Sepsis is a life-threatening condition defined by organ dysfunction caused by the body’s over-reactive and dysregulated response to an infection. When this severe immune reaction leads to an abnormally low blood pressure (hypotension) that requires medication to sustain, it is classified as septic shock. Blood pressure is determined by three main factors: the volume of blood, the pumping strength of the heart, and the resistance of the blood vessels. In septic shock, the infection-fighting process inadvertently attacks all three components, leading to a profound, multi-faceted drop in blood pressure. The resulting hypotension is dangerous because it prevents sufficient blood flow and oxygen delivery to the body’s tissues, a state known as tissue hypoperfusion, which is a key driver of organ failure.
Systemic Vascular Resistance Collapse
The most immediate cause of hypotension in septic shock is a dramatic loss of tone in the blood vessel walls, termed systemic vascular resistance (SVR) collapse. Normally, tiny muscles lining the blood vessels, particularly the small arteries (arterioles), maintain a tight diameter to keep blood pressure high. Sepsis triggers a massive, systemic release of inflammatory mediators, such as the signaling proteins Tumor Necrosis Factor-alpha (TNF-\(\alpha\)) and Interleukin-1 (IL-1).
These inflammatory proteins stimulate cells within the vessel walls to produce enormous quantities of nitric oxide (NO), a potent molecule that causes vasodilation. Nitric oxide signals the smooth muscle cells to relax, causing widespread widening of the blood vessels throughout the body. This massive relaxation drastically reduces the resistance against which the heart has to pump. As systemic vascular resistance (SVR) plummets, hypotension rapidly ensues.
This initial drop in pressure due to vasodilation is often the primary hemodynamic abnormality in early septic shock. The decreased resistance means that even if the heart is pumping normally or even harder, the blood pressure remains dangerously low. This state, known as “distributive shock,” is characterized by low SVR and is a hallmark of the condition.
Plasma Volume Depletion Due to Endothelial Damage
The immune system’s inflammatory response also severely compromises the integrity of the blood vessel lining, the endothelium, leading to plasma volume depletion. The endothelium functions as a selective barrier, maintaining the fluid within the circulatory system using complex structures like the glycocalyx and tight junctions. Inflammatory mediators and toxins released during sepsis directly damage these protective layers.
The damage causes the tight junctions between the endothelial cells to break down, creating gaps. Through these gaps, fluid, proteins, and electrolytes leak out of the capillaries and into the surrounding tissues, a process called capillary leak or “third spacing.” The loss of fluid from the bloodstream reduces the effective circulating blood volume, which lowers the preload—the amount of blood returning to the heart.
A lower preload means less blood is available to be pumped out with each heartbeat, directly contributing to the drop in blood pressure. This volume loss requires fluid resuscitation, but ongoing leakage often necessitates continuous fluid administration. This fluid shift rapidly compounds the hypotension caused by vascular resistance collapse.
Myocardial Depression and Reduced Cardiac Output
While the vascular problems are the dominant cause, sepsis can also directly weaken the heart muscle, a condition called sepsis-induced myocardial depression. Inflammatory cytokines, particularly TNF-\(\alpha\) and IL-1\(\beta\), circulate in the bloodstream and act as depressant factors on the heart muscle cells. These molecules impair the contractility of the myocardium, reducing the force of each heartbeat.
This reduced contractility leads to a lower stroke volume, resulting in a lower cardiac output. Although many patients initially present with a high cardiac output (a hyperdynamic state) to compensate for low SVR, severe sepsis eventually causes the heart to fail. This myocardial depression compounds the existing hypotension, making the circulatory collapse profound. The dysfunction is typically reversible in survivors, with heart function recovering within seven to ten days.
Metabolic Failure and Vasopressor Resistance
A final, complex mechanism contributing to persistent and difficult-to-treat hypotension involves cellular metabolic failure. Sepsis disrupts the normal function of mitochondria, the energy-producing centers within cells, leading to a state of cellular energy failure. This widespread metabolic derangement affects the ability of blood vessel cells to respond to the body’s natural hormones and the powerful medications used in treatment.
During septic shock, physicians administer vasopressor medications like norepinephrine to constrict the blood vessels and raise blood pressure. However, metabolic abnormalities, such as lactic acidosis and the systemic inflammatory response, can cause the receptors on the vascular cells to become less sensitive to these drugs. This phenomenon is known as vasopressor resistance.
The vessels fail to constrict adequately despite high doses of medication, defining refractory septic shock. This resistance is linked to the dysregulation of nitric oxide metabolism and the accumulation of reactive oxygen species, which impair the vascular response to catecholamines. The combination of vasodilation, fluid loss, a weakened heart, and resistance to life-saving drugs creates the persistent, severe hypotension characteristic of septic shock.