Journal Article

Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery—a randomized trial

Westerlind, Anne, Reinsfelt, Björn, Danielson, Mattias, Ricksten, Sven-Erik, Zetterberg, Henrik, Blennow, Kaj

2018

Overview

Background Cognitive dysfunction is a frequent complication to open-heart surgery. Cerebral inflammation caused by blood-brain barrier (BBB) dysfunction due to a systemic inflammatory response is considered a possible etiology. The effects of the glucocorticoid, methylprednisolone, on cerebrospinal fluid (CSF) markers of BBB function, neuroinflammation, and brain injury in patients undergoing cardiac surgery with cardiopulmonary bypass were studied. Methods In this prospective, randomized, blinded study, 30 patients scheduled for elective surgical aortic valve replacement were randomized to methylprednisolone 15 mg/kg ( n  = 15) or placebo ( n  = 15) as a bolus dose administered after induction of anesthesia. CSF and blood samples were obtained the day before and 24 h after surgery for assessment of systemic and brain inflammation (interleukin-6, interleukin-8, tumor necrosis factor-alpha), axonal injury (total-tau, neurofilament light chain protein), neuronal injury (neuron-specific enolase), astroglial injury (S-100B, glial fibrillary acidic protein), and the BBB integrity (CSF/serum albumin ratio). Results In the control group, there was a 54-fold and 17-fold increase in serum interleukin-6 and interleukin-8, respectively. This systemic activation of the inflammatory cytokines was clearly attenuated by methylprednisolone ( p  < 0.001). The increase of the CSF levels of the astroglial markers was not affected. A postoperative BBB dysfunction was seen in both groups as the CSF/serum albumin ratio increased from 6.4 ± 8.0 to 8.0 in the placebo group ( p  < 0.01) and from 5.6 ± 2.3 to 7.2 in the methylprednisolone group ( p  < 0.01) with no difference between groups ( p  = 0.98). In the CSF, methylprednisolone attenuated the interleukin-6 release ( p  < 0.001), which could be explained by the fall in systemic interleukin-6, and the serum to CSF gradient of IL-6 seen both at baseline and after surgery. In the CSF, methylprednisolone enhanced the interleukin-8 release ( p  < 0.001) but did not affect postoperative changes in CSF levels of tumor necrosis factor alpha. Serum levels of S-100B and neuron-specific enolase increased in both groups with no difference between groups. CSF levels of total tau, neurofilament light chain protein, and neuron-specific enolase were not affected in any of the groups. Conclusions Preventive treatment with high-dose methylprednisolone attenuated the systemic inflammatory response to open-heart surgery with cardiopulmonary bypass, but did not prevent or attenuate the increase in BBB permeability or the neuroinflammatory response. Trial registration Clinical Trials, Identifier: NCT01755338 , registered 24 December 2012

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Albumin / Analysis / Anesthesia / Anti-Inflammatory Agents - therapeutic use / Aortic valve / Aortic valve replacement / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Blood-Brain Barrier - drug effects / Brain injury / Brain tumors / Cardiac Surgical Procedures - adverse effects / Cardiopulmonary bypass / Cerebrospinal fluid / Clinical trials / Cognitive ability / cognitive dysfunction / Complications and side effects / Coronary vessels / coronary-artery-bypass / Cytokines / Cytokines - blood / Cytokines - cerebrospinal fluid / decline / Double-Blind Method / Encephalitis - blood / Encephalitis - cerebrospinal fluid / Encephalitis - drug therapy / Encephalitis - etiology / Etiology / Female / Glial fibrillary acidic protein / Glucocorticoids / Health aspects / Heart / Heart surgery / Humans / Immunology / Inflammation / injury / Interleukin 6 / Interleukin 8 / Male / Membrane permeability / Methylprednisolone / Methylprednisolone - therapeutic use / Middle Aged / Neurobiology / Neuroinflammatory / Neuroinflammatory response / Neurologi / Neurology / neuron-specific enolase / Neuronal-glial interactions / Neurosciences / Neurosciences & Neurology / Patients / Permeability / Phosphopyruvate hydratase / Postoperative Complications - blood / Postoperative Complications - cerebrospinal fluid / Postoperative Complications - drug therapy / Prospective Studies / Proteins / Retrospective Studies / S100b protein / Stroke / Surgery / Trauma / Traumatic brain injury / Treatment Outcome / Tumor necrosis factor-TNF / Veins & arteries