Supplementary Epidural Analgesia in Video-Assisted Thoracic Surgery (VATS) - The SEAVATS Study (SEAVATS)

Whereas it, in the case of conventional thoracotomy, has been demonstrated that thoracic epidural analgesia is more effective than systemic opioids in terms of pain relief and preservation of postoperative pulmonary function, the efficacy of epidural analgesia in video-assisted thoracic surgical (VATS) procedures, has not been sufficiently studied, but a beneficial effect might very well be present. On the other hand, the risks associated with placement of a thoracic epidural catheter are well known and if similar pain relief can be achieved without it with no or only insignificant alternative side effects, this would be preferable. The literature regarding the usefulness of epidural analgesia for reducing pain in Video-Assisted Thoracic Surgery is, at best, scarce with two small studies showing some effect and two showing no difference, none of the studies being blinded randomized controlled trials of adequate size. The SEAVATS Study will try to answer this question.

Study plan: The hypothesis is that there is no difference in the amount of pain the patients will experience after VATS for pulmonary neoplasms. Study design and setting: The project is designed as a prospectively, double blinded, randomized, placebo controlled study comparing pain in two groups of patients. Both groups of patients will: Have a epidural catheter placed. Receive a basis level of analgesics consisting of paracetamol and a nonsteroidal anti- inflammatory drug combined with a nerveblock placed intercostally during surgery. Have access to i.v. opioids as needed for any experienced pain after surgery. One group of patients will be given local anaesthetics through the epidural catheter supplemented with placebo medication orally while the other group will receive saline in the epidural catheter supplemented with opioids orally. Data collection: Data will, during hospitalization, be collected in the operating theatre, in the postoperative care unit and in the surgical ward. Six months after surgery a questionnaire will be send to the patients to do follow-up regarding residual sequelae after surgery and placement of epidural catheter. Further follow-up with questionnaire has been planned for subsequent years. As a secondary objective, in fifty-six of the patients from The SEAVATS Study, blood samples will be gathered during surgery and one hour and 24 hours after surgery, and compared with pre-operative levels. These blood samples will be analysed for immune cells (NK-cells, levels and activity) and cytokines (IL-6, IL-10, IL-12 and IFN-gamma) as indicators of immunological response to surgery. Research ethics: The project has obtained ethics approval from The Regional Scientific Ethical Committees for Southern Denmark and acceptance to perform clinical research has been granted by The Danish Health and Medicines Authority. Consent to data collection has been provided by The Danish Data Protection Agency. Before entering the project, consent will be obtained from all patients. Rigorous data security will be maintained for five years and afterwards all data will be deleted. The Study is registered with The European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) with EudraCT number 2014-000760-18 and is monitored by The Good Clinical Practice unit for Southern Denmark.

Pain, Pain Measurement, VAS, Visual Analog Pain Scale, Analgesics, Opioid, Epidural analgesia, VATS, Video-assisted Thoracic Surgery, Lobectomy, Wedge Resection, Segmental Resection, Cytokins, Immune cells

Epidural catheter: Bupivacain 1,0 mg/ml + Fentanyl 2 micrograms/ml. Oral analgesia: Paracetamol, NSAID and placebo tablets.

Self reported pain intensity 5 times a day both in rest and during activity until chest tube is removed or day 4 after operation is reached.

The consumption of i.v. opioids is registered daily until chest tube is removed or day 4 after operation is reached.

Side effects observed using epidural analgesia including itching, nausea, vomiting, procedural pain, hypotension, dizziness, respiratory depression, reduced pulmonary function.

Questionnaire sent to patients 6, 12, 24 and 60 months after surgery. (criteria edited as part of a protocol amendment July 27th 2016 for a subsequent biomarkers study).

Levels of NK-cells will be examined as an indicator of immunological response to surgery. (The secondary outcomes "Immune cells", "Cytokines" and "Survival after VATS" should rightly have been registered in a separate sub study with a separate ClinicalTrials entry with "Immune cells - NK cell levels" as primary outcome measure and "Immune cells - NK cell activity", Cytokines" and "Survival after VATS" as a secondary outcomes as a separate sample size calculation was done to determine the needed inclusion for this part of the study. Now, instead, these outcomes will be defined as "Other Pre-specified Outcomes" with this explanation.)

The NK-cell activity will be examined as an indicator of immunological response to surgery. (The secondary outcomes "Immune cells", "Cytokines" and "Survival after VATS" should rightly have been registered in a separate sub study with a separate ClinicalTrials entry with "Immune cells - NK cell levels" as primary outcome measure and "Immune cells - NK cell activity", Cytokines" and "Survival after VATS" as a secondary outcomes as a separate sample size calculation was done to determine the needed inclusion for this part of the study. Now, instead, these outcomes will be defined as "Other Pre-specified Outcomes" with this explanation.)

Levels of cytokines (IL-6, IL-10, IL-12 and IFN-gamma) will be examined as indicators of immunological response to surgery. (The secondary outcomes "Immune cells", "Cytokines" and "Survival after VATS" should rightly have been registered in a separate sub study with a separate ClinicalTrials entry with "Immune cells - NK cell levels" as primary outcome measure and "Immune cells - NK cell activity", Cytokines" and "Survival after VATS" as a secondary outcomes as a separate sample size calculation was done to determine the needed inclusion for this part of the study. Now, instead, these outcomes will be defined as "Other Pre-specified Outcomes" with this explanation.)

Postoperative survival analysis. (The secondary outcomes "Immune cells", "Cytokines" and "Survival after VATS" should rightly have been registered in a separate sub study with a separate ClinicalTrials entry with "Immune cells" as primary outcome measure and "Cytokines" and "Survival after VATS" as a secondary outcomes as a separate sample size calculation was done to determine the needed inclusion for this part. Now, instead, these outcomes will be defined as "Other Pre-specified Outcomes" with this explanation.) (text initially added October 27th 2021, as the text was by mistake no included in the update after the protocol amendment 27 July 2016)

Inclusion Criteria: Planned elective VATS lobectomy, wedge- or segmental resection. (for the subsequent biomarker study, only lobectomy is a inclusion criteria, specified in protocol amendment July 27th 2016) Patient has accepted to have epidural analgesia as part of the anaesthesia for the procedure. Informed consent is attained. Patient is over 18 years of age. Patient is mentally able to answer questionnaires included in the study. Exclusion Criteria: Allergies to any of the medications used in the trial. History of previous peptic ulcer. History of chronic pain to any degree that will interfere with quantification of pain postoperatively. Dementia or reduced mental capacity to any degree that will interfere with quantification of pain postoperatively. Pregnancy. Contra-indications to placement of epidural catheter. Any concurrent cancer disease or use of immune modulating drugs (criteria added as part of a protocol amendment July 27th 2016 for a subsequent biomarkers study)

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