Even though severe sepsis and septic shock therapy has improved in recent years,
mortality remains high (22-50%). Disturbances in splanchnic organ homeostasis and
increases in gut permeability have long been presumed to contribute to systemic
inflammation and multiple organ dysfunction syndrome in critical illness and septic
shock. In recent years, microcirculatory dysfunction has been highlighted as an
important player in the development of sepsis-induced organ failure. This thesis
investigated splanchnic microcirculatory changes during endotoxaemia, and the
microcirculatory effects of ethyl pyruvate, endothelin (ET) receptor antagonists, and a
norepinephrine-induced increase in perfusion pressure. Laser Doppler flowmetry
(papers I-IV) and sidestream dark field microscopy (paper IV) were used to evaluate
the microcirculation.
In papers I-III a 5-hour model of porcine endotoxaemia was used. In this model, the
systemic haemodynamic response to endotoxin was hypodynamic, with decreasing
cardiac index (CI), hypotension, and systemic acidosis. Splanchnic regional blood flow
and microcirculatory perfusion deteriorated, and ileal mucosal acidosis measured with
air tonometry developed in parallel.
Although intervention with the resuscitation fluid Ringer’s ethyl pyruvate solution
(REPS) temporarily improved systemic haemodynamics, no major differences in
haemodynamic parameters or splanchnic perfusion were found compared to standard
therapy with Ringer’s acetate (RA).
The mixed ETA/ETB receptor antagonist tezosentan did not increase superior
mesenteric artery flow (SMAF), but microcirculatory perfusion in the ileal mucosa and
ileal mucosal acidosis was still improved. Tezosentan also increased portal vein flow
compared to controls, but no significant improvement of hepatic microcirculatory
perfusion could be demonstrated. Selective endothelinA receptor antagonism with
TBC3711 failed to improve splanchnic regional blood flow, splanchnic
microcirculatory perfusion or ileal mucosal acidosis.
A 25-hour model of endotoxaemic shock in sheep, mimicking the hyperdynamic
circulation seen in septic patients, was used in paper IV. After 24 hours of
endotoxaemia, CI was increased and systemic hypotension had developed. Although
SMAF also increased, microcirculation in the ileal mucosa and muscularis was
disturbed, ileal mitochondrial complex I activity decreased, and ileal mucosal acidosis
developed. Increasing perfusion pressure with norepinephrine after 24 hours of
endotoxaemia did not significantly alter SMAF, ileal microcirculation, ileal
mitochondrial enzyme activity or ileal mucosal acidosis.
In conclusion, gut microcirculatory alterations have a weak correlation to systemic and
regional indices of flow and pressure in endotoxaemia, strengthening the hypothesis
that monitoring and therapies directed towards the microcirculation could be of value in
sepsis. The ET system is involved in the development of gut microcirculatory
dysfunction in endotoxaemia, and mixed ET receptor antagonism is necessary to
counteract the effects of ET in this context. Resuscitation with REPS does not appear to
have initial positive haemodynamic or microcirculatory effects compared to RA
