| In our experiments several factors in the pathomechanisms of septic shock-induced multiple organ failure (MOF), like oxidative stress, vascular hyporeactivity (mediated by activation of KATP channels or vasopressin deficiency), activation of NF-kappaB or PARP-1 and failure of cellular energy metabolism have been investigated in a clinically relevant porcine model of long-term resuscitated hyperdynamic endotoxemia using a delayed post-treatment approach. In anesthetized, mechanically ventilated and instrumented pigs 24 hrs of endotoxemia with fluid resuscitation (hydroxyehtyl starch) resulted in hyperdynamic circulation and impaired variables of gas exchange, metabolism, NO formation and oxidative stress. The PARP-inhibitor PJ34 improved cardiac output (CO) and attenuated the progressive deterioration of intestinal energy balance. The antioxidant N-acetylcysteine had no major beneficial effects on global or regional hemodynamics, gas exchange, or metabolism and did not improve oxidative damage. The KATP channel-inhibitor HMR1402 only transiently increased mean arterial pressure (MAP), decreased CO and increased lactate production and lactate/pyruvate ratios suggesting a disturbed cytosolic redox potential. The vasopressin analog terlipressin increased MAP affiliated with decreased CO, and O2 consumption, restored the hepatic arterial buffer response, and maintained hepatosplanchnic O2 exchange. It did not deteriorate any variables of hepatosplanchnic metabolism or organ function, and even attenuated hepatosplanchnic acidosis but it was associated with hyperlactatemia originating from extrasplanchnic organs. Ethyl pyruvate administration was associated with stabilization of systemic hemodynamics, improved pulmonary gas exchange, amelioration of systemic and regional venous acidosis, and decreased evidence of oxidative stress and NO formation. The NF-kB inhibitor 15-deoxy-Delta12,14-prostaglandin-J 2 stabilized MAP, most likely due to improved left ventricular function, but did not affect the other measured parameters of metabolism and organ function. In conclusion, despite many promising results no any approach has reversed most of the deteriorated elements of sepsis-induced MOF within the experimental period, but severe negative side effects have been revealed as well. Further intensive research is needed in clinically relevant long-term models with possible new or combined approaches. |
