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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Pain, Lung Neoplasms, Immune Suppression

Intervention / Treatment
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* Drug: Bupivacaine in epidural catheter
* Drug: Fentanyl in epidural catheter
* Drug: Placebo (for Bupivacain and Fentanyl i epidural catheter)
* Drug: Oral Paracetamol
* Drug: Oral NSAID
* Drug: Oral opioids
* Drug: Placebo (for oral opioids)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Epidural analgesia<br>Epidural catheter: Bupivacain 1,0 mg/ml + Fentanyl 2 micrograms/ml. Oral analgesia: Paracetamol, NSAID and placebo tablets. | Drug: Bupivacaine in epidural catheter<br>* Bupivacain to be given in epidural catheter<br>Drug: Fentanyl in epidural catheter<br>* Fentanyl to be given in epidural catheter<br>Drug: Oral Paracetamol<br>* Paracetamol to be given orally<br>Drug: Oral NSAID<br>* NSAID to be given orally<br>Drug: Placebo (for oral opioids)<br>* Placebo tablets to be given instead of oral opioids<br>|
| Active Comparator: Placebo Epidural analgesia<br>Epidural analgesia: Placebo. Oral analgesia: Paracetamol, NSAID and opioids tablets. | Drug: Placebo (for Bupivacain and Fentanyl i epidural catheter)<br>* Saline to be given in epidural catheter<br>Drug: Oral Paracetamol<br>* Paracetamol to be given orally<br>Drug: Oral NSAID<br>* NSAID to be given orally<br>Drug: Oral opioids<br>* Opioids to be given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensity of pain (Self reported pain intensity) | 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. | 0-4 days | 
| Consumption Rescue Analgesia - i.v. opioids | The consumption of i.v. opioids is registered daily until chest tube is removed or day 4 after operation is reached. | 0-4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of surgery | The duration of the surgical procedure will be registered. | 0-4 days | 
| Length of hospital stay | Admission time after surgery. | 0-4 days | 
| Time used placing epidural catheter | Procedural time and competence level of MD placing catheter | 0-4 days | 
| Side effects of epidural analgesia | Side effects observed using epidural analgesia including itching, nausea, vomiting, procedural pain, hypotension, dizziness, respiratory depression, reduced pulmonary function. | 0-4 days | 
| Sequelae following VATS and placement of epidural catheter | 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). | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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