Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

Background Results of experimental and clinical studies have shown that septic shock is associated with cardiovascular autonomic failure. Thus, we aimed to investigate the existence of ischaemia and apoptosis within the cerebral autonomic centres that control the cardiovascular system in patients with septic shock. Methods In a prospective cohort study, we did post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus coeruleus, and medullary autonomic nuclei in 19 patients with septic shock, seven with non-septic shock and five who died suddenly from extracranial injury. Ischaemic and apoptotic neurons and microglial cells, and expression of tumour necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) were scored. Findings Ischaemic, neuronal, and microglial apoptosis scores differed between groups (p=0.0007, p<0.0001, and p=0.0037, respectively) and were higher in patients with septic shock than in those with non-septic shock (p=0.0033, p=0.0005, and p=0.0235, respectively), and extra-cranial injury related deaths (p=0.0027, p=0.0007, and p=0.0045, respectively). There was little microglial activation and glial expression of TNF alpha. The scores for endothelial iNOS expression were different between the three groups (p<0.0001), and were higher in septic shock than in nonseptic shock (p=0.0009) and than in extracranial injury related deaths (p=0.0007). Vascular expression of iNOS also correlated (Spearman tau=0.57) with autonomic-centre neuronal apoptosis in the combined septic and non-septic shock group. Interpretation Septic shock is associated with neuronal and glial apoptosis within the autonomic centres, which is strongly associated with endothelial iNOS expression.