A growing body of evidence suggests that the potential exists to reduce morbidity and high mortality rates associated with major surgery in high-risk patients. Dopexamine is a dopamine analogue with agonist activity at β2-adrenoceptors and dopaminergic receptors that has been used to maintain tissue perfusion in critically ill and high-risk surgical patients with the aim of improving clinical outcomes. Postoperative complications occur more frequently in the presence of poor tissue microvascular flow and oxygenation, and dopexamine has been shown to improve these abnormalities. However, the effect of dopexamine on clinical outcomes is less clear, and the findings of randomized trials have proved inconsistent. These conflicting findings might be explained by dose-related differences in the hemodynamic and immunologic effects of dopexamine. The series of investigations that make up this thesis set out to explore the nature of any such dose-related effects and reveal potent anti-inflammatory effects of dopexamine in the absence of haemodynamic effects.

Background and aims: Unrecognized intestinal mucosal ischemia in severely ill patients may trigger development of multiple organ failure. Such ischemia can be evaluated by intraluminal tonometry reflecting mucosal PCO2 and intramucosal pH (pHi). The aims were to develop an apparatus for continuous saline tonometry (CST), to analyse circulatory control mechanisms during intestinal hypoperfusion and to evaluate the effect of dopexamine on intestinal circulation. Methods: A modified standard tonometry catheter was integrated in a closed system with circulating saline. By measuring saline PCO2 in a measurement unit pHi could be calculated. This novel system was tested in vitro and in vivo. In a porcine study, CST was evaluated against standard saline tonometry, tissue oxygenation (PO2 TISSUE), jejunal mucosal perfusion (laser doppler flowmetry; LDF) and mesenteric net lactate flux during graded reductions of superior mesenteric arterial pressure (PSMA). Local control mechanisms for maintenance of intestinal oxygenation were analysed. Effects of dopexamine on the intestinal vascular bed were explored. Mucosal lactate production was assessed by microdialysis. Results: CST measured accurate PCO2 values and changes in pHi during restricted intestinal circulation and at reperfusion. Local control mechanisms were insufficient at a PSMA of 30 mmHg, pHi was reduced to 7.10 and intestinal net lactate production was demonstrated. Absence of anaerobic intestinal metabolism was verified at PSMA ≥ 50 mmHg, pHi ≥ 7.22 and a PCO2 gap ≤ 15.8 mmHg. Dopexamine induced negative regional metabolic effects at the lowest PSMA, as expressed by decreased PO2 TISSUE and pHi, increased PCO2 gap and intestinal net lactate production. Conclusions: CST reflected changes in pHi, induced by intestinal hypoperfusion and at reperfusion. Levels of PSMA, pHi and PCO2 gap as indicators of aerobic conditions were defined. Dopexamine induced a decrease of PO2 TISSUE and pHi as well as an increase in lactate flux at the lowest PSMA level.

Die Störung der intestinalen Mikrozirkulation gilt als ein kardinaler Mechanismus für die Entwicklung des Multiorganversagens bei Sepsis. Da das Intestinum für mikrozirkulatorische Studien klinisch kaum zugänglich ist, wurden die Auswirkungen einer Therapie mit den antioxidativen Substanzen Oxypurinol und U-74389G (Lazaroid) bzw. den vasoaktiven Substanzen Iloprost (Prostacyclin-Analogon) und Dopexamin auf die intestinale Mikrozirkulation und die systemische Mediatorfreisetzung in einem Tiermodell mit moderater und hoher Endotoxin-Belastung untersucht. Die intravitalmikroskopische Untersuchung der Kapillarperfusion in der Muskularisschicht bei Endotoxinämie erbrachte eine Verbesserung durch Oxypurinol- und Dopexamingabe. Die Perfusion der Mukosa konnte vor allem durch eine Iloprostapplikation gesteigert werden. Die Endotoxin-induzierte, intestinale Leukozytenadhärenz wurde insbesondere durch die Behandlung mit den antioxidativen Substanzen vermindert. Beide therapeutischen Optionen bewirkten eine ca. 60 %ige Reduktion der initialen Tumornekrosefaktor-alpha-Freisetzung in der Versuchsreihe mit der niedrigeren Endotoxin-Dosis. Parallel dazu konnte anhand von Malondialdehyd-Analysen gezeigt werden, dass Oxypurinol und U-74389G wirksam die intestinale, Radikal-induzierte Lipidperoxidation verringerten. Der intestinale mikrovaskuläre Blutfluss konnte durch beide vasoaktiven Substanzen - sowohl bei moderater als auch bei erhöhter Endotoxin-Dosierung - signifikant gesteigert werden. Die Ergebnisse beider Teilstudien bestätigten, dass sowohl reaktive Sauerstoffspezies als auch eine inadäquate Perfusion in der Mikrozirkulation wesentliche pathogenetische Faktoren bei Endotoxinämie bzw. Sepsis darstellen und entsprechende Therapieformen indiziert und effektiv sind. Eine kombinierte Gabe beider Substanzklassen erscheint daher sinnvoll und sollte in weiteren tierexperimentellen und klinischen Studien evaluiert werden. / The disturbance of the intestinal microcirculation is regarded as a pivotal mechanism in the development of multiorgan failure related to sepsis. Since the intestine is clinically not accessible for microcirculatory studies, the effects of a therapy with the antioxidants oxypurinol and U-74389G (lazaroid) as well as the vasoactive substances iloprost (a prostacyclin analogue) and dopexamine on the intestinal microcirculation and the systemic mediator release was studied in an animal model with moderate and high endotoxin challenge. The intravital microscopic examination of the capillary perfusion in the muscularis layer of the intestine during endotoxemia revealed an improvement by administration of oxypurinol and dopexamine. The perfusion of the mucosa could be increased by iloprost administration. The amount of the endotoxin induced, intestinal leukocyte adherence was especially decreased by the treatment with the antioxidants. Both therapeutic options caused a 60 % reduction in the initial tumor necrosis factor-alpha-release in the experiments with the lower endotoxin dose. Malondialdehyde analyses showed that oxypurinol and U-74389G reduced effectively the intestinal, radical-induced lipid peroxidation. The intestinal microvascular blood flow could be significantly increased by both vasoactive substances - as well as with moderately than also with elevated endotoxin-dosage. The results of the study confirmed that both reactive oxygen-species as well as an inadequate perfusion in the microcirculation represent essential pathogenetic factors during endotoxemia as well as sepsis and index corresponding therapy-forms and participates effective. A combined offering both substance-classes appears therefore meaningfully and should be evaluated in further experimental and clinical studies.