Dopexamine: immunomodulatory, hemodynamic, or both?

Dopexamine is a dopamine analog that has been used for hemodynamic optimization in a number of clinical settings. This animal investigation showed anti-inflammatory effects of dopexamine in a rat endotoxin model without effects on global or regional flow, but it is not time to dispense with hemodynamics altogether just yet. Rather, an integrative approach to the effects of catecholamines, considering both inflammatory and hemodynamic effects, including those on the microcirculation, can help clinicians best understand how to employ them in clinical practice.


Introduction
Busy clinicians sometimes think twice before reading studies of animal models. Yes, it sounds interesting, but is it really going to change my practice? Th ere is so much else I should be reading… Th is writer does not mean to cast aspersions on such an attitude -and, in fact, shares it, at least to some extent. Animal studies are most useful when they illuminate clinical issues. Th e report in the previous issue of Critical Care by Bangash and colleagues is one such study [1].
Dopexamine is a dopamine analog that stimulates βadrenergic and dopamine 1 and 2 receptors, conferring some vasodilatory eff ects. Dopexamine has classically been considered a vasoactive agent with inotropic eff ects, perhaps with more prominent eff ects in some regional vascular beds. As such, dopexamine has been tested in clinical trials to optimize hemodynamics, either in patients with shock or as part of a perioperative regimen.

Inotropic therapy to optimize hemodynamics
Th e clinical benefi ts of inotropic therapy for hemo dy namic optimization remain somewhat uncertain. Myo cardial dysfunction occurs in a subset of patients with septic shock [2], so a strategy of increasing cardiac output and thus oxygen delivery in this setting made some sense. Implementation of this strategy using dobutamine, with or without norepinephrine, to improve cardiac output to predetermined supranormal levels in all patients did not improve outcomes [3][4][5], and use of inotropic therapy for this purpose is not recommended in current guidelines [5]. Subsequent reports of potentially deleterious proinfl ammatory eff ects of catecholamines provided mechanistic support for their lack of effi cacy when used indiscriminately [6].

Dopexamine may be diff erent
Use of dopexamine targeted to increase oxygen delivery to >600 ml/minute/m 2 , however, was shown in a randomized trial reported in 1993 to decrease mortality in the perioperative period [7]. Whether this resulted from diff erential hemodynamic eff ects of dopexamine compared with other agents, perhaps selective vasodilation of regional circulations, or whether use of inotropes for perioperative optimization is diff erent from their use in other settings was not entirely settled.

Or is it?
Further studies since that time have advanced the fi eld with out providing complete resolution. Some reports using perioperative dopexamine found reduced morbidity or mortality [8,9], confi rming the initial study, but others found no diff erence from conventional treatment [10][11][12]. A patient-level meta-analysis suggested that some of the diff erences might be explained by the dose of dopexamine employed [13]. Other studies indicated that dopexamine -in part due to β 2 -adrenergic eff ects, but also through other pathways -might have immunomodulatory eff ects, especially in the spleen [14].

Infl ammation or hemodynamics?
Th e current study investigated both hemodynamic and infl ammatory eff ects of a low dose of dobutamine in a rodent model of endotoxemia. Dopexamine reduced the systemic infl ammatory response to endotoxin, including

Abstract
Dopexamine is a dopamine analog that has been used for hemodynamic optimization in a number of clinical settings. This animal investigation showed antiinfl ammatory eff ects of dopexamine in a rat endotoxin model without eff ects on global or regional fl ow, but it is not time to dispense with hemodynamics altogether just yet. Rather, an integrative approach to the eff ects of catecholamines, considering both infl ammatory and hemodynamic eff ects, including those on the microcirculation, can help clinicians best understand how to employ them in clinical practice. cytokine release, endothelial adhesion molecules, and oxi dative stress, without substantially changing systemic hemodynamics, either blood pressure or stroke volume [1]. Regional fl ow, assessed by laser Doppler in the mesenteric circulation, was also not changed by dopexamineyet lactate levels and organ function were improved [1]. Th e authors concluded that benefi cial eff ects of dopexamine may result from immune modulation.

Or both?
While immunomodulatory eff ects of dopexamine were demonstrated in this study, these results contrast with those of a recent clinical investigation, also carried out by this same group, in which dopexamine improved global oxygen delivery, microvascular fl ow and tissue oxygenation but did not change the infl ammatory response to surgery [15]. Perhaps the diff erence could result in part from microcirculatory heterogeneity, something not assessed by the laser Doppler methodology used in this study. Previous studies have shown that regional heterogeneity may be a good predictor of outcome in shock states [16,17], and such heterogeneity might contribute to both perfusion abnormalities and production of lactate in sepsis and other infl ammatory states. Th us, while this study convincingly demonstrates immunomodulatory eff ects of dopexamine in this model, it seems possible that microcirculatory hemodynamic eff ects are also playing a role.

An integrative approach
Th is animal study addresses some of the mystery of why eff ects of dopexamine may diff er from those of other catecholamines, but that mystery is not yet fully solved. Hemodynamics rule, and those who understand them rock, but this study reminds us that catecholamines have infl ammatory eff ects that must be taken into account when considering their use. Animal studies are usually pursued as part of a reductionist approach aimed at controlling as many variables as possible in order to isolate mechanistic eff ects, but their interpretation and extrapolation to the clinical setting reminds us that in critical care, clinicians think of eff ects on diff erent systems all together. Carefully conducted studies such as this one counteract the nihilistic tendency to think that mechanisms are too complicated and thus only hard clinical endpoints in patients are of any value, and encourage the sort of integrative approach that makes progress possible.