Authors: Persson N.D.Å. et al.
Anesthesiology, October 9, 2025. DOI: 10.1097/ALN.0000000000005794
This preclinical study examined how anesthesia type and systemic osmotic state influence the central nervous system (CNS) distribution of drugs administered via the lumbar intrathecal route. While intrathecal drug delivery bypasses the blood-brain barrier, it often fails to achieve therapeutic concentrations in the brain, limiting efficacy for disorders requiring widespread CNS distribution. The researchers hypothesized that anesthetic choice and systemic hyperosmolality (via hypertonic saline, HTS) could modify cerebrospinal fluid (CSF) flow dynamics along the glymphatic pathway, thereby altering drug transport.
Using female rats, investigators compared two anesthetic regimens—ketamine-dexmedetomidine (K/DEX) versus isoflurane—with or without systemic HTS. A high–molecular-weight radiotracer (technetium-99m–labeled human serum albumin nanocolloid, 66.5 kDa) was injected into the lumbar CSF, and its distribution was tracked with single-photon emission computed tomography (SPECT). Magnetic resonance imaging (MRI) was used to measure anesthetic-induced changes in spinal subarachnoid space volume.
Results showed that K/DEX anesthesia enhanced local spinal retention of the tracer and reduced its intracranial spread compared with isoflurane, suggesting slower upward CSF movement. K/DEX also expanded the spinal subarachnoid space by 46%, potentially explaining the localized concentration increase. In contrast, systemic HTS markedly increased intracranial tracer delivery—but only under K/DEX, not isoflurane—and prolonged CNS retention even in awake animals.
These findings reveal that both anesthetic choice and osmotic modulation can significantly affect the pharmacokinetics of intrathecal agents. By leveraging such physiologic mechanisms, future clinical strategies may enhance targeted CNS drug distribution, improving efficacy while minimizing systemic exposure and side effects.
What You Should Know
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Anesthetic choice alters CSF dynamics and intrathecal drug distribution.
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Ketamine-dexmedetomidine increased spinal drug concentration and reduced brain exposure compared with isoflurane.
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Systemic hypertonic saline enhanced brain delivery of spinally administered drugs under K/DEX anesthesia.
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Osmotic and anesthetic modulation of CSF flow could optimize spinal drug therapies and warrant clinical investigation.
Thank you to Anesthesiology for publishing this innovative study linking anesthesia type and osmotic modulation to intrathecal drug pharmacokinetics.