This randomized clinical trial will investigate the opioid sparing effect of dexmedetomidine and ketmine infusion in cirrhotic patients undergoing liver resection

Patient enrollment will start after approval of the study protocol by the local Ethics and Research Committee and the Institutional Review Board (IRB) of the Departments of Anesthesia, ICU and Pain Management and the National Liver Institute, Faculty of Medicine, Menoufia University. The study will be conducted in the Anesthesia Department, National Liver Institute and will be registered with the ClinicalTrials.gov (http://www.clinicaltrials.gov) before patients enrollment.

The study will include adult patients with liver cirrhosis undergoing liver resection. Patients will be randomly allocated into one of the two study groups using an online randomization program (http://www.randomizer.org). Random allocation numbers will be concealed in opaque closed envelops. A written informed consent will be taken from each patient.

Five leads electrocardiography, pulse oximetry and peripheral perfusion index using masimo pulse oxymetry finger prope (Masimo, Irvine,CA, USA), end-tidal CO2, invasive arterial blood pressure, central venous pressure, The electrical cardiometry (EC) (ICON monitor; Cardiotronics Inc., La Jolla, CA, USA) for cardiac output monitoring (CO). oesophageal temperature, fraction inspired oxygen concentration, fraction inspired and expired desflurane. Bispectral index will be used to monitor the depth of anesthesia (BIS Covidien USA.), The neuromuscular function will be monitored using TOF-Watch SX (Schering-Plough, Swords, Co. Dublin, Ireland).

All patients fulfilling the study inclusion criteria will undergo a thorough clinical evaluation including laboratory assessment of liver and renal functions. Other diagnostic and/or laboratory workup will be requested by the attending anesthetist and the surgeon according to the patient clinical condition and the proposed surgical intervention.

Bilateral transversus abdominis plane (TAP) block:

All patients in the two study groups will receive a single shot ultrasound-guided bilateral TAP block using levopubivacaine. The effectiveness and dermatomal distribution of the block will be checked after 30 minutes and before induction of general anesthesia.

Anesthesia will be induced in all patients using fentanyl 2µg/kg, propofol 2 mg/kg, and rocuronium 0.6 mg/kg to facilitate endotracheal intubation. After induction of anesthesia, patients will be randomly allocated in two groups opioid sparing group (OS) and opioid-based group (OB). Patients in the Opioid Sparing group will receive a loading dose of dexmedetomidine (1µg/kg over 10 minutes). This will be followed by a fixed continuous maintenance infusion of 0.5µg/kg/hour. Furthermore, a single induction analgesic dose of 0.5 mg/kg ketamine will be given to all patients in the OS group. This will be followed by 0.25 mg/kg/h continuous maintenance infusion. Dexmedetomidine and ketamine infusions will be stopped 30 minutes prior to the conclusion of surgery. Patients in the opioid-based group will receive placebo boluses and infusions of saline. The attending anesthesiologist will be blinded to the patient group assignment.

Anesthesia will be maintained with a mixture of air, oxygen and desflurane to keep a BIS between 40 and 60. Muscle relaxation will be maintained by additional top-up doses of rocuronium 0.15mg/kg and will be guided by the response to ulnar nerve stimulation. Ventilation parameters will be adjusted to maintain normocapnia. Intraoperative normothermia will be maintained using a forced air warm blanket (Model 750-Bair Hugger Temperature Management Unit, SMA MISR, Arizant Healthcare Inc, USA), a humidifier, and warm intravenous fluids. Deep venous thrombosis (DVT) prophylaxis will include elastic stockings, sequential compression device (SCD) (Kendall Company, Tyco, USA) on the lower limb until early ambulation. Intraoperative fluid, fresh frozen plasma, and blood replacement therapy will be guided by the continuous monitoring of the central venous pressure and EC Cardiometry. and will be titrated to maintain hemodynamic stability and a hemoglobin level of 10 g/dL.

The intra-operative hemodynamics target will be to maintain the mean arterial blood pressure and heart rate within 20% of baseline value. Significant hemodynamic alterations will be managed as follows:

• Bradycardia (heart rate < 50 beats/min) will be managed by incremental 0.5 mg doses of atropine.
• Hypertension and/or tachycardia defined as more than 20% increase of the baseline readings will be managed by top-up doses of fentanyl 1µg/kg in the two study groups.
• Hypotension defined as more than 20% reduction in the baseline mean arterial blood pressure will be managed by incremental doses of ephedrine 5mg in the two study groups.

At the end of surgery and when two responses to train-of-four ulnar nerve stimulation are detected (T2), residual rocuronium-induced neuromuscular block will be antagonized by sugammadex 2 mg/kg. Patients will be discharged to the surgical intensive care unit after extubation. Postoperative analgesia will be achieved using patient-controlled fentanyl infusion (PCA fentanyl).

Inclusion Criteria:

• Male and female patients with liver cirrhosis [Child A] aged 18 to 65 years undergoing liver resection.
• American Society of Anesthesiologists class II-III.

Exclusion Criteria:

• Renal or cardiac dysfunction
• History of chronic pain
• Alcohol or drug abuse
• Analgesic use in last 24 hours before surgery
• Major intraoperative hemodynamic instability
• The need for postoperative ventilation
• Psychiatric disorders
• Inability to comprehend pain assessment
• Allergy or contraindication to any of the study medications.