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Based on the physiology described in the preceding sections, an increasing number of pharmacologic agents have been used or promoted as protective agents. Although short-term benefits (increased urine flow, improved GFR) are commonly encountered, few definitive data have demonstrated differences in outcome measures such as acute renal failure, dialysis requirement, or mortality. Some of these agents will be discussed here, whereas others will be related to specific high-risk situations in the next section.
Dopaminergic agonists and antagonists may be classified on the basis of their selective or nonselective action on DA1 and DA2 receptors (see Table 20-2 ). Haloperidol,[67] a nonselective dopaminergic antagonist, and metoclopramide, a selective DA1 antagonist,[68] inhibit the effects of dopamine in vitro and are used to categorize receptor activity. Their clinical impact on dopaminergic stimulation is not well studied.
The "triphasic" effects of dopamine have been well characterized by Olsen and colleagues, who performed a dose-response (1 to 12 µg/kg/min) study with dopamine in hydrated, salt-loaded normal subjects.[69] Mean arterial pressure decreased at 1 to 2 µg/kg/min, thus suggesting predominantly vasodilator dopaminergic effects. eRPF peaked at 3 µg/kg/min at 50% above baseline, but the GFR did not increase at any dose. An increase in cardiac output occurred at a dose of 5 µg/kg/min, consistent with a predominantly β-adrenergic inotropic effect. Mean arterial pressure increased progressively above 7.5 µg/kg/min,
Dopamine-induced natriuresis appears to be caused by increased proximal tubular outflow and diminished distal reabsorption.[69] At higher doses, saluresis actually increases, which suggests a pressure-dependent natriuretic effect. In a study comparing equi-inotropic doses of dopamine and dobutamine after cardiac surgery, the two agents had similar effects on GFR, RBF, renal vascular resistance, and FF. However, dopamine results in a greater urine flow rate, natriuresis, FENa , and potassium excretion, thus indicating a diuretic effect independent of changes in RBF and GFR.[70]
Dopamine may theoretically benefit renal function by selectively increasing RBF and inducing saluresis (DA1 effects) or by increasing cardiac output and renal perfusion (β-adrenergic effects). It has been demonstrated to increase RBF in the face of norepinephrine-induced vasoconstriction.[24] However, dopamine's effectiveness is limited by its mixed adrenergic activity, with overlapping dose-response curves. Moreover, in a pharmacokinetic study on normal volunteers, MacGregor and associates found a 30-fold intersubject variability in plasma dopamine levels.[71] Some subjects given an infusion of "low-dose" dopamine had plasma levels consistent with those associated with doses in the high α-adrenergic range. The wide range in dopamine disposition may account for the variable and unpredictable responses observed when dopamine is administered in clinical practice. Even at low doses it can cause unwanted tachycardia. At doses above 10 µg/kg/min, dopamine has increasing activity on the α1 -adrenergic receptor, in part because of its biotransformation to norepinephrine. The net effect is progressive renal vasoconstriction and a diminished urine flow rate.
Perhaps because of the constraints just enumerated, few data are available to support the prophylactic administration of low-dose dopamine for renal protection in surgery, trauma, or sepsis. Low-dose dopamine did not improve RBF, GFR, or urine flow during canine thoracic aortic cross-clamping.[72] It does not significantly increase GFR or RBF in chronic renal insufficiency when the baseline GFR is less than 50 mL/min/1.73 m2 .[73] In a controlled prospective study on patients undergoing orthotopic liver transplantation, prophylactic low-dose dopamine had no significant benefit on intraoperative urine flow, postoperative creatinine clearance, acute renal failure, or mortality.[74] In a randomized, prospective study on cadaveric kidney graft recipients, dopamine at 2 µg/kg/min increased urine flow but did not alter postoperative creatinine clearance or the requirement for dialysis.[75] It was noted to frequently cause tachycardia.
Given this evidence, one concludes that dopamine should be restricted to therapeutic use as an inotropic agent with diuretic activity. If oliguria persists despite intravascular volume repletion, especially when associated with hypotension, dopamine can enhance blood pressure, cardiac output, and RBF and is useful in promoting urine flow.
Dopexamine is a synthetic analog of dopamine. It is a potent β2 receptor agonist and nonselective dopaminergic agonist, with about a third of dopamine's effect on the renal vasculature.[76] Its effects are predominantly chronotropic, with a moderate inotropic effect coupled with intense arterial vasodilation (inodilation). Potential advantages include improved myocardial efficiency through its lusitropic actions (enhanced diastolic relaxation and decreased wall stress) and promotion of renal perfusion. Used in the dose range of 1 to 5 µg/kg/min, it provides left and right ventricular afterload reduction in acute and chronic heart failure while augmenting RBF.[77] Tachycardia is common, but tachyarrhythmias are not. In a sense, dopexamine provides the pharmacologic profile of a phosphodiesterase inhibitor such as milrinone, but with the rapid onset and offset of action of a catecholamine.
Fenoldopam, a benzodiazepine dopamine analog, is a selective DA1 receptor agonist and is devoid of DA2 , β-adrenergic, or α-adrenergic activity. When administered between 0.03 and 0.3 µg/kg/min, it causes a dose-related increase in RBF and natriuresis. In vitro, it antagonizes norepinephrine-induced vasoconstriction. It is rapidly metabolized with a half-life of 10 minutes, and when administered by intravenous infusion, it has a rapid onset and offset of effect.
In 1998 fenoldopam was approved for the short-term parenteral treatment of severe hypertension. Fenoldopam is as effective as sodium nitroprusside in controlling severe renovascular hypertension, but unlike nitroprusside, it induces significant increases in GFR, urine flow, and saluresis without rebound hypertension. [78] The selective DA1 receptor agonist activity of fenoldopam suggests that it may confer protection against nephrotoxic or ischemic renal insults without the β-adrenergic side effects of dopamine. [79] At present, it appears that fenoldopam may have a role only in the realm of attenuation of contrast-induced nephropathy (see later).
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