• Yan Wang, Kerry B Goralski, Derek J Roberts, Kathryn Landry, Mark E Issa, Lekha Sleno, Lisa C Julien, Jeremy Wood, and Richard I Hall.
• College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada.
• Can J Anaesth. 2017 Oct 1; 64 (10): 1009-1022.

PurposeMorphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function.MethodsWe conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n = 18) or endovascular (n = 15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P < 0.017 indicated a significant correlation.ResultsPlasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg·mL-1 vs 29 [16-70] pg·mL-1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL-1 vs 16 [9-80] pg·mL-1, respectively; P = 0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r = -0.009; P = 0.96) or M3G (r = 0.37; P = 0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G.ConclusionMorphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response.Trial Registrationwww.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009.

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