Brainstem mechanisms of autonomic dysfunction in encephalopathy-associatedShiga toxin 2 intoxication

Acute encephalopathy is the major determinant of death in an early stage of Shiga toxin (Stx)-producing Escherichia roll infection. Rapid progress tow ard refractory hypotension and dysfunction of breathing implies autonomic c enter dysfunction of patients. To clarify whether autonomic dysfunction bec omes an ultimate cause of death in Shiga toxemia, we injected purified Stx2 (20 mu g/kg) intravenously into rabbits, and monitored changes in cardiova scular and respiratory function together with renal sympathetic nerve activ ity (RSNA) in the conscious state. After an approximately 24-hour silent (l ag) period, all rabbits given Stx2 developed hemorrhagic diarrhea (25.7 +/- 1.1 hours) and limb paralysis (31.2 +/- 1.3 hours). This limb paralysis wa s observed initially in the hind legs, and then it gradually extended to th e forelegs. After 23.2 +/- 2.3 hours, RSNA increased gradually, and arteria l blood pressure was maintained within normal limits together with an incre ase in the maximum gain of baroreflex response. Severe hypotension develope d within 34.8 +/- 2.2 hours, without any increase in heart rate; RSNA signi ficantly increased by 39.5 +/- 0.9 hours. In the final stage, RSNA decrease d concurrently with decreases in arterial blood pressure, heart rate, and b aroreflex response, suggesting dysfunction of the baroreflex control system . Thereafter, all rabbits died within 47.8 +/- 1.2 hours after the intraven ous Stx2 injection. Magnetic resonance imagings of the central nervous syst em (T2-weighted images) showed high-intensity areas in the dorsal two-third s of the cervical spinal cord and brainstem 48 hours after Stx2 administrat ion. These results show that the cause of death is circulatory failure caus ed by impairment of the cardiovascular center in the medulla. We believe th at this animal model helps to clarify the mechanism of rapid progress to de ath of patients with Shiga toxin-producing E. coli infection.