AVP may be beneficial by reducing mesenteric perfusion.⁹ Moreover, AVP improves mean arterial pressure and may play a role in reversing late-stage decompensated shock.¹² Therefore, simultaneous administration of AVP with blood products for resuscitation is a promising adjunct that can be utilized for combat casualties.

Currently, military medical planners are evaluating large-scale combat operations (LSCO) challenges by analyzing past and emerging conflicts. Analysis of LSCO during World War II (WWII), the War in Ukraine, and a potential conflict in the Indo-Pacific has demonstrated immense implications for combat casualty care.^{13, 14} Specifically, military medical leaders are relearning blood demands in past conflicts (WWII) and examining how to overcome the burden of blood product requirements, distribution, and utilization in future conflicts.¹⁵ Consequently, this paper seeks to mitigate blood product challenges by (1) analyzing the effects of LSCO on blood product requirements, (2) briefly reviewing the pathophysiology of hemorrhagic shock, and assessing the role of AVP as an adjunct in damage control resuscitation (DCR), and (3) describing AVP's potential application in exsanguinating combat casualties.

2 BLOOD PRODUCT SUPPORT IN LARGE-SCALE COMBAT OPERATIONS

The transfusion of whole blood in military patients with traumatic injuries demonstrated increased survival rates at the 48-hour and 30-day periods and has become the standard of care for hemorrhagic resuscitation.¹⁶ As seen previously in the Global War on Terror (GWOT), casualties who required at least one unit of Packed Red Blood Cells or Whole Blood (WB) received a median of 8 units in the first 24 h with an upper quartile of 18 units.¹⁷ Looking forward, LSCO conflicts challenge the current status quo of medical logistics, where a large volume of casualties, lack of aeromedical evacuation, and the need for prolonged casualty care are predicted.¹³ Subsequently, an LSCO conflict can expect enormous demand for the acquisition, storage, and delivery of blood products. Shown in Table 1, a review of blood product requirements during WWII from May 1944 to May 1945 demonstrated that a total of 385,231 units of WB were utilized.¹⁸ For comparison, GWOT data showed that since 2001, 10,785 WB units (fresh WB/emergency collected) were transfused to 1855 patients, and 1928 low-titer O WB units shipped were transfused to 634 patients.¹⁹ Given the immense logistical burden of supplying blood in LSCO, alternative adjuncts are needed to reduce the amount of blood product required per casualty and optimize resuscitation. AVP, with its ability to reduce transfusion requirements, may serve as a critical tool in this setting.¹⁰

3 VASOPRESSIN USE IN HEMORRHAGIC SHOCK AND DAMAGE CONTROL RESUSCITATION

The pathophysiology of hemorrhagic shock is well studied, involving hypothermia, coagulopathy, acidosis, and hypocalcemia, inducing several compensatory body mechanisms.²⁰ One such compensatory pathway is the upregulation of the sympathoadrenal activation, seen in the catecholamine surge, resulting in vasoconstriction of the blood vessels and subsequent maintenance of blood pressure.²¹ As the oxygen debt increases and resultant cellular injury ensues, sympathetic activation precedes the eventual vascular endothelial glycocalyx dysfunction or endotheliopathy.^{1, 22, 23} The shock-induced endotheliopathy and multiple organ dysfunction syndrome are two byproducts of hemorrhagic shock that worsen vascular complications.¹² Without the reversal of hemorrhagic shock, the body progresses to a state of decompensation, unresponsive to fluid resuscitation or catecholamine pressors.

DCR aims to re-establish the physiologic balance in hemorrhagic shock, reducing the risk of tissue hypoxia, oxygen debt, shock burden, and coagulopathy.²⁴ DCR has primarily been focused on blood product resuscitation using whole blood, if available, or ratio-driven blood component therapy. Due to the near physiologic ratios and concentrations, whole blood is the preferred product for restoring blood functionality by decreasing platelet dysfunction, protecting the endothelium, and improving oxygen delivery and tissue perfusion.^{24, 25} However, aggressive fluid resuscitation is associated with an increased risk of transfusion-associated complications such as coagulopathy, acute lung injury, abdominal compartment syndrome, and cardiac dysfunction.¹⁰ Furthermore, in the late sympathoinhibitory vasodilation stage of hemorrhagic shock, fluid resuscitation may not reverse the decompensated state.¹² Therefore, in trauma resuscitation, it is important to consider the balance between fluid resuscitation and vascular tone.

Circulation regulatory factors seen in the sympathetic, renin-angiotensin, and AVP systems are associated with the maintenance of vascular tone.^{1, 26} Inadequately low AVP levels in the setting of blood loss have been postulated as a cause of hemodynamic instability at the endothelial level.¹⁰ AVP, also known as Antidiuretic Hormone, acts via V1, V2, and V3 receptors and mediates plasma osmolality, arterial pressure, and cardiac function.²⁷ Specifically, in the setting of hemorrhage, small increases in AVP plasma concentration (>2 pg/mL) were found to improve blood pressure by acting on V1 receptors.²⁶ At baseline, AVP plasma concentrations are low (0–3 pg/mL).²⁸ Seen in hemorrhagic shock and out-of-hospital cardiac arrest, plasma AVP can increase to 180 and 193 pg/mL, respectively.²⁶ In one study involving 21 hypotensive bleeding trauma patients, AVP was observed to be markedly elevated on admission but decreased rapidly over time.²⁹ The metabolism of AVP occurs in the liver and kidneys with a plasma half-life of 10–35 min.³⁰ Since the metabolic activity of AVP is relatively short, AVP replacement therapy may aid in the setting of hemodynamic instability (Table 2).

Intravenous administration of exogenous AVP has effects within minutes and distributes rapidly from the plasma into the extracellular fluid volume.²⁶ AVP supplementation can enhance platelet aggregation by releasing von Willebrand Factor and Factor VIII_c from the endothelial cells.¹¹ Thus, AVP augments the clotting cascade and improves clot formation but may also increase the risk of thrombosis. Still, clinical data suggests early low-dose supplementation of AVP had a lower rate of deep venous thrombosis compared with the control group.¹⁰

V1 receptors are located on the vascular smooth muscle within the systemic, splanchnic, renal, and coronary circulations.³⁰ As a result, AVP was found to preferentially shunt blood to vital organs such as the heart, brain, liver, and kidneys.^{10, 31} An important consideration is AVP's dose-dependent effect on splanchnic blood flow. At lower doses, splanchnic vasculature does not appear to be affected if there is adequate intravascular volume.³⁰ In contrast, large-dose AVP was found to reduce splanchnic blood flow by selectively decreasing the superior mesenteric arterial flow but simultaneously increasing the hepatic arterial blood flow.³² Hence, hypovolemia and reduced splanchnic blood flow can result in gastrointestinal necrosis. In addition, decreased splanchnic compliance can worsen over-resuscitation due to central fluid distribution, leading to complications like noncardiogenic pulmonary edema in the lungs.³³ Furthermore, AVP constricts the coronary arteries, which can result in myocardial infarction.³³

AVP repletion may also blunt the nitric-oxide-mediated vasodilation as a result of the systemic inflammatory response syndrome to injury.^{34, 35} The mechanism by which AVP achieves this effect is decreasing the synthesis of nitric oxide and cyclic guanosine monophosphate signaling by nitric oxide.³³

Given AVP's role in regulating vascular tone, it is important to examine how repletion may support hemodynamic stabilization in trauma patients. The hemodynamics of acute hypovolemia involve two distinct phases. In the initial phase, the sympathetic response increases the peripheral resistance to preserve blood pressure. However, when blood volume reaches a critical threshold, the second phase sets in, marked by the loss of sympathetic vasoconstrictive drive, bradycardia, a surge in adrenal catecholamines and AVP, and a drop in arterial pressure.³⁶ Despite this compensatory rise in AVP, its short half-life leads to rapid depletion. In addition to its intrinsic metabolism, hemorrhage likely reduces the overall physiologic availability of AVP. Thus, during late-stage vasodilation and decompensation, AVP therapy may primarily replenish physiologic levels and restore sympathetic tone back to baseline rather than exerting the predominant vasoconstrictive effects typically associated with pressor use.

Still, few published studies demonstrate the benefits of AVP for the resuscitation of patients with hemorrhagic shock.³⁷ An early prospective randomized study found the infusion of low-dose AVP maintained elevated serum AVP levels and decreased fluid requirements.³⁷ Notably, Sims et al. demonstrated that low-dose AVP during early resuscitation in trauma patients resulted in a significant total median transfusion reduction of 1.0 L with no change to overall mortality or complications.¹⁰ These findings demonstrate AVP's potential as a DCR adjunct in reducing blood product requirements and managing hemorrhagic shock patients.

However, the repletion of AVP alone is associated with poor outcomes.³⁸ A retrospective cohort analysis demonstrated that AVP is associated with increased mortality in trauma patients with refractory hypotension.³⁸ A possible explanation is the inappropriate use of AVP, such as its administration in isolation and not in conjunction with blood product resuscitation and coagulopathy management. Additionally, prior studies often involved multiple vasopressors and inotropes and varied intervention timing from early injury to late organ failure.⁷

4 VASOPRESSIN UTILIZATION IN THE FUTURE EXSANGUINATING COMBAT CASUALTY

AVP plays a critical role in stabilizing the hemodynamics of trauma patients and presents a promising adjunct to address the logistical gap for LSCO blood product requirements. The Military Health System should reassess and encourage further research on AVP indications, contraindications, and therapeutic goals in DCR. While its primary application has been in refractory hemorrhagic shock, emerging evidence suggests that AVP may also be beneficial as an early adjunct in patients requiring massive blood transfusion.

AVP is typically administered via intravenous or intraosseous access and can be stored at room temperature for up to 12 months before expiration.³⁹ While dosing remains debated, the current standard practice is 2–4 U bolus followed by continuous infusion of 0.04 U/min. The Joint Trauma System currently recommends AVP therapy in several clinical practice guidelines. For anesthesia management, AVP is considered in cases of refractory shock with 2–4 units bolus followed by 0.04 U/min.⁴⁰ For cerebral perfusion pressure management in head injury patients, AVP with 0.01–0.04 U/min is the agent of choice, followed by phenylephrine or norepinephrine.^{41, 42} For burn care, 0.04 U/min of AVP is recommended when central venous pressure (CVP) is >10 cm H₂O, and the patient is still hypotensive (SBP < 90 mm Hg).⁴³ Despite these recommendations, there is limited guidance on the ideal patient population.

Sims and colleagues identified specific groups that may derive greater benefit from AVP therapy.

In the AVP group, 80% had penetrating injuries, with 43% sustaining abdominal injuries and 29% thoracic injuries.¹⁰ These injury patterns align with military trauma trends; an analysis of casualties presenting to military emergency departments in GWOT revealed that 23.6% of patients sustained GSW as their primary injury mechanism, with 16.3% involving thoracic injuries and 11.9% abdominal injuries.⁴⁴ Both groups fall under non-compressible torso hemorrhage, a persistent challenge in trauma care. In particular, intra-abdominal penetrating injuries may benefit from AVP due to its potential to reduce mesenteric perfusion until definitive treatment is available.

Conversely, there is insufficient data to support AVP use in patients with blunt trauma. Notably, more than half of combat casualties sustained injuries primarily from explosives, which often result in polytrauma involving blast, blunt, and penetrating mechanisms.⁴⁴ Common blast and blunt injuries include traumatic brain injury (TBI) and pelvic or long-bone fractures.¹² Given this, another critical research focus is the interaction between TBI and AVP.

As cerebral autoregulation becomes impaired in TBI patients, arterial hypotension can lead to cerebral hypoxia, exacerbating secondary brain injury.¹² Animal studies have demonstrated that AVP V_1a receptors play a role in the pathogenesis of brain edema formation and are associated with secondary brain damage after TBI.⁴⁵ While AVP may increase blood pressure and cerebral perfusion pressure, there is concern that it could worsen brain edema. However, current literature indicates no significant difference in mortality, adverse events, or increased cerebral edema when comparing AVP to other catecholamines.^{46, 47} Further research is needed to clarify AVP's role in TBI management, particularly in combat casualties with polytrauma.

Sims and colleagues demonstrate the feasibility of early AVP in trauma, but their study's single-center design limits generalizability. Nevertheless, the findings remain relevant to military settings, given that the study population primarily consisted of young males with penetrating trauma. Special population considerations should include burn patients and trauma-induced diabetes insipidus.

Future works should validate the effects of AVP, weighing the potential benefits of improved macrovascular perfusion against the potential risk of diminished microvascular perfusion, particularly in visceral organs. Studies should power the data to assess for secondary endpoints such as acute kidney injury, acute respiratory distress syndrome, mechanical ventilation, length of stay, and thromboembolism risk.¹⁰ Simultaneously, the U.S. military should assess the interaction of AVP therapy with existing and potential treatment options. Some examples include tranexamic acid and calcium.²⁴ Sponsored by the Department of Defense (DoD), The CAVALIER trial is an ongoing study assessing early calcium and AVP use in injury and early resuscitation.⁴⁸ Another product is freeze-dried plasma, which is an urgent developmental priority in the DoD.⁴⁹ A final consideration is potential hemoglobin-based oxygen carriers, which are biosynthetic surrogates of RBCs.⁵⁰ As military medicine adapts to LSCO challenges, integrating AVP into resuscitation protocols offers a viable strategy to optimize combat casualty care.

5 CONCLUSION

Further research is needed to better define the role of AVP in trauma resuscitation, particularly its potential to stabilize hemodynamics and enhance DCR in hemorrhagic shock. AVP therapy may reduce blood product requirements, providing a logistic advantage in resource-limited settings, including LSCO. As military medical planners anticipate future challenges, AVP may serve as a promising adjunct to current damage control resuscitation protocols, bridging the gap between patient care and logistical requirements. Continued investigation is essential to determine the optimal use of AVP in relation to other resuscitation strategies and in prehospital settings.

CONFLICT OF INTEREST STATEMENT

The authors have disclosed no conflicts of interest.