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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00878371
First Posted: April 8, 2009
Last Update Posted: October 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Dalhousie University
Information provided by (Responsible Party):
Richard Hall, Nova Scotia Health Authority
  Purpose

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.


Condition Intervention Phase
Dissecting Aneurysm of the Thoracic Aorta Drug: morphine Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Richard Hall, Nova Scotia Health Authority:

Primary Outcome Measures:
  • 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) ]

Secondary Outcome Measures:
  • 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) ]
  • 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) ]

Enrollment: 35
Study Start Date: May 2009
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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).

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 -
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00878371


Locations
Canada, Nova Scotia
Capital Health- Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, Canada, B3H3A7
Sponsors and Collaborators
Nova Scotia Health Authority
Dalhousie University
Investigators
Principal Investigator: Richard I Hall, MD Capital Health- Queen Elizabeth II Health Sciences Center
  More Information

Publications:
Responsible Party: Richard Hall, MD FRCPC FCCP, Nova Scotia Health Authority
ClinicalTrials.gov Identifier: NCT00878371     History of Changes
Other Study ID Numbers: Hall Morphine TAA-01
First Submitted: April 7, 2009
First Posted: April 8, 2009
Last Update Posted: October 12, 2017
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: publication in process

Keywords provided by Richard Hall, Nova Scotia Health Authority:
morphine
blood brain barrier
surgery induced peripheral inflammatory response

Additional relevant MeSH terms:
Aneurysm
Aneurysm, Dissecting
Vascular Diseases
Cardiovascular Diseases
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents