COMPUTER-CONTROLLED EPIDURAL INFUSION TO TARGETED CEREBROSPINAL-FLUIDCONCENTRATIONS IN HUMANS

Background: Pharmacokinetically designed infusions have been demonstra ted to achieve rapidly and maintain desired concentrations of drug in plasma after intravenous administration, In this study we tested wheth er a similar approach, targeting concentrations in cerebrospinal fluid (CSP), could be used with epidural administration of the alpha(2)-adr energic analgesic clonidine. Methods: After institutional review board approval and informed consent had been obtained, seven healthy volunt eers received a clonidine infusion through a lower lumbar epidural cat heter. Infusion of clonidine (10 mu g/ml) was controlled by the STANPU MP program for sequential 75-min periods to targeted CSF clonidine con centrations of 25, 50, 75, and 150 ng/ml. Before reprogramming to the next higher targeted concentration, mean arterial blood pressure and h eart rate were measured; blood was obtained for clonidine and catechol amine assays; and visual analog score for sedation and pain to immersi on of foot and hand in ice water were obtained, CSF was collected duri ng infusion with an indwelling lumbar intrathecal catheter and was ana lyzed for clonidine, catecholamines, and acetylcholine. Results: CSF c lonidine concentrations rapidly increased and were maintained at stead y values with the stepped infusion, although observed concentrations w ere consistently greater than targeted. The relation between CSF cloni dine concentration and analgesia in the foot was similar to that previ ously observed after epidural bolus administration. Clonidine also was associated with concentration-dependent sedation; decreased mean arte rial blood pressure, heart rate, and CSF norepinephrine concentration; and increased CSF acetylcholine concentration. Conclusions This study suggests that pharmacokinetically designed infusions of drugs in the epidural space in humans can maintain steady concentrations of drug in CSF. In addition to providing a useful tool for investigation of mech anisms of action and drug interactions, this technique may improve ana lgesia and diminish side effects from epidurally administered analgesi cs.