Effects of a Surgery-induced Peripheral Inflammatory Response on the Blood Brain Barrier

Dissecting Aneurysm of the Thoracic Aorta Clinical Trial

Official title:

Identification and Quantification of the Effects of a Surgery-induced Peripheral Inflammatory Response on Changes in Drug Efflux Transporter Function in the Brain

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00878371
• Other study ID #: Hall Morphine TAA-01
• Status: Completed
• Phase: Phase 4
• First received: April 7, 2009
• Last updated: June 22, 2016
• Start date: May 2009
• Est. completion date: February 2013

Study information

• Verified date: June 2016
• Source: Nova Scotia Health Authority
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose for this study is to determine if surgery (repair of descending thoracic aneurysm) causes a temporary decrease in the Blood Brain Barrier's ability to remove drugs from the brain back into the blood. The Blood Brain Barrier surrounds the brain and the spinal cord. This Blood Brain Barrier acts as a filter and allows some things to cross into the brain and allows other matter to be removed. Studies have shown the Blood Brain Barrier is affected by inflammation.

Functions of the Blood Brain Barrier in animals have been studied. Human studies with multiple causes of inflammation (e.g. Alzheimer's, Epilepsy, trauma and severe infections in critically

Hypothesis: Surgically-induced inflammation will temporarily reduce blood-brain barrier drug efflux transporter function in proportion to the degree of inflammation. The investigators anticipate that inflammation-mediated reductions in drug transporter function will be reflected by an increased cerebral spinal fluid (CSF) concentration of morphine (a PGP substrate) and M3G and M6G (MRP1 substrates). The corresponding in vitro studies will allow us to elucidate the mechanism(s) by which inflammation alters blood brain barrier efflux transport of morphine, M3G and M6G.

Description:

Study Objectives: To determine the role of surgery-induced inflammation on the transport of morphine and its metabolites, M3G and M6G, across the blood-brain barrier.

Study phase: IV Study Design: This is a sequential enrolment study design in which elective surgical patients presenting for repair of an ascending thoracic aneurysm and fitted with a CSF drain as part of their standard of care will be approached for permission to draw blood samples at specified times during their hospital course. Concomitantly, samples of CSF will be collected from the CSF drainage system (CSF is normally wasted).

Morphine will be used as the primary analgesic agent (this is within the standard of care). Samples will be collected at specified time intervals for 5 days or until the CSF drain is removed (whichever comes first). Samples collected will be analysed for morphine, its 3- and 6- glucuronide metabolites, inflammatory cytokines, markers of CNS injury and anatomical integrity of the BBB. Area under the concentration vs. time curve will be calculated and the effect on morphine metabolism and penetration across the BBB will be determined using a repeated measures analysis of variance technique (as used in our previous study).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. Subjects who are to undergo elective surgery for thoracic aortic vascular disease requiring insertion of a lumbar CSF drain

2. Informed consent will be obtained from the subject or authorized legal representative -

Exclusion Criteria:

1. Unwilling or unable to provide informed consent

2. Sensitivity or documented allergy to morphine

3. Inability to place lumbar CSF drain

4. Dialysis dependent -

Related Conditions & MeSH terms

• Aneurysm
• Aneurysm, Dissecting
• Dissecting Aneurysm of the Thoracic Aorta

Intervention

Drug:
• morphine
All patients treated with Morphine during induction after the lumbar drain inserted. Morphine was prescribed as Standard of care post operatively

Locations

Country	Name	City	State
Canada	Capital Health- Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia

Sponsors (2)

Lead Sponsor	Collaborator
Nova Scotia Health Authority	Dalhousie University

Country where clinical trial is conducted

Canada, 

References & Publications (1)

Roberts DJ, Goralski KB. A critical overview of the influence of inflammation and infection on P-glycoprotein expression and activity in the brain. Expert Opin Drug Metab Toxicol. 2008 Oct;4(10):1245-64. doi: 10.1517/17425255.4.10.1245 . Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome variables are the correlation between the ratio of CSF/plasma morphine , morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) levels and the plasma concentration of IL-6 over time.		CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
Secondary	Correlation between CSF/Plasma ratios of morphine, M3G, M6G and plasma concentration of TNFa and ET-1 over time.		CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
Secondary	Correlation between CSF/plasma ratios for morphine, M3G, M6G and CSF/Plasma ratios for albumin and S-100ß over time.		CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)