vs. norepinephrine in endotoxic shock: systemic, renal, and splanchnic hemodynamic and oxygen transport effects. J Appl Physiol 95: 803-809, 2003; 10.1152/ japplphysiol.00017.2003.-The effects of intravenous norepinephrine (NE, group 1) and vasopressin (AVP, group 2) infusions on systemic, splanchnic, and renal circulations were studied in anesthetized dogs under basal conditions and during endotoxic shock. Under basal conditions, AVP infusion induced a 12 Ϯ 7% drop in left ventricular stroke work, a 45 Ϯ 5% fall in portal venous blood flow, and a 31 Ϯ 13% decrease in intestinal mucosal blood flow (P Ͻ 0.05). AVP also decreased splanchnic oxygen delivery (DO 2) and increased splanchnic and renal oxygen extraction significantly during basal conditions. Except for more pronounced bradycardia among animals in group 2, the systemic and splanchnic changes were comparable between study groups during endotoxic shock. AVP infusion restored renal blood flow and DO 2 in endotoxic shock compared with animals resuscitated with NE, which had persistently low renal blood flow and DO 2. Our data demonstrate that, in contrast to NE, administration of AVP effectively restores renal blood flow and DO2 with comparable systemic and splanchnic hemodynamic and metabolic effects in endotoxin-induced circulatory shock.vasopressors; resuscitation; blood flow SEPTIC SHOCK IS A FORM OF distributive circulatory collapse caused by severe infections (6,22). The hallmark of clinical septic shock is marked peripheral arteriolar vasodilatation, which results in low systemic vascular resistance, elevated cardiac output, hypotension, and inadequate tissue perfusion. Although the mechanism of the vasodilatation of septic shock remains incompletely understood, growing evidence implicates abnormalities of vasomotor regulation (11, 31). In addition, inappropriately low plasma vasopressin levels have been suggested as contributory to the hypotension in advanced vasodilatory septic shock (10).Therapy for septic shock typically includes administration of intravenous fluids, antibiotics, and vasopressor agents (33). However, development of adrenergic hyposensitivity with gradual loss of catecholamine pressor responsiveness resulting in refractory hypotension is a frequent clinical challenge (2, 21). Arginine vasopressin (AVP), a potent endogenous vasoconstrictor, has been proposed as a vasopressor alternative or adjuvant to conventional catecholamine treatment for management of septic shock (16,23,29). In this setting, AVP infusion improved mean arterial blood pressure, facilitated withdrawal of catecholamine vasopressor support, and improved some measures of renal function (16,23,29). However, organ-specific heterogeneity in the vascular responsiveness to AVP has been described. For example, AVP causes cerebral and pulmonary vasodilatation (9, 30), whereas increases in systemic vascular resistance and reduction of skeletal muscle and skin blood flow have been described as well (5). The effects of AVP on intestinal and renal blood flow during sepsis-ind...

The effects of fenoldopam, a dopamine-1 (DA-1) receptor agonist, were studied in two groups of anesthetized dogs before and after induction of splanchnic ischemia by way of hemorrhage. During the first portion of the experiment, both groups received fenoldopam (1.5 microg x kg(-1) x min(-1)) for 45 min followed by a 45-min washout. During the second portion, hemorrhage (10 ml/kg) was induced, followed by no intervention in group I (controls) and restarting of the fenoldopam infusion in group II. Prehemorrhage, fenoldopam increased composite portal blood flow by 33% (P < 0.01). After hemorrhage-induced splanchnic ischemia, fenoldopam restored portal vein blood flow to near baseline, maintained the splanchnic fraction of cardiac output, and attenuated the rise in gut mucosal PCO(2). DA-1 receptor stimulation increased portal blood flow and redistributed blood flow away from the serosal layer in favor of the mucosa during basal conditions and after hemorrhage, suggesting a more concentrated distribution of splanchnic DA-1 receptors within the mucosal layer vasculature. Fenoldopam maintained splanchnic blood flow during hypoperfusion and attenuated the splanchnic vasoconstrictive response to hemorrhage.

. Dopamine-1 receptor stimulation impairs intestinal oxygen utilization during critical hypoperfusion. Am J Physiol Heart Circ Physiol 284: H668-H675, 2003; 10.1152/ ajpheart.00636.2002.-Effects of a dopamine-1 (DA-1) receptor agonist on systemic and intestinal oxygen delivery (Ḋ O2)-uptake relationships were studied in anesthetized dogs during sequential hemorrhage. Control (group 1) and experimental animals (group 2) were treated similarly except for the addition of fenoldopam (1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in group 2. Both groups had comparable systemic critical Ḋ O2 (Ḋ O2crit), but animals in group 2 had a higher gut Ḋ O2crit (1.12 Ϯ 1.13 vs. 0.80 Ϯ 0.09 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05). At the mucosal level, a clear biphasic delivery-uptake relationship was not observed in group 1; thus oxygen consumption by the mucosa may be supply dependent under physiological conditions. Group 2 demonstrated higher peak mucosal blood flow and lack of supply dependency at higher mucosal Ḋ O2 levels. Fenoldopam resulted in a more conspicuous biphasic relationship at the mucosa and a rightward shift of overall splanchnic Ḋ O2crit despite increased splanchnic blood flow. These findings suggest that DA-1 receptor stimulation results in increased gut perfusion heterogeneity and maldistribution of perfusion, resulting in increased susceptibility to ischemia. oxygen supply dependency; splanchnic ischemia; vasodilators AT A GIVEN LEVEL OF METABOLIC demand, systemic oxygen consumption is maintained constant despite moderate changes in systemic oxygen delivery (Ḋ O 2 ) (6,14,25,30,31). This is accomplished by changes in peripheral oxygen extraction, with a consequent decrease in mixed venous oxygen content. However, once Ḋ O 2 falls below a critical threshold, parallel decreases in oxygen uptake (V O 2 ) are observed. This "oxygen supply dependency" is accompanied by maximal tissue oxygen extraction, development of anaerobic metabolism, and venous hypercarbia (12,14).The splanchnic circulation is particularly susceptible to ischemia during shock (1, 17). This regional ischemia is thought to play an important role in the development of multiple-system organ failure by activation of a systemic inflammatory response (22,35). In an effort to prevent or decrease gut ischemia, numerous gut-directed therapeutic approaches have been attempted with conflicting results (12). To date, clinical attempts to improve gut perfusion have focused mainly on the use of vasoactive drugs (16,20,21). However, the lack of splanchnic selectivity by these vasoactive agents could yield unwanted effects on gut oxygenation and desired outcomes. The most "gut-selective" vasoactive agent in common clinical use is dopamine given at relatively low doses. In animal models, low-dose dopamine infusions accelerate the onset of gut ischemia, impair gut oxygen extraction, and decrease gut V O 2 (9, 32). It is unclear from these data whether the adverse effects of low-dose dopamine are secondary to redistribution of flow within the gut or due to dopamine-induced alterations i...

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