Hemodynamic homeostasis disequilibrium in critical illness

Abstract

Over millions of years, the circulatory system evolved from primitive forms into a highly specialized network capable of overcoming time-distance constraints and enhancing diffusion efficiency. This structural advancement laid the physiological foundation for the regulation of hemodynamics and systemic homeostasis. Hemodynamic homeostasis is a fundamental biological process that ensures the continuous delivery of oxygen and substrates while facilitating the removal of carbon dioxide and metabolic waste. Such balance is essential for sustaining cellular metabolism and maintaining the function of vital organs throughout embryonic development and the human lifespan. Disruption of this equilibrium, primarily driven by the Host/Organ Unregulated Response (HOUR), compromises the cardiovascular-respiratory system, resulting in hemodynamic homeostasis disequilibrium. HOUR specifically targets the critical unit-a constellation of elements essential for oxygenation and cell energetics, including the microcirculation, endothelial glycocalyx, and mitochondria, impairing the oxygenation process, ultimately triggering critical illness. Although intervention targeting systemic hemodynamic variables (e.g., pressure, flow) may temporarily improve regional perfusion, restoring full homeostasis remains challenging. This is largely due to the activation of multiple positive feedback loops (e.g., coagulation cascades) and impairment of key negative feedback mechanisms (e.g., blood pressure regulation). In the presence of ongoing HOUR, inappropriate or delayed interventions may exacerbate injury and accelerate irreversible organ damage or death. Therefore, it is both essential and urgent to elucidate the initiation, recognition, progression, and modulation of hemodynamic homeostasis disequilibrium.

Keywords: HOUR (Host/Organ Unregulated Response); critical unit; hemodynamic homeostasis; hemodynamic homeostasis disequilibrium; hypoxia.

FIGURE 1

Evolutionary continuum from single-cell organisms to modern critical illness. This illustration depicts the evolutionary trajectory of biological complexity—from unicellular organisms to vertebrates and eventually Homo sapiens—highlighting the emergence of integrated cardiovascular-respiratory systems. The rightmost progression shows the modern critically ill patient supported by advanced life-sustaining technologies, such as mechanical ventilation and extracorporeal membrane oxygenation (ECMO). This continuum emphasizes how evolutionary adaptations for oxygen regulation and energy balance are challenged under conditions of critical illness.

FIGURE 2

Schematic overview of hemodynamic homeostasis regulation. Systemic insults are sensed by peripheral cells (sensors), which relay signals to central controllers—primarily neural and neuroendocrine centers—that integrate input and generate regulatory outputs. These signals target systemic effectors, including the heart, lungs, kidneys, gastrointestinal tract, liver, skeletal muscle, and microvasculature, to maintain oxygen delivery (O₂), carbon dioxide clearance (CO₂), and overall hemodynamic disequilibrium. The figure illustrates the feedback loop sustaining hemodynamic homeostasis.

FIGURE 3

Disruption of neural control and cardiovascular-respiratory (CVRS) in critical illness. The figure illustrates damage to the regulatory brain centers (controller), pulmonary gas exchange interface, and cardiac tissue during critical illness. The top segment highlights neurovascular uncoupling and neuroinflammation, impairing autonomic and neuroendocrine control. The left and right insets show mismatched ventilation-perfusion (V/Q) relationships: impaired perfusion with preserved ventilation (dead space) and impaired ventilation with preserved perfusion (shunt), respectively. The bottom panel depicts myocardial injury characterized by inflammatory infiltration and structural disarray, further disrupting CVRS coordination and oxygen delivery.

FIGURE 4

Hypoxia and critical unit injury. Hypoxia disrupts endothelial integrity and causes cellular damage, leading to mitochondrial release into the extracellular space. These mitochondria act as damage signals, triggering immune activation and further microvascular injury. This process contributes to local perfusion failure and systemic hemodynamic imbalance.