Treatment Of Milrinone Induced Hypotension With Vasopressin

The standard of treatment of decompensated class IV congestive heart failure (CHF) usually involves positive ionotropic agents such as continuous infusion of dobutamine. When this is inadequate, or the patient is unable to tolerate the dobutamine, secondary to refractory tachycardia/malignant arrhythmia, phosphodiesterase inhibitors, such as Milrinone/Amrinone are commonly employed. The mechanism of action of these agents is believed to be secondary to the inhibition of Phosphodiesterase III (PDEIII) and to a lesser extent PDEIV 12 The inhibition of PDEIII results in an intracellular accumulation of cyclic AW (cAMP) in both cardiac tissue and vascular smooth muscle. As a result patients usually exhibit both increased cardiac contractility, and peripheral vasodilatation resulting in increased cardiac output. Furthermore at higher dosages, Milrinone inhibits PDEIV, found in aortic endothelium, which results in the intracellular accumulation of cGMP and consequent further vasodilatation. Initial evidence in animals show that inhibition of PDEIV in the presence of increased cAW has a synergistic effect on decreasing vascular tone and possible hypotension. Clinically, these agents may result in a marked increase in cardiac output and decrease in systemic and pulmonary vascular resistance (SVR, PVR). Studies in humans, testing intracoronary infusion of Milrinone have shown approximately 40% of Milrinone's increase in cardiac output is due solely to its positive ionotropic action, while the remaining 60% is due to its effect on vascular tone. Furthermore, some studies have shown a possible synergistic effect of combining Milrinone and traditional ionotropes such as dobutamine. Although initially promising, a small but significant percentage (between 3-10%) of patients are unable to tolerate Milrinone, especially at higher doses, because of profound vasodilatation. When this occurs, further pressor agents must be instituted, or the Wrinone must be discontinued and other non pharmacological approaches such as balloon pumps, left ventricular assist devices and CVVH must be considered. Finally, even patients whose systemic blood pressure may be able to tolerate Milrinone, may still have a decrease in GFR secondary to efferent arteriole vasodilatation (relative intrarenal hypotension), thus possibly negating any positive renal effects gained via increasing cardiac output. Vasopressin is an endogenously occurring compound involved in the maintenance of vascular tone and free water resorbtion. In an ongoing trial, vasopressin is being investigated as a possible new agent in the treatment of vasodilatory/septic shock. These patients being are characterized by high cardiac outputs and low SVR. Although the mechanism of action has not been fully elucidated, one possibility is that sepsis, besides resulting in a down regulation of vasopressin production (these patients are relatively vasopressin deficient), produces hypotension via Nitric Oxide intermediate. Nitric Oxide in turn, results in the intracellular accumulation of cGMP and subsequent vasodilatation. 9 This is similar to the in-vitro effects of inhibition of PDEIV in aortic endothelium in rats. Vasopressin, via its VI receptor, has been shown to inhibit the intracellular rise of cGMP in rat aortic cells stimulated with ANF (Atrial Naturetic Factor) , an endogenous vasodilator, which works by increasing levels of cGMP similar to Nitric Oxide. It has also been demonstrated that vasopressin will blunt the intracellular rise of cAMP in rat aortic smooth muscle stimulated by isoproterinol, resulting in contraction (or the inhibition of dilatation) of rat aortic smooth muscle. In an ongoing trial, the use of low dose vasopressin in patients with vasodilatory shock has resulted in marked increased in blood pressure, reduction in the need for endogenous pressors, and increased urine output, without having a negative effect on cardiac output. Recently, the open heart ICU (CTCU) has been using vasopressin on a large number of patients as a second line pressor agent. It has been difficult to ascertain the effectiveness of vasopressin in this