Acute brain dysfunction is a complication of sepsis, and its pathophysiology remains poorly understood. We studied the brain metabolism in a resuscitated animal model of sepsis. Twelve anesthetized, mechanically ventilated, and invasively monitored pigs were allocated to a sham procedure (N = 5) or sepsis (N = 7). Sepsis was induced through fecal inoculation in the peritoneum. Fluid resuscitation was maintained during the entire study period. Animals were observed until spontaneous death or for a maximum of 24 h. In addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis (MD) were evaluated at baseline, 6, 12, 18, and 24 h after sepsis induction. After euthanasia, the brain was rapidly removed and a fragment from the frontal cortex was analyzed for markers of neuroinflammation, metabolism, and neurotransmission. Septic animals developed a hyperdynamic state associated with increased arterial lactate. Cerebral microdialysis showed unchanged levels of lactate/pyruvate ratios and brain glucose between the groups. Brain/serum glucose ratios were increased in the septic animals during the study period despite a progressive decrease in serum glucose. Moreover, extracellular glutamine levels were elevated starting at 6 h after sepsis. Tissue analysis showed elevated glutamate, glutamine, and glutamine synthetase in the sepsis group. However, C-Fos, a marker of neuronal activity, was unchanged between groups. In this animal model of resuscitated sepsis, we found increased oxidative stress and alterations in neuroenergetics characterized by exacerbated activity of the glutamate/glutamine cycle and increased glucose utilization by the brain, however without any evidence of decompensated energy metabolism.
National Institute of Infectology, Oswado Cruz Foundation and D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
Address reprint requests to Fernando A. Bozza, MD, PhD, Instituto Nacional de Infectologia, Fundação Oswado Cruz and Instituto D’Or de Ensino e Pesquisa, Rio de Janeiro, Brazil. E-mail: email@example.com; Co-correspondence: Pedro Kurtz, MD, PhD, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Rio de Janeiro Brazil. E-mail: firstname.lastname@example.org.
Received 4 December, 2017
Revised 20 December, 2017
Accepted 14 March, 2018
LCPA and FAB equally contributed to this work.
This work was supported by unrestricted grants from Brazilian Council for Scientific and Technological Development, Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro and Research and Education Institute Hospital Sirio-Libanes.
Authors’ contributions: PK was responsible for conception, experimental design, data acquisition, and interpretation; JCA, DP, CM, CVL, and RP were responsible for the acquisition of data and data interpretation; LCPA was responsible for conception, experimental design, data acquisition, and interpretation; FAB was responsible for conception, experimental design, and data interpretation. All authors were responsible for drafting the article or revising it critically for important intellectual content and for final approval of the version. All authors read and approved the final manuscript.
The authors report no conflicts of interest.
Ethics approval: The study protocol was approved by the Institutional Animal Research Ethics Committee at Hospital Sirio-Libanes and was performed according to National Institute of Health guidelines for the use of experimental animals.