1. The study was approved by the ethics committee of Peking University Cancer Hospital & Institute,Beijing,China on Dec. 2017. The protocol number is 2017KT107. The trial was registered at Chinese Clinical Trial Registry. The registration number is ChiCTR1900023167. The patients undergoing elective partial hepatectomy by open procedure during 2018.12 - 2019.7 were chosen as the candidate for this study in our hospital. Written informed consent was taken from each participant before surgery. The patients with no cirrhosis or with cirrhosis grading below CHILDA were selected. The disease types included primary hepatocellular carcinoma and colorectal cancer liver metastasis. Exclusion criteria were an age of 17 years younger, age older than 75 years, a hemoglobin level of lower than 9g/dL, repeated liver resections or general condition ≥Ⅲ on American Society of Anesthesiologists (ASA) scale. Patients with a history of hypertension or diabetes with uncontrolled hypertension/ blood glucose were excluded from this study. One hundred and ten patients were enrolled prospectively in the study and no one dropped out. The central venous catheter was inserted in the internal jugular vein or subclavian vein one day before surgery, and the position of the catheter was tested by chest X ray. The routine monitoring of ECG, pulse oxygen saturation, end-tidal carbon dioxide, invasive arterial pressure, urine output, CVP, and bispectrum index (BIS) were performed after the patient entered the operation room.
2. Fluid regimen and anesthetic techniques:Intraoperative fluid was maintained by colloid and crystalloid. The rate of fluid infusion was limited to 6 ml·kg–1·h–1 from the moment of patient entering the operating room to right before the liver lesion was removed. When urinary output was less than 20 ml/h, an additional fluid infusion of 200 ml crystalline solution was given over a period of 10 mins. When systolic blood pressure (SBP) was below 90mmHg for 1 min, and more than 3 times, an additional fluid infusion of 200 ml crystalline solution was given over a period of 10 mins. When the liver lesion was removed, the fluid infusion rate was increased to 1000–1500 ml/h. Packed red blood cells were transfused when the hemoglobin was less than 8g/dl.
Anesthesia was inducted with midazolam 1mg intravenous (IV), sufentanil 0.4–0.5ug/kg IV, CIS atracurium 0.2 mg/kg IV, propofol 2–2.5mg/kg IV followed by endotracheal intubation. General anesthesia was maintained with inhalation of 1% sevoflurane and intravenous infusion of propofol and remifentanil to keep BIS between 40 and 50. Mechanical ventilation in all patients was performed with 50% oxygen, which was adjusted to maintain end-tidal carbon dioxide between 35–45mm Hg. Ephedrine 6mg was injected when SBP was less than 90 mm Hg for 1 minute. All patients were sent to the post-anesthesia care unit (PACU) after surgery. The patient was moved back to the ward after the endotracheal tube was removed in the PACU.
3. Patients’ Demographic data, surgical treatment, operation time, frequency of ephedrine, frequency of additional fluid infusion of 200ml crystalline solution, intraoperative urine output, and blood loss were recorded. The extent of liver resections was divided into major resection and minor resection. The major hepatic resection was defined as resection of more than three or more segments. The extent of liver resections was assessed by hepatobiliary surgeons. The overall duration of PTC and the value of CVP were recorded. The serum lactate was measured from an arterial blood-gas analysis at the following time points: before anesthesia (T1), after liver dissection and immediately before liver resection (T2), 10 min after the liver lesion was removed (T3), and before the patient was discharged from the PACU (T4). Lactate clearance was calculated as following: Lactate clearance = (serum lactate at T3 - serum lactate at T4)/ (time interval (h) of T3 and T4* serum lactate at T3) * 100%. The mean values of the maximum and minimum values of CVP measured during liver resection was used as CVP values.
4. Outcome and simple size calculation: The primary outcome of interest was serum lactate. The secondary outcomes were frequency of ephedrine, frequency of additional fluid infusion of 200ml crystalline solution, intraoperative blood loss, duration of PTC, the mean value of CVP during hepatectomy.
Sample size was estimated with PASS software (version 11.0; NCSS, LLC, Kaysville, UT, USA). Sample size was calculated based on preliminary trial for 10 patients conducted by the authors, and estimated standard deviation of serum lactate was 2.0 mmol/L. The procedure of confidence intervals for one mean was selected with a confidence interval of 95%,with a distance from the mean to the limits of 0.5. The sample size calculated was 96 patients. Therefore, a total of 110 patients were recruited for possible dropouts.
5. Statistical analyses: All statistical analyses were performed by SPSS software (SPSS 18.0 for Windows; SPSS Inc., Chicago, IL, USA). All data were tested for a normal distribution. Data that were normally distributed were expressed as mean value ± standard deviation (X±SD). Repeated measures ANOVA was used to compare mean differences of serum lactate at T1, T2, T3, T4. Non-normally distributed data were expressed by median and interquartile range. Multivariate linear regression analysis was employed as the primary analysis to identify the relationship between serum lactate level or lactate clearance and influencing factors. The influencing factors includes presence of cirrhosis, mean CVP value during hepatectomy, the duration of all PTC, the frequency of ephedrine, the frequency of additional fluid infusion, blood transfusion requirement, the extent of liver resections, operation time, intraoperative blood loss and output. Selection of variables was based on literature and physiologically and clinically valid model of the phenomenon being studied. A subgroup analysis was performed. All the patients were divided into two subgroups according to portal triad clamping or not. The independent sample t test was used to compare data between two subgroups. A value of P< 0.05 was considered statistically significant.
1. Demographic data
There were 90 males and 20 females, a total of 110 patients, with an age range of 26 - 70 years enrolled in this study. No patient dropped out, thus data from 110 patients was available for analysis. The patients were selected for elective partial hepatectomy by open procedure due to primary liver carcinoma (n = 50) or liver metastases following colorectal cancer (n = 60) in our hospital. Demographic data are shown in table 1. Thirty-two patients with hepatitis B virus (HBV) and 2 patients with hepatitis C virus (HCV) related chronic hepatitis presented liver cirrhosis. Three patients with HBV infection related chronic hepatitis did not present liver cirrhosis. Drug induced liver cirrhosis was found in 1 patient. Alcohol abuse induced liver cirrhosis was found in 2 patients. Liver cirrhosis was determined by pathology diagnosis.
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2. Clinical details
Intraoperative events and anesthesia details are presented in Table 2. There were 86 patients treated with PTC and 24 patients without PTC. The longest total PTC duration was 76 mins and the shortest was 4 mins. The operation time ranged from 51 mins to 464 mins. The maximum and minimum intraoperative blood loss was 1200 ml and 50 ml respectively. Fifty-three patients didn’t require ephedrine, and the most frequent administration of ephedrine was 5 times. The mean value of CVP during hepatectomy ranged from 1 to 9 mm Hg.
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3. In all 110 patients, the highest level of serum lactate was observed at T3. As shown in figure 1. The result of repeated measures ANOVA showed that serum lactate differed significantly (F = 108.233, P< 0.001) at T1, T2, T3, and T4.
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