Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien : une étude observationnelle

Yan Wang; Kerry B. Goralski; Derek J. Roberts; Kathryn Landry; Mark E. Issa; Lekha Sleno; Lisa C. Julien; Jeremy Wood; Richard I. Hall

doi:10.1007/s12630-017-0933-x

Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien : une étude observationnelle

Translated title of the contribution: An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid

Yan Wang, Kerry B. Goralski, Derek J. Roberts, Kathryn Landry, Mark E. Issa, Lekha Sleno, Lisa C. Julien, Jeremy Wood, Richard I. Hall

Medicine

Medicine

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

Purpose: Morphine 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. Methods: We 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. Results: Plasma 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⁻¹vs 29 [16-70] pg·mL⁻¹, respectively; P = 0.013) and CSF (79 [26-133] pg·mL⁻¹vs 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. Conclusion: Morphine 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 registration: www.clinicaltrials.gov, NCT 00878371. Registered 7 April 2009.

Translated title of the contribution	An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid
Original language	French
Pages (from-to)	1009-1022
Number of pages	14
Journal	Canadian Journal of Anaesthesia
Volume	64
Issue number	10
DOIs	https://doi.org/10.1007/s12630-017-0933-x
Publication status	Published - Oct 1 2017

Bibliographical note

Funding Information:
Funding Financial support for this investigation was provided by the Heart and Stroke Foundation of Canada (Nova Scotia Chapter), the Canadian Anesthesiologists’ Society, the Canadian Anesthesiologists Research Foundation, and the Dalhousie University Pharmacy Endowment Fund.

Funding Information:
We are indebted to the patients for their willingness to participate in this investigation and to the Cardiovascular Intensive Care Unit nurses for their help with data collection and collection of samples. The authors declare they have no conflicts of interest with respect to this work. This submission was handled by Dr. Hilary P. Grocott, Editor-in-Chief, Canadian Journal of Anesthesia. Kerry B. Goralski and Richard I. Hall , the study co-principal investigators, conceived and designed the research. Yan Wang , Kathryn Landry , Mark E. Issa, and Lekha Sleno performed the research and generated experimental data. Lisa C. Julien coordinated the clinical trial and recruited patients. Jeremy Wood was the study surgeon and recruited patients. Yan Wang , Derek J. Roberts , Kathryn Landry , Kerry B. Goralski, and Richard I. Hall analyzed and interpreted the study data. Yan Wang , Derek J. Roberts , Kerry B. Goralski, and Richard I. Hall wrote the manuscript. Kerry B. Goralski supervised the trainees Yan Wang, Kathryn Landry, and Mark E. Issa. Financial support for this investigation was provided by the Heart and Stroke Foundation of Canada (Nova Scotia Chapter), the Canadian Anesthesiologists? Society, the Canadian Anesthesiologists Research Foundation, and the Dalhousie University Pharmacy Endowment Fund. This article is accompanied by an editorial. Please see Can J Anesth 2017; 64: this issue.

Publisher Copyright:
© 2017, Canadian Anesthesiologists' Society.

ASJC Scopus Subject Areas

Anesthesiology and Pain Medicine

Access to Document

10.1007/s12630-017-0933-x

Cite this

Wang, Y., Goralski, K. B., Roberts, D. J., Landry, K., Issa, M. E., Sleno, L., Julien, L. C., Wood, J., & Hall, R. I. (2017). Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien : une étude observationnelle. Canadian Journal of Anaesthesia, 64(10), 1009-1022. https://doi.org/10.1007/s12630-017-0933-x

Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien : une étude observationnelle. / Wang, Yan; Goralski, Kerry B.; Roberts, Derek J. et al.
In: Canadian Journal of Anaesthesia, Vol. 64, No. 10, 01.10.2017, p. 1009-1022.

Research output: Contribution to journal › Article › peer-review

Wang, Y, Goralski, KB, Roberts, DJ, Landry, K, Issa, ME, Sleno, L, Julien, LC, Wood, J & Hall, RI 2017, 'Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien : une étude observationnelle', Canadian Journal of Anaesthesia, vol. 64, no. 10, pp. 1009-1022. https://doi.org/10.1007/s12630-017-0933-x

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title = "Les effets d{\textquoteright}une r{\'e}action inflammatoire induite par chirurgie sur la distribution de morphine et de ses m{\'e}tabolites dans le liquide c{\'e}phalorachidien : une {\'e}tude observationnelle",

abstract = "Purpose: Morphine 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. Methods: We 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. Results: Plasma 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−1vs 29 [16-70] pg·mL−1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL−1vs 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. Conclusion: Morphine 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 registration: www.clinicaltrials.gov, NCT 00878371. Registered 7 April 2009.",

author = "Yan Wang and Goralski, {Kerry B.} and Roberts, {Derek J.} and Kathryn Landry and Issa, {Mark E.} and Lekha Sleno and Julien, {Lisa C.} and Jeremy Wood and Hall, {Richard I.}",

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doi = "10.1007/s12630-017-0933-x",

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T1 - Les effets d’une réaction inflammatoire induite par chirurgie sur la distribution de morphine et de ses métabolites dans le liquide céphalorachidien

T2 - une étude observationnelle

AU - Wang, Yan

AU - Goralski, Kerry B.

AU - Roberts, Derek J.

AU - Landry, Kathryn

AU - Issa, Mark E.

AU - Sleno, Lekha

AU - Julien, Lisa C.

AU - Wood, Jeremy

AU - Hall, Richard I.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Purpose: Morphine 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. Methods: We 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. Results: Plasma 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−1vs 29 [16-70] pg·mL−1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL−1vs 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. Conclusion: Morphine 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 registration: www.clinicaltrials.gov, NCT 00878371. Registered 7 April 2009.

AB - Purpose: Morphine 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. Methods: We 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. Results: Plasma 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−1vs 29 [16-70] pg·mL−1, respectively; P = 0.013) and CSF (79 [26-133] pg·mL−1vs 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. Conclusion: Morphine 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 registration: www.clinicaltrials.gov, NCT 00878371. Registered 7 April 2009.

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