Norepinephrine remains the first-line vasopressor for septic shock and is often highly effective at restoring arterial pressure. However, a subset of patients develop refractory vasodilatory shock despite escalating doses.
Understanding when and why to add additional agents requires an appreciation of the underlying physiology. Septic shock is characterized by profound vasodilation driven by inflammatory mediators, nitric oxide production, vascular smooth muscle dysfunction, and impaired responsiveness to endogenous catecholamines.
As shock progresses, increasing doses of norepinephrine may produce diminishing returns. One reason involves receptor biology.
Prolonged exposure to high catecholamine concentrations can result in receptor desensitization and downregulation. The vascular smooth muscle simply becomes less responsive to adrenergic stimulation.