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

June 22, 2016 updated by: Richard Hall, Nova Scotia Health Authority

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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).

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H3A7
        • Capital Health- Queen Elizabeth II Health Sciences Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 -

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: morphine
All patients treated with Morphine during induction after the lumbar drain inserted. Morphine was prescribed as Standard of care post operatively
Drug: morphine
All patients treated with Morphine during induction after the lumbar drain inserted. Morphine was prescribed as Standard of care post operatively

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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.
Time Frame: CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
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 Outcome Measures

Outcome Measure
Time Frame
Correlation between CSF/Plasma ratios of morphine, M3G, M6G and plasma concentration of TNFα and ET-1 over time.
Time Frame: CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
Correlation between CSF/plasma ratios for morphine, M3G, M6G and CSF/Plasma ratios for albumin and S-100β over time.
Time Frame: CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)
CSF and Blood samples will be taken in the OR, post operatively ( every 6 hrs until POD 5 if CSF drain still in place)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nova Scotia Health Authority

Collaborators

Dalhousie University

Investigators

  • Principal Investigator: Richard I Hall, MD, Capital Health- Queen Elizabeth II Health Sciences Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

February 1, 2013

Study Completion (Actual)

February 1, 2013

Study Registration Dates

First Submitted

April 7, 2009

First Submitted That Met QC Criteria

April 7, 2009

First Posted (Estimate)

April 8, 2009

Study Record Updates

Last Update Posted (Estimate)

June 23, 2016

Last Update Submitted That Met QC Criteria

June 22, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Hall Morphine TAA-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

publication in process

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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