Bedeutung von Adrenomedullin für die hyper- und hypodyname Phase der Endotoxämie

Septic shock is characterized by two distinct hemodynamic phases, an early hyperdynamic and a late hypodynamic state. The latter condition contributes to organ hypoperfusion and is, therefore, associated with increased mortality rates. Adrenomedullin (AM) has been identified as a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular functions. However, it is still not fully understood whether the circulatory failure in sepsis and systemic inflammatory response syndrome (SIRS) is linked to vascular hyporeactivity against AM. This study was designed as a prospective, controlled laboratory experiment to determine whether administration of exogenous AM may be useful to prevent or reverse the moribund hypodynamic stage in ovine endotoxemia. Twenty-four ewes, weighing 36,9 ± 1,1 kg were instrumented with a pulmonary catheter and a femoral artery catheter for chronic study. Following a 24-hour recovery period, a baseline measurement (BL) in the healthy state was performed. The sheep were randomly allocated to one of the three study groups: control (n = 8), treatment (n = 8) and prophylaxis (n = 8). All groups were subjected to a continuous endotoxin infusion (ETX, Salmonella typhosa) started with 10 ng·kg-1·min-1 and doubled every hour for six times, until a maximum dose of 640 ng·kg-1·min-1 was given. Since pilot experiments demonstrated that this approach reliably produces a hypodynamic circulation after four hours, the treatment group received AM (50 ng·kg-1·min-1) at this point of time for the remaining three hours of ETX challenge. In the prophylaxis group, AM and ETX (50 ng·kg-1·min-1) were infused simultaneously from the beginning to the end of the seven-hours treatment period. Then, the surviving sheep were anaesthetized with propofol and killed with a lethal dose of potassium chloride. The following data were recorded: cardiac index (CI), heart rate (HR), mean arterial pressure (MAP), systemic vascular resistance index (SVRI), central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), pulmonary vascular resistance index (PVRI), pulmonal capillary wedge pressure (PCWP), oxygen delivery (DO2), oxygen consumption (VO2), oxygen extraction rate (O2-ER),arterial lactate concentration (lac) and core body temperature (temp.). Data are expressed as mean ± S.E.M. Following four hours of endotoxemia, the control group exhibited a hypodynamic circulation characterized by a decrease in CI (4,9 ± 0,3 vs. 7,5 ± 0,5 l·min-1·m-2; p<0,001), and a 16% reduction in MAP, accompanied by an increase in SVRI (1443 ± 68 vs. 1012 ± 64 dyne·cm-5·m2; p<0,001). Compared with baseline, ETX infusion also increased MPAP (31 ± 2 vs. 20 ± 1 mmHg) and PVRI (313 ± 31 vs. 98 ± 9 dyne·cm-5·m2; each p<0,001). In the course of the experiment, these hemodynamic changes further deteriorated and were associated with a decrease in DO2 and VO2, followed by an increase in arterial lactate concentration (7 hours vs. BL: 3,6 ± 0,4 vs. 0,9 ± 0,1 mmol·l-1; p<0,001). Assessment of the CI/O2-ER-ratio suggested the presence of oxygen supply dependency in five sheep. Following four hours of endotoxemia, similar changes were found in the treatment group. Administration of AM led to a successive increase in CI (7 hours vs. 4 hours: 9,5 ± 0,7 vs. 5,7 ± 0,3 l·min-1·m-2; p<0,001) and caused a shift from the hypodynamic circulation to a hyperdynamic state. The associated improvement in systemic O2-transport prevented the occurrence of tissue dysoxia in any sheep. Prophylactic administration of AM caused a hyperdynamic circulation and prevented the shift to the moribund hypodynamic stage. In addition, AM infusion evaded not only the occurrence of oxygen supply dependency but also of pulmonary hypertension. Compared with controls, sheep from prophylaxis group showed a lesser increase in lactate levels (7 hours vs. 4 hours; 2,7 ± 0,4 vs. 3,6 ± 0,4 mmol·l-1; p<0,001). In the experimental setting of ovine endotoxemia, AM has proven to be a useful agent, reversing and preventing both hypodynamic circulation and tissue dsyoxia. Whether administration of exogenous AM may also reduce the incidence of multiple organ failure and mortality remains to be investigated. However, the beneficial effects of AM deserve further studies and support its investigative use in humans.