General Anesthesia and Systemic Hyperosmolality Modulate Lumbar Intrathecal Drug Distribution in Female Rats.

Abstract

Spinal administration of drugs largely bypasses the blood-brain barrier that reduces the central nervous system (CNS) availability of most systemically administered drugs. Current methods for lumbar intrathecal drug delivery fail to deliver therapeutic concentrations to the brain, whereas intracranial drug administration carries marked risks. Cerebrospinal fluid flow along the glymphatic pathway can be pharmacologically modified with a variety of drugs including anesthetics and hypertonic saline (HTS). However, the effect of anesthetics and HTS on spinally administered drugs is highly understudied. The authors investigated how two anesthetic regimens and HTS influence the distribution of a spinally administered high-molecular-weight radiotracer. Female rats were anesthetized with ketamine-dexmedetomidine or isoflurane. HTS (40 mOsm/kg) or isotonic saline (ITS) was administered intraperitoneally. The whole-body distribution of lumbar spinal tracer (technetium-99m radiolabeled human serum albumin nanocolloid, 66.5 kDa) was assessed with in vivo single-photon emission computed tomography. Anesthetic-induced changes in spinal subarachnoid space volume were investigated with magnetic resonance imaging. Compared with isoflurane, ketamine-dexmedetomidine enhanced local spinal tracer availability (area under the time-activity curve between 0 and 116 min [AUC 0-116 ] ratio, 1.78; P = 0.0016) and reduced intracranial exposure (AUC 0-116 ratio, ∞; P = 0.0260) in ITS-treated rats. Moreover, ketamine-dexmedetomidine increased the spinal subarachnoid space volume (T13-T6) by 46% ( P = 0.0051) compared with isoflurane. HTS markedly increased intracranial tracer availability compared with ITS during ketamine-dexmedetomidine anesthesia (AUC 0-116 ratio, ∞; P = 0.0047) but not isoflurane (AUC 0-116 ratio, 3.10; P = 0.1320), and prolonged CNS retention in awake rats. Anesthesia modulates the distribution of intrathecally administered drugs at the spinal and intracranial levels. Systemic HTS increased the intracranial availability of spinally administered drugs during ketamine-dexmedetomidine and prolonged the CNS availability of spinal drugs in the awake state. These interventions should be taken to clinical trials to improve efficacy and to reduce side effects of spinally administered drugs.