Endothelin receptor antagonism and hypertonic solutions in experimental endotoxin shock

Abstract

Sepsis is a common and serious condition among patients in the intensive care unit. It is characterized by a systemic inflammatory response, resulting in cardiovascular instability and impaired organ tissue oxygenation due to hypoperfusion and inflammatory changes. The supportive treatment includes fluid resuscitation and other measures to promote organ perfusion. Hypertonic saline/dextran (HSD) resuscitation has shown improved haemodynamics in haemorrhage. In addition, immuno-modulatory effects have been reported in experimental studies. These effects would in theory also be of benefit in septic shock. The vasoconstrictive peptide endothelin (ET) is involved in several of the sepsis manifestations. Experimental results of ET antagonism in endotoxemia have demonstrated beneficial effects on cardiac performance and regional perfusion. Hypotension due to vasodilation may however be of concern in septic conditions, requiring measures to secure perfusion pressure.

The overall aim of this thesis was to evaluate two different interventions and their ability to affect vital organ perfusion through effects on systemic and regional haemodynamics in porcine endotoxin shock. Specifically, the cardiovascular effects of HSD resuscitation were further evaluated, with focus on regional perfusion. In addition, effects of the new parenteral ET antagonist, tezosentan, on systemic and regional haemodynamics were investigated. Furthermore, tezosentan was combined with HSD with the purpose of preventing ET antagonism-related hypotension, and possibly augment positive cardiovascular effects. In addition, early pro-inflammatory cytokine reponse was studied with both treatments to further evaluate their immunomodulating potential.

A model of endotoxin shock in anaesthetized pigs was used in two series of experiments. Haemodynamic responses were assessed using a pulmonary artery catheter, invasive arterial blood pressure and ultrasonic flow probes positioned around the portal vein and the renal and carotid arteries. Plasma TNF-á and IL-6 levels were monitored.

Endotoxemia resulted in a hypodynamic shock including reduced regional blood flow and development of metabolic acidosis. An inflammatory response with increases in cytokine and endothelin-1 levels was elicited. HSD resuscitation transiently improved cardiac index and mean arterial pressure. Regional blood flow increased in the renal and carotid, but not portal circulation. The progression of acidosis was delayed and the macro- and microcirculatory improvements resulted in improved survival rates. Tezosentan treatment resulted in vasodilation, which improved cardiac index, reversed pulmonary hypertension and increased portal and carotid, but not renal blood flow. Addition of HSD to tezosentan did not increase mean arterial pressure, but markedly increased portal and carotid perfusion. None of the interventions affected TNF-á and IL-6 response.

In conclusion, transient beneficial effects of HSD on systemic and renal haemodynamics were confirmed, and improved early survival indicated. From a clinical perspective, HSD resuscitation may gain time for other treatments to have their effects. The immunomodulatory potential of HSD in endotoxemia was not supported by the results from this study. However, ET antagonism as a means to promote organ perfusion was supported by the results. The improved regional flow demonstrated with combined tezosentan/HSD emphasizes the importance of additional measures to secure perfusion pressure during ET antagonism.