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

Официальное название

Effect of a Perioperative Opioid Free Anaesthesia-Analgesia (OFA-A) Strategy on Surgical Stress Response and Immunomodulation in Elective VATS Lobectomy for NSCLC Lung Cancer: A Prospective Randomized Study

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат 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, Clo

Первичные конечные точки

• Neutrophil to Lymphocyte ratio (NLR) [Срок оценки: Preoperatively]
• Platelet to Lymphocyte ratio (PLR) [Срок оценки: Preoperatively]
• Lymphocyte to monocyte ratio (LMR) [Срок оценки: Preoperatively]
• Advanced Lung Cancer Inflammation Index (ALI) [Срок оценки: Preoperatively]
• Systemic Immune Inflammation Index (SII) [Срок оценки: Preoperatively]
• Prognostic Nutritional Index (PNI) [Срок оценки: Preoperatively]
• Surgical Stress Response - IL-6 - preoperatively [Срок оценки: Preoperatively (as a baseline)]
• Surgical Stress Response - IL-6 - end of surgery [Срок оценки: End of surgery (end of placement of last suture/ surgical clip on patient)]
• Surgical Stress Response - IL-6 - 24 hours after the end of surgery [Срок оценки: 24 hours after the end of surgery (end of placement of last suture/ surgical clip on patient)]
• Surgical Stress Response - IL-8 - preoperatively [Срок оценки: Preoperatively (as a baseline)]

Вторичные конечные точки (12)

• Acute postoperative pain - Numerical Rating Scale (NRS) - Immediately Postoperatively [Срок оценки: Immediately postoperatively]
• Acute postoperative pain - Numerical Rating Scale (NRS) - First postoperative day [Срок оценки: First postoperative day]
• Acute postoperative pain - Numerical Rating Scale (NRS) - Second postoperative day [Срок оценки: Second postoperative day]
• Acute postoperative pain - Numerical Rating Scale (NRS) - Third postoperative day [Срок оценки: Third postoperative day]
• Acute postoperative pain - Critical Care Pain Observation Tool (CPOT) - Immediately Postoperatively [Срок оценки: Immediately postoperatively]
• Acute postoperative pain - Critical Care Pain Observation Tool (CPOT) - First postoperative day [Срок оценки: First postoperative day]
• Acute postoperative pain - Critical Care Pain Observation Tool (CPOT) - Second postoperative day [Срок оценки: Second postoperative day]
• Acute postoperative pain - Critical Care Pain Observation Tool (CPOT) - Third postoperative day [Срок оценки: Third postoperative day]
• Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - First postoperative day [Срок оценки: First postoperative day]
• Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Second postoperative day [Срок оценки: Second postoperative day]
• Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Third postoperative day [Срок оценки: Third postoperative day]
• Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Tolerable with discomfort - First postoperative day [Срок оценки: First postoperative day]

Критерии участия

Критерии включения

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

Критерии исключения

• 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

Group-specific exclusion criteria:

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Фундаментальное исследование

Центры проведения

Греция · 1 центр

• University of Crete — Heraklion

Публикации

• 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. PMID 29945217
• 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. PMID 16119599
• 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. PMID 16829725
• 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. PMID 18685933
• 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. PMID 1640860
• 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. PMID 22170499
• 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. PMID 32215455
• 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. PMID 28213891

Идентификаторы

NCT: NCT05172739 · OFA-Thoracic

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗