The hemodynamic effects of norepinephrine: far more than an increase in blood pressure!

Abstract

Comment on: Hamzaoui O, Jozwiak M, Geffriaud T, et al. Norepinephrine exerts an inotropic effect during the early phase of human septic shock. Br Vasopressors are commonly used to correct hypotension. Among these, norepinephrine is the preferred first line vasopressor. Compared to dopamine, norepinephrine improves outcome in patients with septic shock (1) and in cardiogenic shock (2). Recently a trial comparing norepinephrine to ephedrine boluses in peri-operative p e r i o d , d e m o n s t r a t e d t h a t n o r e p i n e p h r i n e w a s associated with lower occurrence of postoperative organ dysfunction (3). Compared to epinephrine, n o r e p i n e p h r i n e a d m i n i s t r a t i o n i n p a t i e n t s w i t h cardiogenic shock improved shock resolution and was associated to a trend in a lower mortality (4). During shortage of norepinephrine in the US, substitution of norepinephrine was associated with a transient increase in mortality rate in septic shock patients (5). Thus, norepinephrine is the vasopressor agent of choice, but what are the hemodynamic effects of norepinephrine beyond increasing blood pressure? Interestingly, it has been demonstrated in different trials that correction of hypotension with administration of norepinephrine at early stages of shock is associated with an increase in cardiac output. Intuitively, one may expect that raising blood pressure, and thus afterload, would rather be associated with a decrease in cardiac output. What mechanisms could be associated with this increase in cardiac output? Theoretically norepinephrine may act on the four determinants of cardiac output (6): heart rate, preload, contractility and afterload. As norepinephrine minimal affects heart rate, most of the hemodynamic effects are related to its effects on stroke volume. First norepinephrine markedly affect preload. In 25 septic shock patients who were fluid responsive, as defined by a positive passive leg raising test, norepinephrine increased central venous pressure by 23%, left ventricular end-diastolic area by 9% and global end diastolic volume by 9% (7). This effect on preload was accompanied by an 11% increase in cardiac index. Venoconstriction is the mechanism by which norepinephrine increases preload, redistributing blood from unstressed to stressed volume. This hypothesis was confirmed by the demonstration that norepinephrine increased mean systemic pressure, an estimate of the distending pressure in the small veins and venules, which contain most of the blood in the body (8). As mean systemic pressure increased without altering right atrial pressure, the gradient for venous return (and thus cardiac output) increased. Of note, norepinephrine also hindered somewhat the gradient for venous return by increasing venous vascular resistances, so that a greater mean systemic pressure is required to preserve venous return. Interestingly, norepinephrine decreases the need for volume replacement (9). The sepsis induced vasodilation also affects capacitance veins. Hence a large amount of volume is required to refill the tank. Norepinephrine also restore vascular tone in capacitance veins, thereby decreasing amount of fluids needed to restore the gradient for venous return. There are nevertheless two negative counterparts to the use of norepinephrine. On the one hand, excessive vasoconstriction is not desired, and the aim