Ischemic Limb Necrosis and Symmetrical Peripheral Gangrene During Vasopressor Support in Severe Shock States: Thromboinflammatory Microvascular Injury as the Pathogenic Mechanism.

Ischemic limb necrosis and resulting symmetrical peripheral gangrene (SPG) are devastating complications of severe shock states, particularly septic shock, and are associated with major morbidity, limb loss, and mortality. These complications usually occur in patients requiring vasopressor support for cardiovascular resuscitation during profound circulatory collapse. In this setting, however, thromboinflammatory microvascular injury represents the principal mechanism underlying ischemic tissue injury. Life-threatening shock is characterized by endothelial injury, glycocalyx disruption, disseminated intravascular coagulation (DIC), impaired fibrinolysis, and ischemic hepatic injury ("shock liver") with endogenous natural anticoagulant factor depletion (antithrombin, protein C, protein S) that promotes diffuse thromboinflammatory microvascular thrombosis and impaired tissue perfusion independent of vasopressor therapy. Importantly, most critically ill patients receiving prolonged or high-dose vasopressor therapy do not develop ischemic limb necrosis in the absence of severe coagulopathy, DIC, or shock liver. In contrast, patients developing SPG typically exhibit DIC (severe thrombocytopenia, greatly elevated D-dimer levels), hepatic dysfunction, and multiorgan failure. Under these conditions, progressive microthrombosis in distal limbs produces acral ischemia and tissue necrosis. This review examines SPG in severe shock states through the framework of thromboinflammatory microvascular dysfunction, hepatic dysfunction, dysregulated coagulation with natural anticoagulant depletion, and endothelial injury, culminating in acral microthrombosis; we evaluate key limitations and confounders in the literature on vasopressor-associated ischemia; and discuss the clinical phenotype of SPG in septic shock and critical illness. Finally, we address some of the important clinical and treatment implications of ischemic limb necrosis during vasopressor support in critically ill patients with shock.