Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase blood-brain barrier permeability: Possible link to postoperative delirium and cognitive decline

Brain Res. 2015 Sep 16;1620:29-41. doi: 10.1016/j.brainres.2015.04.054. Epub 2015 May 8.


A large percentage of patients subjected to general anesthesia at 65 years and older exhibit postoperative delirium (POD). Here, we test the hypothesis that inhaled anesthetics (IAs), such as Sevoflurane and Isoflurane, act directly on brain vascular endothelial cells (BVECs) to increase blood-brain barrier (BBB) permeability, thereby contributing to POD. Rats of young (3-5 months), middle (10-12 months) and old (17-19 months) ages were anesthetized with Sevoflurane or Isoflurane for 3h. After exposure, some were euthanized immediately; others were allowed to recover for 24h before sacrifice. Immunohistochemistry was employed to monitor the extent of BBB breach, and scanning electron microscopy (SEM) was used to examine changes in the luminal surfaces of BVECs. Quantitative immunohistochemistry revealed increased BBB permeability in older animals treated with Sevoflurane, but not Isoflurane. Extravasated immunoglobulin G showed selective affinity for pyramidal neurons. SEM demonstrated marked flattening of the luminal surfaces of BVECs in anesthetic-treated rats. Results suggest an aging-linked BBB compromise resulting from exposure to Sevoflurane. Changes in the luminal surface topology of BVECs indicate a direct effect on the plasma membrane, which may weaken or disrupt their BBB-associated tight junctions. Disruption of brain homeostasis due to plasma influx into the brain parenchyma and binding of plasma components (e.g., immunoglobulins) to neurons may contribute to POD. We propose that, in the elderly, exposure to some IAs can cause BBB compromise that disrupts brain homeostasis, perturbs neuronal function and thereby contributes to POD. If unresolved, this may progress to postoperative cognitive decline and later dementia.

Keywords: Anesthesia; Blood−brain barrier; Delirium; Isoflurane; Postoperative delirium; Sevoflurane.

MeSH terms

  • Aging / drug effects
  • Aging / metabolism
  • Aging / pathology
  • Anesthetics, Inhalation / toxicity*
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / growth & development
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Capillary Permeability / drug effects*
  • Capillary Permeability / physiology
  • Cognition Disorders / chemically induced
  • Cognition Disorders / etiology
  • Delirium / chemically induced
  • Delirium / etiology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Immunoglobulin G / metabolism
  • Immunohistochemistry
  • Isoflurane / toxicity*
  • Methyl Ethers / toxicity*
  • Microscopy, Electron, Scanning
  • Postoperative Complications / chemically induced
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / pathology
  • Rats, Sprague-Dawley
  • Sevoflurane
  • Time Factors


  • Anesthetics, Inhalation
  • Immunoglobulin G
  • Methyl Ethers
  • Sevoflurane
  • Isoflurane