Thirty minutes before induction of anesthesia, all patients received 10 mg intramuscular ketoralac trometamina (Toradol™, Recordati, Milano, Italy) or 100 mg tramadolo cloridrato (Contramal™, AIC Formenti, Milano, Italy), 100 mg ranitidine (Ranidil™, Menarini, Firenze, Italy), and 0.5 mg atropine (Industria Farmaceutica Galenica Senese, Siena, Italy). Prior to starting anesthesia, a FloTrac pressure transducer was connected (Edwards Lifesciences, Irvine, CA) to the Vigileo system (Edwards Lifesciences, v.1.07) and inserted into a radial artery to monitor dynamic variables. In addition, central venous pressure and central venous oxygen saturation (ScvO2) were monitored from the right internal jugular vein.
Before starting surgery, patients in the TIVA-TCI group received a combination of propofol (Diprivan™, ASTRA-Zeneca, Milano, Italy) and remifentanyl (Ultiva™, GlaxoSmith-Kline AB, Verona, Italy). Propofol was administered with TCI though infusion pumps (Alaris PK CardinalHealth, Rolle, Switzerland). At induction, the target plasma dose was 4 mg/m and was decreased to 3 μg/ml during the operation. Remifentanil was administered as a continuous intravenous infusion. At induction, the dose was 0.25 μg kg-1 min-1, and it was lowered to 0.15 μg kg-1 min-1 during surgery. This combination was modified by 0.05-μg kg-1 min-1 steps according to analgesic needs and hemodynamic parameters.
In the BAL group, patients received inhalation anesthesia with sevoflurane/O2/air (Sevorane™, Abbott, Latina, Italy) throughout the entire surgery. Before induction of anesthesia, 1–2 μg/kg fentanyl (Fentanest™, Pftzer, Latina, Italy) was administered. Anesthesia was induced by 0.1-0.2 mg/kg midazolam (Hameln pharmaceuticals Gmbh, Hameln, Germany), and the inhalation anesthesia was comprised of a mixture of sevoflurane/O2/air. For maintenance, the end-tidal sevoflurane concentration was kept at 1.4-2.8 vol %.
In both groups, 0.1-0.5 mg/kg cisatracurium besylate (Nimbex™, Glaxo Smith Kline) was given to facilitate orotracheal intubation, followed by the continuous application of 0.06-0.12 mg kg-1 h-1 cisatracurium via infusion pumps. The lungs were mechanically ventilated in a volume-control mode with settings aimed at achieving normocapnia, reaching a tidal volume up to 8–10 ml/kg and a respiratory frequency of 10–12 breaths/min. Mechanical ventilation was initiated with a mixture of 50% O2 and 50% air, and the inspired oxygen concentration was 40% during surgery. All patients were kept supine during the operation. No patient received inotropes, vasopressors or methoclopramide during or after surgery.
Monitoring included evaluation of cardiac hemodynamic parameters (electrocardiogram, heart rate, invasive blood pressure, systolic, diastolic, mean blood pressure [MAP], central venous pressure, stroke volume variation, cardiac index); tissue perfusion markers (ScvO2, O2 delivery index, arterial lactates, base excess, diuresis), respiratory parameters (pulse oximetry, end-tidal CO2, airway pressure, end-tidal sevoflurane), esophageal temperature, and blood glucose. The type of fluids (colloid and crystalloid) and the total volume were administered according to the goals optimized for a Cardiac Index >2.5 L/min/m2, MAP >90-105 mmHg, and Oxygen Delivery Index >600 ml/min/m2. Furthermore, the ScvO2 value was maintained at ≥70%. Patients received 1 packed red cell unit for each 1 g/dl of hemoglobin when its value was <8 g/dl.
After surgery, the residual neuromuscular blockade was reversed with a mixture of atropine and neostigmine (Intrastigmina™, Lusofarmaco, Milano, Italy) only if deemed clinically necessary. Anesthetic agents were switched off, and 100% O2 was given with 8 l/min fresh gas flow for 1 min. Supplemental oxygen was not given postoperatively.
Hypothermic prevention during anesthesia was achieved by warm venous infusion (warmed serum), and a thermal blanket was applied to cover the upper part of the body. In addition, a warming forced-air blanket was used post-surgery (Equator Covective Warming™, Smith Medical Italia, Milano, Italy).
After tracheal extubation, all patients received an intravenous bolus of 2 mg morphine (Recordati). A patient-controlled analgesia device (Deltec™ , Smiths Medical ASD, St Paul, MN) was then connected to an intravenous infusion device and was set to deliver 1 mg morphine with a 7-min lockout time. Patient-controlled analgesia was maintained until daily morphine consumption was <10 mg. In addition, patients received 20 mg ketoralac for 3 days or 100 mg tramadolo cloridrate for 1 day.
Before the induction of anesthesia (T0), 6–8 hours post-surgery (T1), and 5 days post-surgery (T2), blood samples were drawn to determine immunologic parameters, including Tregs and the serum concentration of IL-1β, IFN-γ, TNF-α, IL-2, IL-6, and IL-10.
The following clinical parameters were evaluated: (a) histological type and pathological tumor-node-metastasis stage, (b) quantity and type of liquids administered, (c) blood loss, (d) transfusion of allogenic blood and/or autotransfusion, (e) pre and post-operative complications such as hypertension, hyperglycemia, hypothermia, and pain (evaluated by a 6-point verbal rating scale: 0: no pain to 5: most severe pain imaginable), (g) post-operative infection rate.
Furthermore, follow-up was performed to assess the disease-free interval, metastasis, and survival of each patient.