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

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

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

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.

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.

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

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

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.

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.

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.

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

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

Neutrophil to Lymphocyte ratio (NLR) is a prognostic index that predicts patients' overall survival. Higher NLR has been correlated with worse outcome.

Platelet to Lymphocyte ratio (PLR) is a prognostic index that predicts patients' overall survival. Higher PLR has been correlated with worse outcome.

Lymphocyte to monocyte ratio (LMR) is a prognostic index that predicts patients' overall survival. Lower LMR has been correlated with worse outcome.

Advanced Lung Cancer Inflammation Index (ALI) is a prognostic index that predicts patients' recurrence-free survival and overall survival. ALI is calculated as (BMI x Alb / NLR) where BMI = body mass index, Alb = serum albumin, NLR (neutrophil lymphocyte ratio, a marker of systemic inflammation). Higher ALI scores have been correlated with worse outcome.

Systemic Immune Inflammation Index (SII) is a prognostic index that predicts patients' overall survival. SII is calculated as follows: SII = platelet count × neutrophil/lymphocyte count. Higher SII scores have been correlated with worse outcome.

Prognostic Nutritional Index (PNI) is a prognostic index that predicts patients' overall survival. PNI is calculated as follows: PNI = 10 × serum albumin value (g/dL) + 0.005 × total lymphocyte count (per mm3) in the peripheral blood. Higher PNI scores have been correlated with worse outcome.

Inflammatory response and stress response as quantified by IL-6 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-6 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-6 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-8 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-8 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-8 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-10 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-10 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by IL-10 serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by TNF-a serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by TNF-a serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by TNF-a serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by CRP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by CRP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by CRP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by WBC count. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by WBC count. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by WBC count. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by AVP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by AVP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by AVP serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by cortisol serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by cortisol serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by cortisol serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by HIF-1α serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by HIF-1α serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by HIF-1α serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by VEGF serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by VEGF serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by VEGF serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by NF-κB serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by NF-κB serum levels. Blood sample collection will take place in both study groups

Inflammatory response and stress response as quantified by NF-κB serum levels. Blood sample collection will take place in both study groups

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate - PR. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean PR will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate - PR. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum PR will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate - PR. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum PR will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate - PR. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation PR will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate change 1 minute after anesthesia induction, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Pulse Rate change 1 minute after surgical incision, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure - SBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean SBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure - SBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum SBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure - SBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum SBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure - SBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation SBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure change 1 minute after anesthesia induction, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Systolic Blood Pressure change 1 minute after surgical incision, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure - DBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean DBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure - DBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum DBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure - DBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum DBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure - DBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation DBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure change 1 minute after anesthesia induction, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Diastolic Blood Pressure change 1 minute after surgical incision, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure - MBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean MBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure - MBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum MBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure - MBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum MBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure - MBP. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation MBP will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure change 1 minute after anesthesia induction, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Mean Blood Pressure change 1 minute after surgical incision, compared to 1 minute prior. Data will be collected from a pulse contour analysis monitor.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Output - CO. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean CO will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Output - CO. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum CO will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Output - CO. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum CO will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Output - CO. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation CO will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Index - CI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean CI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Index - CI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum CI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Index - CI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum CI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Cardiac Index - CI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation CI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume - SV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean SV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume - SV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum SV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume - SV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum SV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume - SV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation SV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Variation - SVV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean SVV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Variation - SVV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum SVV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Variation - SVV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum SVV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Variation - SVV. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation SVV will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Index - SVI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Mean SVI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Index - SVI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Minimum SVI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Index - SVI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Maximum SVI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Haemodynamic Stability as quantified by hemodynamic markers, specifically Stroke Volume Index - SVI. Data will be collected from a pulse contour analysis monitor, and values will be collected every 20 seconds. Standard Deviation SVI will be reported for each patient, extracted from the collected data.

Every 20 seconds from anesthesia induction, until the end of surgery (end of placement of last suture/ surgical clip on patient), assessed up to 8 hours]

Intraoperative Tachycardia (defined as PR≥ 100 bpm), with episodes lasting ≥1 minute. Data will be reported in total seconds of intraoperative tachycardia.

Intraoperative Bradycardia (defined as PR≤ 60 bpm), with episodes lasting ≥1 minute. Data will be reported in total seconds of intraoperative bradycardia.

Intraoperative Hypotension (defined as SBP≤100mmHg or ≤70% of preoperative Baseline), with episodes lasting ≥1 minute. All patients will have a 5 minute preoperative SBP baseline, with measurements every 20 seconds. Intraoperative data will be compared to the mean preoperative 5 minute SPB baseline. Data will be reported in total seconds of intraoperative hypotension.

Intraoperative Hypertension (defined as SBP ≥130% of preoperative Baseline), with episodes lasting ≥1 minute. All patients will have a 5 minute preoperative SBP baseline, with measurements every 20 seconds. Intraoperative data will be compared to the mean preoperative 5 minute SPB baseline. Data will be reported in total seconds of intraoperative hypertension.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Crystalloid Fluid Requirements.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Colloid Fluid Requirements.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Concentrated Red Blood Cell unit Requirements.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Platelet unit Requirements.

Haemodynamic Stability as quantified by hemodynamic markers, specifically Nitroglycerine requirements

Evaluation of patients' pain using scales: Numerical Rating Scale (NRS). The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").

Evaluation of patients' pain using scales: Numerical Rating Scale (NRS). The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").

Evaluation of patients' pain using scales: Numerical Rating Scale (NRS). The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").

Evaluation of patients' pain using scales: Numerical Rating Scale (NRS). The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").

Evaluation of patients' pain using scales: Critical Care Pain Observation Tool (CPOT). The scale consists of four behavioral domains: facial expression, body movements, muscle tension and compliance with the ventilation for intubated patients or vocalization for extubated patients. Patient's behavior in each domain is scored between 0 and 2. The possible total score ranges from 0 (no pain) to 8 (maximum pain).

Evaluation of patients' pain using scales: Critical Care Pain Observation Tool (CPOT). The scale consists of four behavioral domains: facial expression, body movements, muscle tension and compliance with the ventilation for intubated patients or vocalization for extubated patients. Patient's behavior in each domain is scored between 0 and 2. The possible total score ranges from 0 (no pain) to 8 (maximum pain).

Evaluation of patients' pain using scales: Critical Care Pain Observation Tool (CPOT). The scale consists of four behavioral domains: facial expression, body movements, muscle tension and compliance with the ventilation for intubated patients or vocalization for extubated patients. Patient's behavior in each domain is scored between 0 and 2. The possible total score ranges from 0 (no pain) to 8 (maximum pain).

Evaluation of patients' pain using scales: Critical Care Pain Observation Tool (CPOT). The scale consists of four behavioral domains: facial expression, body movements, muscle tension and compliance with the ventilation for intubated patients or vocalization for extubated patients. Patient's behavior in each domain is scored between 0 and 2. The possible total score ranges from 0 (no pain) to 8 (maximum pain).

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Intolerable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Intolerable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Intolerable - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Intolerable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Tolerable with discomfort - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Tolerable with Discomfort" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Tolerable with discomfort - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Tolerable with Discomfort" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Tolerable with discomfort - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Tolerable with Discomfort" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Comfortably manageable - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Comfortably manageable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Comfortably manageable - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Comfortably manageable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Comfortably manageable - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Comfortably manageable" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Negligible Pain - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Negligible Pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Negligible Pain - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Negligible Pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Comfort - Negligible Pain - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to how comfortable patients feel with their pain, available answers will be: Intolerable Tolerable with discomfort Comfortably manageable Negligible Pain The percentage of patients that report pain that is "Negligible Pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting Worse - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting worse" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting Worse - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting worse" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting Worse - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting worse" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - About the same - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "About the same" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - About the same - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "About the same" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - About the same - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "About the same" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting better - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting Better" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting better - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting Better" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Change in Pain - Getting better - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to changes in pain perception by patients, available answers will be: Getting worse About the same Getting better The percentage of patients that report pain that is "Getting Better" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Inadequate pain control - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Inadequate pain control" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Inadequate pain control - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Inadequate pain control" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Inadequate pain control - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Inadequate pain control" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Effective, just about right - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Effective, just about right" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Effective, just about right - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Effective, just about right" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Effective, just about right - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Effective, just about right" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Would like to reduce medication - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Would like to reduce medication" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Would like to reduce medication - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Would like to reduce medication" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Pain control - Would like to reduce medication - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to pain control reported by patients, available answers will be: Inadequate pain control Effective, just about right Would like to reduce medication The percentage of patients that report "Would like to reduce medication" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can't do anything because of pain - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can't do anything because of pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can't do anything because of pain - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can't do anything because of pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can't do anything because of pain - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can't do anything because of pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Pain keeps me from doing most of what I need to do - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Pain keeps me from doing most of what I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Pain keeps me from doing most of what I need to do - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Pain keeps me from doing most of what I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Pain keeps me from doing most of what I need to do - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Pain keeps me from doing most of what I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do most things, but pain gets in the way of some - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do most things, but pain gets in the way of some" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do most things, but pain gets in the way of some - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do most things, but pain gets in the way of some" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do most things, but pain gets in the way of some - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do most things, but pain gets in the way of some" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do everything I need to do - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do everything I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do everything I need to do - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do everything I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Functioning - Can do everything I need to do - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to functioning - for the usual things patients need to do, available answers will be: Can't do anything because of pain Pain keeps me from doing most of what I need to do Can do most things, but pain gets in the way of some Can do everything I need to do The percentage of patients whose functioning is reported as "Can do everything I need to do" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with pain most of the night - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Awake with pain most of the night" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with pain most of the night - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Awake with pain most of the night" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with pain most of the night - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Awake with pain most of the night" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with occasional pain - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as " Awake with occasional pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with occasional pain - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as " Awake with occasional pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Awake with occasional pain - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as " Awake with occasional pain" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Normal sleep - First postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Normal sleep" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Normal sleep - Second postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Normal sleep" will be reported

Acute postoperative pain - Clinically Aligned Pain Assessment Tool (CAPA) - Sleep - Normal sleep - Third postoperative day

Evaluation of patients' pain using scales: Clinically Aligned Pain Assessment Tool (CAPA). Patients will be given a standardized CAPA questionaire that has pre-determined answers that patients will be able to choose from, to best describe their pain. In regards to sleep, if the pain is waking patients up, available answers will be: Awake with pain most of the night Awake with occasional pain Normal sleep The percentage of patients whose sleep is reported as "Normal sleep" will be reported

Evaluation of patients' pain by recording the number of times that rescue analgesia (tramadol) was required.

Evaluation of patients' pain by recording the number of times that rescue analgesia (tramadol) was required.

Evaluation of patients' pain by recording the number of times that rescue analgesia (tramadol) was required.

Aspiration pneumonitis (defined as respiratory failure after the inhalation of regurgitated gastric contents)

Moderate respiratory failure (SpO2 < 90% or PaO2 < 60 mmHg for 10 min in room air, responding to oxygen > 2 L/min)

Severe respiratory failure (need for non-invasive or invasive mechanical ventilation due to poor oxygenation)

Pulmonary infection (defined as new or progressive radiographic infiltrate plus at least two of the following: antibiotic treatment, tympanic temperature > 38 °C, leukocytosis or leucopenia (white blood cell (WBC) count < 4000 cells/mm3 or > 12,000 cells/mm3) and/or purulent secretions)

Atelectasis (suggested by lung opacification with shift of the mediastinum, hilum, or hemidiaphragm towards the affected area, and compensatory over-inflation in the adjacent non-atelectatic lung)

Cardiopulmonary edema (defined as clinical signs of congestion, including dyspnea, edema, rales, and jugular venous distention, with the chest x-ray demonstrating increase in vascular markings and diffuse alveolar interstitial infiltrates)

Pleural effusion (chest x-ray demonstrating blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm in upright position, evidence of displacement of adjacent anatomical structures, or (in supine position) a hazy opacity in one hemithorax with preserved vascular shadows)

Pneumothorax (defined as air in the pleural space with no vascular bed surrounding the visceral pleura)

Pulmonary infiltrates (chest x-ray demonstrating new monolateral or bilateral infiltrate without other clinical signs)

Purulent pleuritic (receiving antibiotics for a suspected infection, as far as not explained by the preoperative patient condition alone)

Pulmonary embolism (as documented by pulmonary arteriogram or autopsy, or supported by ventilation/perfusion radioisotope scans, or documented by echocardiography and receiving specific therapy)

Lung hemorrhage (bleeding through the chest tubes requiring reoperation, or three or more red blood cell packs)

Evaluation of patients' pain using the standardized "Pain Detect" questionnaire. The "Pain Detect" questionnaire has been standardized for screening the presence of a neuropathic pain component. Patients will be interviewed by phone interview, 3 months after the end of surgery. The possible score a patient can have, ranges from 0 to 38.

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 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

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