Opioid Free Anaesthesia-Analgesia Strategy on Surgical Stress and Immunomodulation in Elective VATS-Lobectomy for NSCLC

NCT ID: NCT05172739

Last Updated: 2021-12-29

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE4

Total Enrollment

70 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-10-01

Study Completion Date

2026-11-01

Brief Summary

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Lobectomy is a major, high-risk surgical procedure that in addition to one-lung ventilation (OLV) exerts a potent surgical stress response. An overwhelming immune cell recruitment may lead to excessive tissue damage, peripheral organ injury and immunoparesis. The effect of anesthesia on the immune system is modest, compared to the effects induced by major surgery. However, to an immunocompromised patient, due to cancer and/or other comorbidities, the immunosuppressive effects of anesthesia may increase the incidence of post-operative infections, morbidity, and mortality. Exogenous opioids have been correlated with immunosuppression, opioid-induced hyperalgesia, and respiratory depression, with deleterious outcomes. An Opioid-Free Anaesthesia-Analgesia (OFA-A) strategy is based on the administration of a variety of anaesthetic/analgesic and other pharmacological agents with different mechanisms of action, including immunomodulating and anti-inflammatory effects. Our basic hypothesis is that the implementation of a perioperative multimodal OFA-A strategy, will lead to an attenuated surgical stress response and attenuated immunosuppression, compared to a conventional Opioid-Based Anaesthesia-Analgesia (OBA-A) strategy. The aforementioned effects, are presumed to be associated with equal or improved analgesia and decreased incidence of postoperative infections compared to a perioperative OBA-A technique.

Detailed Description

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Surgical manipulation and one lung ventilation (OLV) exert different and synergic effects to generate an inflammatory response during lung resection surgery. Surgery, such as lobectomies, often leads to severe immunosuppression that in turn can lead to infectious complications and sepsis. Both anesthesia-related and surgery-related perioperative measures may modulate the patient's immune response and lead to the activation of different components of the immune system. Anesthesia-induced activation, in particular of the adaptive immune system, may also induce persistent, postoperative immunosuppression. An overwhelming immune cell recruitment may lead to excessive tissue damage, peripheral organ injury and immunoparesis.

Opioid analgesia remains the corner stone of acute pain management in perioperative analgesic regimes. Opioid receptors are not only expressed in the central nervous system to regulate pain perception but also occur on immune and tumour cells. Exogenous opioid administration has been correlated with immunosuppression, opioid-induced hyperalgesia, and respiratory depression, with deleterious outcomes.

An Opioid-Free Anaesthesia-Analgesia (OFA-A) strategy is based on the administration of a variety of anaesthetic/analgesic and other pharmacological agents with different mechanisms of action, including immunomodulating and anti-inflammatory effects where at least one factor causes inhibition of central sensitization and at least another factor inhibits the peripheral sensitization of the nervous system, as a response to painful surgical stimuli. This combination of factors has to have a synergistic or additive effect so that best analgesic effects can be achieved with the lowest possible dosage.

Our basic hypothesis is that a perioperative OFA-A strategy on cancer patients undergoing VATS lung surgery for tumour resection will be accompanied by abolished or attenuated immunosuppression. The additional potential clinical implication of a perioperative OFA-A strategy is the avoidance of the onco-proliferative side effects of both exogenous and endogenous opioids, released by cytokine-mediated immune cell activation. Inflammatory response inhibition is expected to reduce the possibility of acute and chronic post-operative pain developement, compared to a perioperative Opioid-Based Anaesthesia- Analgesia (OBA-A) technique. Additionally, the aforementioned inflammatory response inhibition is expected to lead to an overall reduction of overall postoperative pulmonary complications.

Conditions

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Systemic Inflammatory Response Syndrome Postoperative Pain, Acute Postoperative Pain, Chronic Infections Postoperative Opioid Use Anesthesia Non-small Cell Lung Cancer

Keywords

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Opioid-free Anesthesia-Analgesia Opioid-based Anesthesia-Analgesia Cytokines NSCLC Hemodynamic stability Immunomodulation Inflammatory markers Acute postoperative pain Chronic postoperative pain

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Administration of a multimodal anaesthetic opioid-free strategy that includes pregabalin, ketamine, dexmedetomidine, lidocaine, dexamethasone, magnesium sulphate, paracetamol and dexketoprofen is expected to affect the inflammatory and stress response, measured by levels of inflammatory markers and haemodynamic stability, when compared to conventional opioid based techniques. An Opioid-Free Anaesthesia-Analgesia strategy, is expected to also lead to an attenuated immunosuppression, due to the avoidance of opioids, whose administration has been corelated with immunosuppressive effects. An overall decreased inflammatory and stress response as expressed by reduced levels of inflammatory biomarkers and hemodynamic stability, is expected to decrease peripheral and central sensitization, contributing to better postoperative analgesia.
Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Opioid-Based Anaesthesia Analgesia

Premedication: IM Midazolam 0.05-0.07mg/kg. Anesthesia induction: Midazolam 0.03mg/kg, Propofol 2-3mg/kg, Fentanyl 1-2mcg/kg and Cisatracurium 0.2mg/kg or alternatively Rocuronium 0.6-1.2mg/ kg. Anesthesia maintenance: Desflurane set at approximately 1 MAC, Morphine 0.1-0.12mg/kg, Fentanyl 1-2mcg/kg during induction and 50-100mcg prn, Paracetamol 1g +/- Dexketoprofen trometamol 50mg, along with Ondansetron 4mg or Droperidol 0.625mg. Wound infiltration: Ropivacaine 75-150mg. Surgical ward: PCA pump with Morphine for the first 3 postoperative days. Additional postoperative analgesia: Paracetamol 1g 1x3 +/- Dexketoprofen trometamol 50mg 1x2. Rescue therapy only: Tramadol 50-100mg.

Group Type ACTIVE_COMPARATOR

Opioid-Based Anesthesia-Analgesia Strategy

Intervention Type DRUG

A perioperative Opioid-Based multimodal Anesthesia- Analgesia strategy will be implemented that incorporates the following pharmacological agents:

Premedication: Midazolam, Anaesthesia induction \& maintenance: Midazolam, Propofol, Fentanyl, Cisatracurium or alternatively Rocuronium, Desflurane, Morphine, Paracetamol, Dexketoprofen trometamol, Ondansetron or Droperidol, Ropivacaine Surgical ward: Morphine, Paracetamol, Dexketoprofen trometamol Rescue therapy only: Tramadol

Opioid-Free Anesthesia Analgesia

Premedication: Pregabalin 150mg 1x2, IM Midazolam 0.05-0.07mg/kg. Anesthesia induction: Midazolam 0.03mg/kg, Dexmedetomidine 0.5-1mcg/kg, Lidocaine 1mg/kg, Propofol 2-3mg/kg, Ketamine 1-1.5mg/kg, Hyoscine 10mg, Cisatracurium 0.2mg/ kg or alternatively Rocuronium 0.6-1.2mg/kg, Magnesium sulphate 2.5-5g and Dexamethasone 8-16mg. Anesthesia maintenance: Desflurane set at \~1 MAC, Dexmedetomidine 0.5-1.2mcg/kg/h, Lidocaine 0.5-1mg/kg/h, Ketamine 0.3-0.5mg/kg prn, Paracetamol 1g +/- Dexketoprofen trometamol 50mg, and Ondansetron 4mg or Droperidol 0.625mg. Wound infiltration: Ropivacaine 75-150mg. Surgical ward: PCA pump with Ketamine, Lidocaine, Clonidine, Droperidol and Midazolam for the first 3 postoperative days. Additionally, Pregabalin 50mg per os 1x1 and 25mg 1x1, Paracetamol 1g 1x3 +/- Dexketoprofen trometamol 50mg 1x2. Rescue therapy only: Tramadol 50-100mg.

Group Type ACTIVE_COMPARATOR

Opioid-free Anesthesia-Analgesia Strategy

Intervention Type DRUG

A perioperative Opioid-Based multimodal Anesthesia- Analgesia strategy will be implemented that incorporates the following pharmacological agents:

Premedication: Pregabalin, Midazolam, Anesthesia induction \& maintenance: Midazolam, Dexmedetomidine, Lidocaine, Propofol, Ketamine, Hyoscine, Cisatracurium or alternatively Rocuronium, Magnesium sulphate, Dexamethasone, Desflurane, Paracetamol, Dexketoprofen trometamol, Ondansetron or Droperidol, Ropivacaine, Surgical ward: Ketamine, Lidocaine, Clonidine, Droperidol and Midazolam, Pregabalin, Paracetamol, Dexketoprofen trometamol Rescue therapy only: Tramadol

Interventions

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Opioid-Based Anesthesia-Analgesia Strategy

A perioperative Opioid-Based multimodal Anesthesia- Analgesia strategy will be implemented that incorporates the following pharmacological agents:

Premedication: Midazolam, Anaesthesia induction \& maintenance: Midazolam, Propofol, Fentanyl, Cisatracurium or alternatively Rocuronium, Desflurane, Morphine, Paracetamol, Dexketoprofen trometamol, Ondansetron or Droperidol, Ropivacaine Surgical ward: Morphine, Paracetamol, Dexketoprofen trometamol Rescue therapy only: Tramadol

Intervention Type DRUG

Opioid-free Anesthesia-Analgesia Strategy

A perioperative Opioid-Based multimodal Anesthesia- Analgesia strategy will be implemented that incorporates the following pharmacological agents:

Premedication: Pregabalin, Midazolam, Anesthesia induction \& maintenance: Midazolam, Dexmedetomidine, Lidocaine, Propofol, Ketamine, Hyoscine, Cisatracurium or alternatively Rocuronium, Magnesium sulphate, Dexamethasone, Desflurane, Paracetamol, Dexketoprofen trometamol, Ondansetron or Droperidol, Ropivacaine, Surgical ward: Ketamine, Lidocaine, Clonidine, Droperidol and Midazolam, Pregabalin, Paracetamol, Dexketoprofen trometamol Rescue therapy only: Tramadol

Intervention Type DRUG

Other Intervention Names

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Opioid-Based Anesthesia OBA-A Opioid-Free Anesthesia OFA-A

Eligibility Criteria

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Inclusion Criteria

* patients undergoing elective VATS lobectomy
* early stage NSCLC (up to T3N1M0)

Exclusion Criteria

* Immunocompromised patients
* previous lung surgery
* preoperative corticosteroid or immunosuppressive drug use
* uncontrolled Diabetes Mellitus
* cardiac failure (NYHA 3 and 4)
* preoperative infection (CRP \>5mg/ml, WBC \>10x10\^9/L)
* preoperative anemia (Hb\<12g/dl)
* chronic inflammatory diseases
* inflammatory bowel disease


* OFA-Α: perioperative opioid administration, within the study period
* OBA-Α: perioperative dexmedetomidine or lidocaine infusion, ketamine, gabapentinoid or corticosteroid administration within the study period
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Crete

OTHER

Sponsor Role lead

Responsible Party

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Periklis Vasilos

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Vasileia Nyktari, MD, PhD

Role: STUDY_CHAIR

University of Crete, Medical school

Locations

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University of Crete

Heraklion, Crete, Greece

Site Status RECRUITING

Countries

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Greece

Central Contacts

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Periklis Vasilos, MD

Role: CONTACT

Phone: 00306978702023

Email: [email protected]

Georgios Stefanakis, MD, PhD

Role: CONTACT

Phone: 00306978779726

Email: [email protected]

Facility Contacts

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Periklis Vasilos, MD

Role: primary

References

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Sanchez-Pedrosa G, Vara Ameigeiras E, Casanova Barea J, Rancan L, Simon Adiego CM, Garutti Martinez I. Role of surgical manipulation in lung inflammatory response in a model of lung resection surgery. Interact Cardiovasc Thorac Surg. 2018 Dec 1;27(6):870-877. doi: 10.1093/icvts/ivy198.

Reference Type BACKGROUND
PMID: 29945217 (View on PubMed)

Schneemilch CE, Hachenberg T, Ansorge S, Ittenson A, Bank U. Effects of different anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol. 2005 Aug;22(8):616-23. doi: 10.1017/s0265021505001031.

Reference Type BACKGROUND
PMID: 16119599 (View on PubMed)

Homburger JA, Meiler SE. Anesthesia drugs, immunity, and long-term outcome. Curr Opin Anaesthesiol. 2006 Aug;19(4):423-8. doi: 10.1097/01.aco.0000236143.61593.14.

Reference Type BACKGROUND
PMID: 16829725 (View on PubMed)

Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth. 2008;22(3):263-77. doi: 10.1007/s00540-008-0626-2. Epub 2008 Aug 7.

Reference Type BACKGROUND
PMID: 18685933 (View on PubMed)

Calogero AE, Norton JA, Sheppard BC, Listwak SJ, Cromack DT, Wall R, Jensen RT, Chrousos GP. Pulsatile activation of the hypothalamic-pituitary-adrenal axis during major surgery. Metabolism. 1992 Aug;41(8):839-45. doi: 10.1016/0026-0495(92)90164-6.

Reference Type BACKGROUND
PMID: 1640860 (View on PubMed)

Ninkovic J, Roy S. Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids. 2013 Jul;45(1):9-24. doi: 10.1007/s00726-011-1163-0. Epub 2011 Dec 15.

Reference Type BACKGROUND
PMID: 22170499 (View on PubMed)

Kosciuczuk U, Knapp P, Lotowska-Cwiklewska AM. Opioid-induced immunosuppression and carcinogenesis promotion theories create the newest trend in acute and chronic pain pharmacotherapy. Clinics (Sao Paulo). 2020 Mar 23;75:e1554. doi: 10.6061/clinics/2020/e1554. eCollection 2020.

Reference Type BACKGROUND
PMID: 32215455 (View on PubMed)

Plein LM, Rittner HL. Opioids and the immune system - friend or foe. Br J Pharmacol. 2018 Jul;175(14):2717-2725. doi: 10.1111/bph.13750. Epub 2017 Mar 23.

Reference Type BACKGROUND
PMID: 28213891 (View on PubMed)

Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004 Sep-Oct;11(5):354-65. doi: 10.1097/01.mjt.0000132250.95650.85.

Reference Type BACKGROUND
PMID: 15356431 (View on PubMed)

Finley MJ, Happel CM, Kaminsky DE, Rogers TJ. Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression. Cell Immunol. 2008 Mar-Apr;252(1-2):146-54. doi: 10.1016/j.cellimm.2007.09.008. Epub 2008 Feb 14.

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PMID: 18279847 (View on PubMed)

Parkhill AL, Bidlack JM. Reduction of lipopolysaccharide-induced interleukin-6 production by the kappa opioid U50,488 in a mouse monocyte-like cell line. Int Immunopharmacol. 2006 Jun;6(6):1013-9. doi: 10.1016/j.intimp.2006.01.012. Epub 2006 Feb 17.

Reference Type BACKGROUND
PMID: 16644488 (View on PubMed)

Busch-Dienstfertig M, Stein C. Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects. Brain Behav Immun. 2010 Jul;24(5):683-94. doi: 10.1016/j.bbi.2009.10.013. Epub 2009 Oct 29.

Reference Type BACKGROUND
PMID: 19879349 (View on PubMed)

Stein C, Kuchler S. Non-analgesic effects of opioids: peripheral opioid effects on inflammation and wound healing. Curr Pharm Des. 2012;18(37):6053-69. doi: 10.2174/138161212803582513.

Reference Type BACKGROUND
PMID: 22747536 (View on PubMed)

Other Identifiers

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OFA-Thoracic

Identifier Type: -

Identifier Source: org_study_id