Does sevoflurane (anesthetic) affect cerebral glymphatic activity?

Sevoflurane Significantly Impairs Cerebral Glymphatic Activity

Sevoflurane disrupts macroscopic cerebrospinal fluid (CSF) flow in humans, which is the primary driver of glymphatic waste clearance from the brain, and this impairment persists after emergence from anesthesia. 1

Direct Evidence of Glymphatic Disruption

The most recent and highest-quality evidence demonstrates that sevoflurane at 2 vol% causes:

• Decreased cisternal CSF peak-to-trough amplitude (median difference 1.00; 95% CI 0.17-1.83; P=0.013), indicating reduced macroscopic CSF flow through the basal cisternae 1
• Disrupted global gray matter-CSF coupling (median difference 1.19; 95% CI 0.36-2.02; P=0.002), which is essential for coordinated glymphatic transport 1
• Disrupted global cortical blood oxygenation level-dependent connectivity (median difference 1.5; 95% CI 0.67-2.33; P<0.001), which drives the pulsatile CSF flow necessary for glymphatic function 1

Critical Post-Anesthetic Persistence

The impairment of glymphatic activity does not immediately resolve upon emergence from anesthesia:

• Global gray matter-CSF coupling remained disrupted 45 minutes after regaining consciousness (median difference 1.06; 95% CI 0.23-1.89; P=0.008) 1
• Global connectivity impairment persisted post-emergence (median difference 0.94; 95% CI 0.11-1.77; P=0.022) 1

This prolonged disruption may contribute to postoperative neurocognitive symptoms, particularly in older patients or those with pre-existing dementia 1

Mechanism of Glymphatic Disruption

Sevoflurane impairs glymphatic function through multiple pathways:

Cerebral Blood Flow Alterations

• Sevoflurane at 1 MAC reduces cerebral blood flow by 38% while maintaining constant mean arterial pressure 2
• At 0.88 MAC, sevoflurane produces CBF of 28±4 ml×100g⁻¹×min⁻¹ 3
• Sevoflurane causes intrinsic cerebral vasodilation that impairs CBF autoregulation during cardiopulmonary bypass, with a steeper slope between CBFV and cerebral perfusion pressure compared to control 4

Flow-Metabolism Uncoupling

• Sevoflurane reduces cerebral metabolic rate of oxygen by 47% and glucose by 39% 2
• During burst-suppression doses, sevoflurane causes a 17% decrease in CBFV and 22% decrease in cerebral oxygen extraction, indicating CBF is in excess relative to oxygen demand 4
• This represents a partial loss of cerebral flow-metabolism coupling, which is essential for coordinated glymphatic transport 4

Regional Effects

• Propofol reduces regional CBF more uniformly (to 53-70% of baseline) across all brain structures, while sevoflurane shows more variable regional effects (73-80% in some areas) 5
• Both agents reduce regional cerebral metabolic rate of oxygen similarly (56-70% for sevoflurane, 50-68% for propofol) 5

Age-Dependent Vulnerability

Young patients show selective vulnerability to sevoflurane-induced neuroinflammation:

• Repeated exposures to clinical concentrations of sevoflurane in young mice caused microglial activation and accumulation of IL-6 and TNF-α with associated cognitive impairment 6
• These detrimental changes were absent in adult mice, suggesting age-specific mechanisms 6
• Aged rodents (18-25 months) undergoing sevoflurane anesthesia with surgery demonstrated memory and learning impairments in multiple preclinical models 6

Clinical Implications

Common Pitfalls to Avoid

• Do not assume glymphatic function normalizes immediately after emergence - the disruption persists for at least 45 minutes and potentially longer 1
• Do not overlook the cumulative effect of repeated exposures - particularly concerning in young patients requiring multiple anesthetics 6
• Do not ignore the potential contribution to postoperative delirium - sevoflurane-induced glymphatic impairment may mechanistically link to postoperative neurocognitive dysfunction 1

Balancing Cardioprotection vs. Glymphatic Effects

While sevoflurane demonstrates cardioprotective properties (decreased troponin release, enhanced LV function) 6, 7, clinicians must weigh these benefits against glymphatic disruption, particularly in:

• Patients with pre-existing dementia or cognitive impairment 1
• Elderly patients at high risk for postoperative delirium 1
• Procedures where neurologic outcomes are paramount 1

The American College of Cardiology and American Heart Association recommend sevoflurane for cardiovascular patients based on cardioprotective effects 6, 7, but these guidelines predate the 2025 evidence of glymphatic disruption 1