Opioid Free Anesthesia-Analgesia Strategy and Surgical Stress in Elective Open Abdominal Aortic Aneurysm Repair

Official title

Effect of a Perioperative Opioid Free Anesthesia-Analgesia (OFA-A) Strategy on Surgical Stress Response in Elective Open Abdominal Aortic Aneurysm Repair: A Prospective Randomized Study

Overview

Open Abdominal Aortic Aneurysm (AAA) repair is a high-risk surgical procedure accompanied by intense endocrine and metabolic responses to surgical stress, with subsequent activation of the inflammatory cascade, cytokine and acute-phase protein release, and bone marrow activation. There is a proven correlation of surgical stress, which patients undergoing open AAA repair are subjected to, with patient outcome, morbidity/mortality, intensive care unit stay and overall length of stay. Modern general anesthetic techniques have been revised and rely on perioperative multimodal anesthetic and analgesic strategies for improved overall patient outcome. Based on this context of a multimodal anesthetic technique and having taken into consideration the international "opioid-crisis" epidemic, an Opioid Free Anesthesia-Analgesia (OFA-A) strategy started to emerge. It is based on the administration of a variety of anesthetic/analgesic 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, involving the administration of pregabalin, ketamine, dexmedetomidine, lidocaine, dexamethasone, dexketoprofen, paracetamol and magnesium sulphate, will lead to attenuation of surgical stress response compared to a conventional Opioid-Based Anesthesia-Analgesia (OBA-A) strategy. Furthermore, the anticipated attenuation of the inflammatory response, is pressumed to be associated with equal or improved analgesia, compared to a perioperative OBA-A technique.

Detailed description

Open abdominal aortic aneurysm (AAA) repair surgery is a high-risk operation, often performed on high-risk patients. Despite advancements made in diagnosis, management, surgical techniques and treatment of these patients, morbidity and mortality remain high. Mortality after open AAA repair remains higher than the average mortality of the matched population for age and sex. Debate is ongoing as to whether open AAA repair or endovascular aneurysm repair (EVAR) is better in terms of overall long-term survival rate.

Regarding open AAA repair, the very nature of the surgery itself, with surgical trauma, aortic cross clamping and its resulting ischemia-reperfusion injury, and cellular interactions of blood with the biomaterial surface of the graft, causes intense and varied metabolic, endocrine and immunological responses. These surgical stress-related responses are evident as marked increases in inflammatory cytokines such as TNF-a, IL-1a, IL-6, IL-8, IL-10, stimulation of the sympathetic system, and stimulation of the hypothalamic-pituitary-adrenal axis, caused by release of CRH and AVP. High levels of IL-6, peaking at 4-48h after clamp removal, have been associated with serious postoperative complications and its levels reflect the intensity of surgical trauma following AAA repair. Other inflammation markers such as CRP and leukocytes have also been shown to increase postoperatively.

While the surgical technique has been extensively studied as to the role it plays on the control of the surgical stress response, patient outcome, morbidity and overall mortality, fewer studies have been conducted to study the effect of the anesthetic management on these factors. While most of them have been focusing on the comparison of general anesthetic vs regional techniques, only few compare different general anesthetic techniques on patient outcome.

Modern general anesthetic techniques have been revised and rely on a multimodal anesthetic and analgesic perioperative regimen for improved patient outcome. A multimodal regimen requires the administration of at least 2 factors with different mechanisms of action. At least one factor causes inhibition of central sensitization and at least another one inhibits the peripheral sensitization of the nervous system, as a response to painful surgical stimuli, mitigating adverse neuroplasticity. One such example, is an Opioid-Free Anesthetic-Analgesic (OFA-A) strategy, which implements a variety of pharmacological agents, including some with demonstrated immunomodulating and anti-inflammatory effects. Apart from sparing any opioid-related adverse effects, an OFA-A multimodal strategy targets optimal analgesia with a multitude of factors in the lowest possible dose, aiming for additive or synergistic effects. An additional advantage of using an OFA-A technique is the prevention of opioid-induced hyperalgesia.

Our hypothesis is that implementation of a multimodal OFA-A strategy, leads to a decreased sympathetic and inflammatory response, compared to conventional opioid-based anesthetic techniques. A decreased inflammatory and stress response as expressed by reduced levels of IL-6, IL-8, IL-10, TNF-a, CRP, cortisol, arginine vasopressin (AVP), white blood cells count and hemodynamic stability is expected to decrease peripheral and central sensitization, contributing to better postoperative analgesia.

Interventions

• Drug Opioid-Based Anesthesia-Analgesia Strategy
  A perioperative Opioid-Based multimodal Anesthesia-Analgesia strategy will be implemented as described in the Opioid-Based arm of the study.
• Drug Opioid-free Anesthesia-Analgesia Strategy
  A perioperative Opioid-Free multimodal Anesthesia-Analgesia strategy will be implemented as described in the Opioid-Free arm of the study.

Primary outcome measures

• Surgical Stress Response - IL-6 - Preoperatively [Time frame: 1) Preoperatively (as a baseline)]
• Surgical Stress Response - IL-6 - 15 minutes after aortic cross-clamp [Time frame: 2) 15 minutes after aortic cross-clamping]
• Surgical Stress Response - IL-6 - 60 minutes after aortic cross-clamp [Time frame: 3) 60 minutes after aortic cross-clamp release]
• Surgical Stress Response - IL-6 - 24 hours after aortic cross-clamp release [Time frame: 4) 24 hours after aortic cross-clamp release]
• Surgical Stress Response - IL-8 - Preoperatively [Time frame: 1) Preoperatively (as a baseline)]
• Surgical Stress Response - IL-8 - 15 minutes after aortic cross-clamp [Time frame: 2) 15 minutes after aortic cross-clamping]
• Surgical Stress Response - IL-8 - 60 minutes after aortic cross-clamp [Time frame: 3) 60 minutes after aortic cross-clamp release]
• Surgical Stress Response - IL-8 - 24 hours after aortic cross-clamp release [Time frame: 4) 24 hours after aortic cross-clamp release]
• Surgical Stress Response - IL-10 - Preoperatively [Time frame: 1) Preoperatively (as a baseline)]
• Surgical Stress Response - IL-10 - 15 minutes after aortic cross-clamp [Time frame: 2) 15 minutes after aortic cross-clamping]

Secondary outcome measures (12)

• Postoperative pain - Numerical Rating Scale (NRS) - Immediately Postoperatively [Time frame: 1) Immediately postoperatively (if awakened prior to ICU admission)]
• Postoperative pain - Numerical Rating Scale (NRS) - First postoperative day [Time frame: 2) First postoperative day]
• Postoperative pain - Numerical Rating Scale (NRS) - Second postoperative day [Time frame: 3) Second postoperative day]
• Postoperative pain - Numerical Rating Scale (NRS) - Third postoperative day [Time frame: 4) Third postoperative day]
• Postoperative pain - Critical Care Pain Observation Tool (CPOT) - Immediately Postoperatively [Time frame: 1) Immediately postoperatively (if awakened prior to ICU admission)]
• Postoperative pain - Critical Care Pain Observation Tool (CPOT) - First postoperative day [Time frame: 2) First postoperative day]
• Postoperative pain - Critical Care Pain Observation Tool (CPOT) - Second postoperative day [Time frame: 3) Second postoperative day]
• Postoperative pain - Critical Care Pain Observation Tool (CPOT) - Third postoperative day [Time frame: 4) Third postoperative day]
• Postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - First postoperative day [Time frame: 1) First postoperative day]
• Postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Second postoperative day [Time frame: 2) Second postoperative day]
• Postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Third postoperative day [Time frame: 3) Third postoperative day]
• Postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Tolerable with discomfort - First postoperative day [Time frame: 1) First postoperative day]

Eligibility criteria

Inclusion criteria

• Patient Consent
• Age between 40 and 85 years old
• Patients undergoing Elective Open Abdominal Aortic Infrarenal Aneurysm Repair

Exclusion criteria

• Immunocompromised patients
• Patients with active infection
• Reoperation on the aorta
• Inflammatory bowel Disease
• Malignancy
• Chronic Inflammatory conditions (e.g. Rheymatoid arthritis, Psoriatic arthritis)
• Chronic corticosteroid or immunosuppressive drug use
• Intraoperative transfusion with >2 units of packed Red Blood Cells

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

Greece · 1 center

• University of Crete — Heraklion

Publications

• Norman PE, Semmens JB, Lawrence-Brown MM. Long-term relative survival following surgery for abdominal aortic aneurysm: a review. Cardiovasc Surg. 2001 Jun;9(3):219-24. doi: 10.1177/096721090100900303. PMID 11336844
• Johal AS, Loftus IM, Boyle JR, Heikkila K, Waton S, Cromwell DA. Long-term survival after endovascular and open repair of unruptured abdominal aortic aneurysm. Br J Surg. 2019 Dec;106(13):1784-1793. doi: 10.1002/bjs.11215. PMID 31747067
• Moris DN, Kontos MI, Mantonakis EI, Athanasiou AK, Spartalis ED, Bakoyiannis CN, Chrousos GP, Georgopoulos SE. Concept of the aortic aneurysm repair-related surgical stress: a review of the literature. Int J Clin Exp Med. 2014 Sep 15;7(9):2402-12. eCollection 2014. PMID 25356092
• Tsilimigras DI, Sigala F, Karaolanis G, Ntanasis-Stathopoulos I, Spartalis E, Spartalis M, Patelis N, Papalampros A, Long C, Moris D. Cytokines as biomarkers of inflammatory response after open versus endovascular repair of abdominal aortic aneurysms: a systematic review. Acta Pharmacol Sin. 2018 Jul;39(7):1164-1175. doi: 10.1038/aps.2017.212. Epub 2018 May 17. PMID 29770795
• Pearson S, Hassen T, Spark JI, Cabot J, Cowled P, Fitridge R. Endovascular repair of abdominal aortic aneurysm reduces intraoperative cortisol and perioperative morbidity. J Vasc Surg. 2005 Jun;41(6):919-25. doi: 10.1016/j.jvs.2005.02.040. PMID 15944585
• Wilt TJ, Lederle FA, Macdonald R, Jonk YC, Rector TS, Kane RL. Comparison of endovascular and open surgical repairs for abdominal aortic aneurysm. Evid Rep Technol Assess (Full Rep). 2006 Aug;(144):1-113. PMID 17764213
• Moore WS, Kashyap VS, Vescera CL, Quinones-Baldrich WJ. Abdominal aortic aneurysm: a 6-year comparison of endovascular versus transabdominal repair. Ann Surg. 1999 Sep;230(3):298-306; discussion 306-8. doi: 10.1097/00000658-199909000-00003. PMID 10493477
• Salartash K, Sternbergh WC 3rd, York JW, Money SR. Comparison of open transabdominal AAA repair with endovascular AAA repair in reduction of postoperative stress response. Ann Vasc Surg. 2001 Jan;15(1):53-9. doi: 10.1007/s100160010014. PMID 11221945

Identifiers

NCT: NCT04894864 · OFA-aneurysm

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗