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.

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.

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

The responsible investigators will consider data sharing, considered compliance with General Data Protection Regulation (GDPR) regulations and data sharing agreement.

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.