The role of the adrenergic system in septic encephalopathy

Encephalopathy is a common complication of systemic sepsis, but its pathogenesis has received little attention. The adrenergic system has been implicated in the inflammatory response to sepsis and therefore the effects of adrenergic agents on the brain were investigated in an animal model of systemic sepsis.

Thirty-two pigs (25–30 kg) were anaesthetised, intubated and a thermodilution catheter placed in the pulmonary artery. Peritonitis was induced by spreading caecal contents around the peritoneum. Non-septic pigs underwent laparotomy without caecotomy. The effects of the predominantly β₂ adrenoceptor agonist dopexamine (0.6 mg/kg/h; i.v.), the α₁-agonist methoxamine (80 mg/h; i.v.) and the β₂-blocker ICI 118,551 (a 20 μg/kg bolus given hourly; i.v.) were investigated. Samples of frontal cortex were obtained 8 h after induction of sepsis, processed for electron microscopy and subjected to quantitative morphometry.

Septic pigs showed significantly more (P < 0.0004) peri-microvessel (PMV) oedema than non-septic pigs. However, there was no difference between the amount of PMV oedema in septic pigs that received dopexamine and in non-septic pigs. Neither was there any significant difference between the amount of PMV oedema in septic pigs treated with dopexamine + methoxamine and in non-septic pigs. However, non-septic pigs treated with methoxamine showed significantly more PMV oedema than non-septic pigs (P = 0.0044). There was significantly more PMV oedema in septic pigs treated with ICI 118,551 than in non-septic pigs (P = 0.0028). The mean cross-sectional area of cerebral microvessel endothelial cells in methoxamine-treated septic pigs was significantly greater than that in pigs with sepsis (P = 0.0036) and in non-septic pigs (P = 0.0004). The mean endothelial cell area was also significantly greater in methoxamine-treated non-septic pigs (P = 0.0036) and in dopexamine + methoxamine septic pigs (P = 0.0036) than in non-septic pigs. The mean cerebral microvessel lumen area was significantly larger in septic than in non-septic pigs (P = 0.012). None of the drug treatments used resulted in a mean lumen area significantly different from that of non-septic pigs.

Therefore, sepsis resulted in PMV oedema, which was protected against by dopexamine treatment. Conjoint methoxamine treatment did not impair this protective effect of dopexamine in septic pigs, but methoxamine alone caused PMV oedema formation in non-septic pigs. β₂ adrenoceptor blockade did not affect the formation of PMV oedema in sepsis. Methoxamine treatment resulted in the swelling of microvessel endothelial cells in both septic and non-septic pigs, but conjoint dopexamine treatment did not prevent this swelling. These results suggest that β₂ adrenoceptor stimulation is beneficial and α₁ adrenoceptor stimulation is detrimental to the treatment of septic encephalopathy.

Table 1