Patients and Methods
This randomized controlled study was conducted on adult (≥ 18 years old) patients of either sex, who underwent LDLT with right lobe graft from family-related donors between 10 December 2017 and 22 October 2019 at the Gastrointestinal Surgery Center, Mansoura University, Egypt. Institutional review board approval was obtained (MD/17.08.28) on 7 September 2017 and all methods were performed in accordance with declaration of Helsinki. The study was registered at the Pan African Clinical Trials Registry (PACTR202203622900599) on 23 March 2022. All the included patients were granted informed consent. This study was reported according to the CONsolidated Standards of Reporting Trials (CONSORT) guidelines.[10]
Exclusion criteria were acute fulminant hepatitis, estimated graft/recipient weight ratio (GRWR) <0.8, and portal hypertension with mean pulmonary blood pressure >35 mmHg. Patients with preoperative S.Cr >1.4 mg/dL or had dialysis within the last 3 months, diabetes mellitus (>10 years), preoperative serum sodium [Na+] <125 mEq/L, or serum potassium [K+] >5.5 mEq/L were also excluded.
Randomization and Blinding
A total of 84 patients were randomly assigned to two equal groups: mannitol group (M group) and saline group (S group) using a computer-generated table of random numbers with four or six permuted blocks. The group allocation was concealed in sequentially numbered, sealed, and opaque envelopes.
An anesthetist—who was not involved in the study—opened the envelopes before the end of the dissection phase. He then prepared the study drug as indicated in the envelope using a similar volume of either 1 g/kg mannitol 20% or saline 0.9% in a similar warmed unlabeled bottle wrapped by an opaque cover.
The patients, outcome assessors, and the statistician were blinded to the study group until the results were reported.
Patients' Preparation and Anesthesia
All patients fasted for 6 h preoperatively for solids and were encouraged to freely drink water up to 4 h preoperatively with an infusion of 500 mL Ringer's acetate during the fasting period.
Baseline recipients' characteristics and laboratory data were collected 24 h before the operation. Donor age and gender were recorded in the study after considering the donors' data. General anesthesia was induced by intravenous (IV) fentanyl 2 mcg/kg, propofol 1–2 mg/kg, and rocuronium bromide 0.8–1 mg/kg. Anesthesia was maintained by sevoflurane in 40%–60% oxygen in addition to a fentanyl infusion of 0.5–1 mcg/kg/h and rocuronium bromide 200–400 mcg/kg/h. All the patients were kept warm by forced-air warming blankets.
Invasive arterial blood cannula and pulmonary artery catheter were inserted for continuous intraoperative cardiac output (CO) and temperature monitoring (ABBOTT, critical care systems, USA).
Ringer's acetate was used as the maintenance solution. Our center adopted a goal-directed fluid protocol in LDLT and targeted to maintain the mean arterial pressure (MAP) of ≥ 65 mmHg. Patients with stroke volume variation (SVV) >10% were considered fluid responders and received boluses of 200 mL albumin 4% in Ringer's acetate. The hemoglobin concentration threshold for red blood cells (RBCs) transfusion was 7–8 g/dL according to the clinical judgment. Norepinephrine infusion was started in fluid non-responders.
Random blood glucose was kept between 110 mg/dL and 180 mg/dL by intravenous insulin infusion or boluses of 10% or 25% glucose solution as appropriate. Also, serum potassium (K+) and ionized calcium (Ca2+) levels were monitored and corrected if needed, especially around the reperfusion phase.
Mannitol and Reperfusion
The graft preservation time was minimized by synchronizing the surgical steps of both recipient and donor operations. It was flushed with 3–4 L of cold histidine-tryptophan-ketoglutarate (Custodial, Bensheim, Germany) via antegrade flushing of the portal vein (without flushing via the hepatic artery) to get completely clear fluid after excision of the donor's right liver lobe.
The study solution was infused for over 20 min at the beginning of warm ischemia. The right hepatic vein was unclamped, followed by the portal vein, and then the graft preservative contents were washed into the systemic circulation by the portal blood.
Postreperfusion Syndrome and Hemodynamic Parameters
Hypotension was defined as a 20% reduction below the basal MAP while PRS was defined as a 30% drop in the MAP compared to the basal reading sustained for 1 min within 5 min after portal unclamping.
Both groups were managed by rapid 500 mL 4% albumin infusion or packed RBCs (according to the anhepatic phase hemoglobin) and 20 mcg norepinephrine boluses, and then infusion if needed. Incremental boluses of 10 mcg epinephrine were administered if MAP was still less than 65 mmHg after 1 min.
The intraoperative hemodynamic parameters [MAP, CO, systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), pulmonary artery occlusion pressure (PAOP), mean pulmonary arterial pressure (MPAP), and central venous pressure (CVP)], and serum electrolyte [Na+, K+, Ca2+ and chloride (Cl-)] levels were recorded at six intraoperative measurement points. These moments were (1) immediately before skin incision, (2) at the beginning of the anhepatic phase (portal vein clamping), (3) 5 min before portal reperfusion (basal), (4) at 5 min after portal unclamping, (5) at 5 min after hepatic arterial declamping, and (6) at skin closure.
At the end of Surgery and in the Intensive Care Unit (ICU)
Early ICU tracheal extubation was adopted once the patient was hemodynamically stable [MAP >65 mmHg, heart rate (HR) <100 beats per min, and peripheral oxygen saturation (SpO2) >96% on 0.4 fractions of inspired oxygen (FiO2)] and pH >7.3 with adequate consciousness level and muscle power.
Daily zero fluid balance was targeted during the ICU stay. Fluid maintenance was Ringer's acetate and glucose 10% encouraging early oral fluids from the first postoperative day. Albumin was administered to keep the serum albumin ≥ 3.0 g/dL.
Early AKI (primary outcome) was defined as a 0.3 mg/dl increase in the serum creatinine (S.Cr) in the early 48 postoperative hours, according to the International Club of Ascites' revised classification of AKI in cirrhotic patients.[11,12] The AKI has been classified as follows: Stage 1, when S.Cr = 1.5–1.9 times at the baseline or >0.3 mg/dl increase from the baseline; Stage 2, when S.Cr = 2–2.9 times at the baseline; and Stage 3, when S.Cr = 3 times at the baseline increases to >4 mg/dl or results in the initiation of renal replacement therapy.[11,12]
Urine Output (UO) During Surgery and in the ICU
The UO was monitored hourly intraoperatively. Furosemide 5 mg IV was administered when UO is less than 0.5 mL/kg/h after ensuring adequate fluid status. In the ICU, 5–10 mg furosemide was given if UO is less than 0.5 mL/kg/h and evaluated every 6 h if volume overload was estimated.
Immunosuppression
Patients received IV 0.5 gm methylprednisolone at the beginning of the warm ischemia. A 500 mg mycophenolate mofetil through the nasogastric tube and IV 20 mg basiliximab were administered after hepatic artery anastomosis and declamping.
Patients received oral tacrolimus from the day after the operation (adjusting the dose targeting serum level of 5–10 ng/mL) and mycophenolate mofetil 500 mg 4 days after the operation. Tacrolimus was replaced, temporarily, with methylprednisolone if AKI is diagnosed until normal kidney function was restored.
Postoperative Data
Laboratory assessment of the graft function included pH, serum lactate, and lactate dehydrogenase (LDH) recorded on the 1st and 2nd days, while S.Cr, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin, and international normalized ratio (INR) were measured at the 1st, 2nd, 7th, 28th days and also after 3 months postoperatively. The ICU and the duration of hospitalization, early postoperative surgical complications (within 28 days), and 3-month survival after the operation were reported.
BMC Anesthesiol. 2022;22(393) © 2022 BioMed Central, Ltd.
