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

University of Crete

Status and phase: Enrolling; Phase 4

Conditions: Postoperative Pain; Abdominal Aortic Aneurysm Without Rupture; Interleukin 6; Vascular Surgical Procedure; Elective Surgical Procedures; Opioid Use; Immunomodulators; Anesthesia

Treatments: Drug: Opioid-Based Anesthesia-Analgesia Strategy; Drug: Opioid-free Anesthesia-Analgesia Strategy

Study type: Interventional

Funder types: Other

Identifiers

NCT04894864

OFA-aneurysm

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 40 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patient Consent
2. Age between 40 and 85 years old
3. Patients undergoing Elective Open Abdominal Aortic Infrarenal Aneurysm Repair

Exclusion criteria

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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40 participants in 2 patient groups

Opioid-Based Anesthesia Analgesia

Active Comparator group

Description:

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. ICU stay sedation: Remifentanil infusion, until removal of the endotracheal tube. Surgical ward: PCA pump with Morphine for the first 3 postoperative days. Additional postoperative analgesia: Paracetamol 1g x3 +/- Dexketoprofen trometamol 50mg x2. Rescue therapy only: Tramadol 50-100mg.

Treatment:

Drug: Opioid-Based Anesthesia-Analgesia Strategy

Opioid-Free Anesthesia Analgesia

Active Comparator group

Description:

Premedication: Pregabalin 50-150mg x2, IM Midazolam 0.05-0.07mg/kg. Anesthesia induction: Midazolam 0.03mg/kg, Dexdmedetomidine 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 0.2-1.2mcg/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. ICU sedation: Dexmedetomidine + Lidocaine infusions, until removal of the ETT. Surgical ward: PCA pump with Ketamine, Lidocaine, Clonidine and Midazolam for the first 3 postoperative days. Additionally, Pregabalin 50mg per os x1 and 25mg x1, up to x2, Paracetamol 1g x3 +/- Dexketoprofen trometamol 50mg x2. Rescue therapy only: Tramadol 50-100mg.

Treatment:

Drug: Opioid-free Anesthesia-Analgesia Strategy