Authors: Persson NDA et al.
Journal: Anesthesiology, December 12, 2025. DOI: 10.1097/ALN.0000000000005794
Summary
This preclinical imaging study examined how general anesthetic technique and systemic hyperosmolality influence the distribution of intrathecally administered drugs delivered at the lumbar level. Because lumbar intrathecal drug delivery often fails to achieve therapeutic intracranial concentrations, the investigators explored whether anesthetic choice and hypertonic saline could modulate cerebrospinal fluid dynamics and glymphatic transport to improve central nervous system exposure.
Female rats received lumbar intrathecal injections of a high–molecular-weight radiotracer under either ketamine–dexmedetomidine or isoflurane anesthesia, with concurrent administration of hypertonic saline or isotonic saline. Whole-body tracer distribution was quantified using serial single-photon emission computed tomography, while magnetic resonance imaging was used to assess anesthetic-induced changes in spinal subarachnoid space volume.
Ketamine–dexmedetomidine anesthesia significantly increased local spinal tracer availability while reducing intracranial tracer exposure compared with isoflurane under isotonic conditions. This anesthetic regimen was also associated with a marked expansion of the spinal subarachnoid space, suggesting altered cerebrospinal fluid geometry and flow. In contrast, systemic hypertonic saline substantially increased intracranial tracer availability during ketamine–dexmedetomidine anesthesia and prolonged central nervous system retention of spinally administered drugs in awake animals. These effects were not observed to the same extent during isoflurane anesthesia.
Together, the findings demonstrate that both anesthetic state and systemic osmolality are powerful modulators of intrathecal drug distribution. The results suggest that targeted manipulation of anesthesia and serum osmolality may improve efficacy and reduce side effects of spinally administered therapies, with potential translational relevance.
Key Points
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General anesthesia significantly alters spinal and intracranial distribution of intrathecal drugs.
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Ketamine–dexmedetomidine increases spinal drug retention and expands spinal subarachnoid space compared with isoflurane.
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Systemic hypertonic saline enhances intracranial availability of spinally administered drugs during ketamine–dexmedetomidine anesthesia.
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Hypertonic saline prolongs CNS drug retention even in the awake state.
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Modulating anesthesia and serum osmolality may improve clinical intrathecal drug delivery strategies.
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