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Neuroplasticity Induced by General Anaesthesia (DANA1)

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.
 
ClinicalTrials.gov Identifier: NCT04125121
Recruitment Status : Completed
First Posted : October 14, 2019
Last Update Posted : August 20, 2021
Sponsor:
Information provided by (Responsible Party):
Signe Sloth Madsen, Rigshospitalet, Denmark

Brief Summary:
The aim of this study is to use magnetic resonance imaging to explore and compare possible de novo neuroplastic changes induced by the isolated effects of the hypnotic agents sevoflurane and propofol, respectively. In addition, to explore possible associations between neuroplastic changes and clinical and/or biochemical outcomes. It is a randomised, cross-over, single blinded clinical study. N = 30. Female:male ratio 1:1.

Condition or disease Intervention/treatment Phase
Healthy Volunteers General Anaesthesia Neuroplasticity Drug: Sevoflurane-propofol Not Applicable

Detailed Description:

Background

In the perioperative period, severe changes can be observed in the endocrine, immune, and nervous system. These changes are called the surgical stress response. Clinically, this can be observed as increased pain response and disturbances in the circadian rhythm, memory, cognitive and executive functions, and may lead to post-operative delirium. The post-operative cognitive dysfunction is associated with increased mortality and risk of prematurely leaving occupation. Post-operative delirium with fluctuating levels of attention and consciousness is a serious condition associated with poor outcome, including longer hospitalisation and increased early mortality.

General anaesthesia may contribute to the surgical stress response. Some data indicate that general anaesthesia per se can cause alterations and disturbances in the brain such as sleep and circadian disturbances. Recent evidence suggests that anaesthetic agents may impair neurogenesis and cause memory impairment. In addition, inhalation anaesthesia may result in more cerebral disturbances compared to total intravenous anaesthesia (TIVA). In this study, we will isolate the effects of the two primary hypnotic agents used in general anaesthesia, sevoflurane and propofol, without the interactions and confounders of polypharmacy and varying levels of disease among a surgical population.

Materials

The study consists of two study sessions. In each study session magnetic resonance imaging (MRI) scans will be obtained before and after general anaesthesia, and in addition after one and eight days.

The following imaging modalities will be employed: (i) T1-weighted 3D anatomy (T1w3D), (ii) Diffusion Tensor Imaging (DTI), (iii) resting state functional MRI (rsfMRI). The MRI scans will be supplemented with cognitive testing, sleep evaluation and blood sampling. Thus, the set-up for each volunteer will be:

Session one:

Day 0: MRI 1, cognitive testing, questionnaires, and blood sampling. General anaesthesia (maintenance phase with sevoflurane OR propofol according to randomisation), and post-anaesthesia care. MRI 2 and repeated cognitive testing, questionnaires, and blood sampling.

Day +1: MRI 3, cognitive testing, questionnaires, and blood sampling.

Day +8: MRI 4, cognitive testing, and questionnaires.

Session two: Identical to session one, except the volunteer will receive the remaining type of general anaesthesia (sevoflurane or propofol, opposite to session one).

Data evaluation will be conducted with assessor blinded to anaesthesia type.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomisation to one of two options in session 1: sevoflurane or propofol. In session 2, the remaining option is administered.
Masking: Double (Participant, Outcomes Assessor)
Masking Description: The participants will not be present during randomisation. The participants will be anaesthetised when the investigational drug (maintenance anaesthetic) is administered, and will thus not be aware what type of anaesthesia is administered in which (otherwise identical) session.
Primary Purpose: Basic Science
Official Title: Neuroplasticity Induced by General Anaesthesia
Actual Study Start Date : September 26, 2019
Actual Primary Completion Date : August 13, 2021
Actual Study Completion Date : August 13, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Sevoflurane-Propofol

Session one: Sevoflurane as maintenance anaesthetic during general anaesthesia.

Session two: Propofol as maintenance anaesthetic during general anaesthesia.

Drug: Sevoflurane-propofol
General anaesthesia with a maintenance phase of two hours duration with either sevoflurane or propofol.
Other Name: Propofol-sevoflurane

Active Comparator: Propofol-Sevoflurane

Session one: Propofol as maintenance anaesthetic during general anaesthesia.

Session two: Sevoflurane as maintenance anaesthetic during general anaesthesia.

Drug: Sevoflurane-propofol
General anaesthesia with a maintenance phase of two hours duration with either sevoflurane or propofol.
Other Name: Propofol-sevoflurane




Primary Outcome Measures :
  1. Changes in T1w3D [ Time Frame: 8 days ]
    Volume and morphology of selected brain regions and anatomical structures as recorded by T1w3D anatomy MRI.

  2. Changes in DTI [ Time Frame: 8 days ]
    White matter microstructure as measured using Diffusion Tensor Imaging (DTI)


Secondary Outcome Measures :
  1. Changes in rsfMRI [ Time Frame: 8 days ]
    Differences in resting state functional MRI induced by general anaesthesia

  2. Changes in fatigue [ Time Frame: 8 days ]
    Differences in severity and characteristics of fatigue related to general anaesthesia, as measured by Multidimensional Fatigue Inventory (MFI-20, a scale of 0-5 in each of 20 questions, with higher scores indicating more fatigue).

  3. Cognitive performance [ Time Frame: 8 days ]
    Changes in cognitive function related to general anaesthesia, measured with a combination of Test of Attentional Performance, Paced Auditory Serial Addition Test and Conners Continuous Performance Test.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age ≥18 and ≤35.
  • Healthy individual.
  • BMI ≥18 kg/m2 and ≤30kg/m2.
  • Normal electrocardiogram (ECG).
  • Normal physical examination, including neurological examination, auscultation of the heart and lungs, and measurement of blood pressure and pulse.
  • American Society of Anaesthesiologists (ASA) class 1.
  • Mallampati I-II and simplified airway risk index (SARI) 0-2 (i.e. no indication of difficult intubation). See appendix for details.
  • Right-handed.
  • Female participants must use safe contraceptives (hormonal or mechanical, including intrauterine devices).
  • Speaks and understand Danish.
  • Provides oral and written informed consent.

Exclusion Criteria:

  • Contraindications to MRI.
  • Left-handedness or ambidexterity.
  • History of complications to general anaesthesia, including malignant hyperthermia.
  • Family history of malignant hyperthermia.
  • Known incident of malignant hyperthermia or any unexplained complication to general anaesthesia among close relatives.
  • Allergy to any kind of medication or material to which the volunteer could be exposed during this study.
  • History of serious illness.
  • History of cancer, immune disease, autoimmune disease, chronic pain or neurological / psychiatric illness.
  • Major trauma or head trauma with any symptoms present at the time of inclusion.
  • Surgery less than six weeks prior to the study period.
  • Infection (with fever) less than two weeks prior to or during the study sessions.
  • Daily use of any medication (not counting contraceptives).
  • Consumed anti-depressants during the last 30 days before study days.
  • Weakly intake of >21 (for females >14) units of alcohol.
  • Heavy intake of caffeine (> 5 cups/day).
  • Smoking during the last 30 days before study days.
  • Substance abuse (assessed by the investigator).
  • Pregnancy
  • Reflux or dyspepsia.
  • Poor dental status or oral health.
  • Expected or suspected difficult airway.
  • Declines receiving information regarding accidental pathological findings during MRI scans of the brain.
  • Cannot cooperate to tests.
  • Otherwise judged unfit for participation by the investigator.

Exclusion Criteria during the study:

  • Any of the above-mentioned exclusion criteria.
  • Major trauma or head trauma during the study period.
  • Surgery during the study period.
  • Infection (with fever) during the study period.
  • Consumption of more than 3 units of alcohol within 24 hours before each study day (intervention day or MRI scan day)
  • Consumed analgesics within 3 days before each study day
  • Consumed anti-histamines less than 48 hours before each study day
  • Intake of caffeine 12 h prior to each study day
  • Smoking

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): NCT04125121


Locations
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Denmark
Department of Neuroanaesthesiology
Glostrup, Capital Region, Denmark, 2600
Functional Imaging Unit, Department for Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup
Glostrup, Capital Region, Denmark, 2600
Sponsors and Collaborators
Signe Sloth Madsen
Investigators
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Principal Investigator: Signe Madsen, MD Rigshospitalet, Denmark
Additional Information:
Publications:
Miller G. Miller's Anesthesia. 2015 ed. Philadelphia: Elsevier Saunders; 2015.
Steinmetz LRaJ. Anæstesi. 4 ed. Denmark: FADL's Forlag; 2014 24. marts 2014.
Editors ICoMJ. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals [Web page, recommandation]. Online: Annals of Internal Medicine / American College of Physicians.; 1978 (updated 2017) [cited 2018 20.03.2018]. Available from: http://www.icmje.org/recommendations/.
Universities WgsubtMoHEaSatoD. The Danish Code of Conduct for Research Integrity [Code of conduct]. Online (www.ufm.dk): Danish Ministry of Higher Education and Science; 2014 [updated June 02, 2015; cited 2018 20.03.2018]. Available from: https://ufm.dk/en/publications/2014/the-danish-code-of-conduct-for-research-integrity.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Signe Sloth Madsen, Principal Investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04125121    
Other Study ID Numbers: H-18028925
First Posted: October 14, 2019    Key Record Dates
Last Update Posted: August 20, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The responsible investigators will consider data sharing, considered compliance with General Data Protection Regulation (GDPR) regulations and data sharing agreement.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Signe Sloth Madsen, Rigshospitalet, Denmark:
Neuroplasticity
Neuroplastic changes
General anaesthesia
Magnetic resonance imaging
Sevoflurane
Propofol
Healthy volunteers
Consciousness
Cognitive
Fatigue
Additional relevant MeSH terms:
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Propofol
Sevoflurane
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Platelet Aggregation Inhibitors
Anesthetics, Inhalation