key: cord-0046429-o0yxnzzv authors: Ni, Chenlu; Masters, Joe; Zhu, Ling; Yu, Weifeng; Jiao, Yingfu; Yang, Yuting; Cui, Cui; Yin, Suqing; Yang, Liqun; Qi, Bo; Ma, Daqing title: Study design of the DAS-OLT trial: a randomized controlled trial to evaluate the impact of dexmedetomidine on early allograft dysfunction following liver transplantation date: 2020-06-26 journal: Trials DOI: 10.1186/s13063-020-04497-7 sha: cbc9adce1b5b5890b240d20147692d0ba208f093 doc_id: 46429 cord_uid: o0yxnzzv BACKGROUND: Perioperative ischemia/reperfusion (I/R) injury during liver transplantation is strongly associated with early allograft dysfunction (EAD), graft loss, and mortality. Hepatic I/R injury also causes remote damage to other organs including the renal and pulmonary systems. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist which is used as an adjuvant to general anesthesia, has been shown in preclinical studies to provide organ protection by ameliorating the effects of I/R injury in a range of tissues (including the liver). However, prospective clinical evidence of any potential benefits in improving outcomes in liver transplantation is lacking. This study aimed to verify the hypothesis that the application of dexmedetomidine during the perioperative period of liver transplantation can reduce the incidence of EAD and primary graft non-function (PNF). At the same time, the effects of dexmedetomidine application on perioperative renal function and lung function were studied. METHODS: This is a prospective, single-center, randomized, parallel-group study. Two hundred participants (18–65 years) scheduled to undergo liver transplantation under general anesthesia will be included in this study. For participants in the treatment group, a loading dose of DEX will be given after induction of anesthesia (1 μg/kg over 10 min) followed by a continuous infusion (0.5 μg/kg /h) until the end of surgery. For participants in the placebo group, an equal volume loading dose of 0.9% saline will be given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. All other supplements, e.g., opioids, sedatives, and muscle relaxant, will be identical in both arms and administered according to routine clinical practice. DISCUSSION: The present trial will examine whether DEX confers organoprotective effects in the liver, in terms of reducing the incidence of EAD and PNF in orthotopic liver transplantation recipients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03770130. Registered on 10 December 2018. https://clinicaltrials.gov/ct2/show/NCT03770130 Hepatic failure is associated with considerable morbidity and mortality. Decompensated cirrhosis with the development of ascites has a 2-year survival rate of only around 50% [1] . Cirrhosis affected an estimated 2.8 million people worldwide and resulted in 1.8 million deaths in 2015 [2, 3] . Hepatic failure also has multiorgan implications with detrimental effects on cardiovascular, pulmonary, renal, and neurological systems. Liver transplantation (LT), being the most effective treatment for patients with end-stage liver disease, confers a significant survival benefit (85-95% 1-year survival in many centers; 70-80% alive at 5 years) [4, 5] . Due to a widespread shortage of donor organs, there has been an increase in the acceptance of organs of marginal quality that are particularly prone to perioperative injury and are at increased risk of early postoperative dysfunction and failure [6, 7] . There is therefore significant interest in the development of new strategies to prevent liver graft dysfunction and early graft loss. Primary nonfunction (PNF) occurs in up to 7% of grafts and requires urgent retransplantation [4] . Initial dysfunction of the liver graft (EAD or PNF) in the immediate postoperative period is indicative of hepatocellular damage and synthetic impairment and is strongly predictive of poor graft and patient survival [8] [9] [10] [11] . As such, EAD serves as an important surrogate end point in LT clinical trials. The incidence of EAD is approximately 25% in most large studies, although reports range from 9.3 to 43.7% [4, 9, 12, 13] . EAD is multifactorial; among other factors, donor and recipient characteristics play a role. Currently, no treatment to prevent EAD is available. Anesthesia for LT has evolved significantly since the first transplants in the 1960s, with increasing recognition that the anesthetist plays a key role in influencing outcomes (such as graft function and survival) by optimizing parameters such as the patient's hemodynamic status, coagulation profile, and volume status. In addition to this, it has been postulated that the type of anesthetic drugs administered in the perioperative period may also affect outcomes [14, 15] . Hepatic ischemia/reperfusion (I/R) injury is a recognized complication of LT and is strongly linked to EAD, PNF, longer hospital stays, and lower long-term graft survival [14] . Therefore, strategies to attenuate I/R injury may improve graft function and survival. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist, is a useful adjuvant to general anesthesia which has sedative, anxiolytic, analgesic, and hypotensive properties. In vitro and in vivo preclinical studies have widely demonstrated that DEX provides organ protection in kidney, lung, brain, heart, and liver tissues by ameliorating I/R injury, inhibiting pro-inflammatory signaling pathways, and decreasing cell death [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] . Regarding hepatic protection, both Chen et al. and Wang et al. have demonstrated that DEX treatment protects against liver I/R injury in rodents. Inhibition of the toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway has been implicated as one of the mechanisms underlying these protective effects [26, 27] . In the clinical setting, a randomized controlled trial by Wang et al. of 44 patients undergoing hepatectomy found that intraoperative treatment with DEX (loading dose of 1 μg/kg over 10 min followed by a maintenance dose of 0.3 μg/kg/h) resulted in lower serum AST and ALT levels in the first 72 h postoperatively. However, the trial only looked at these biomarkers of hepatocellular damage and did not study patient outcomes [28] . Likewise, a study by Fayed et al. of 40 patients undergoing live donor LT showed that intraoperative infusion of DEX (0.8 μg/kg/h) improved postoperative liver function tests (on days 1, 3, and 5) and showed improved histopathological changes in liver tissue taken by biopsy at the end of surgery compared to controls. Again the authors did not look at long-term graft function or survival, and it is unclear whether these initial biochemical and histological benefits were associated with an improved clinical picture and better patient prognosis [29] . Considering the strength of these preclinical data demonstrating the organoprotective effects of DEX, urgent randomized clinical trials are needed to evaluate its potentially beneficial impact in LT. This study aimed to verify the hypothesis that the application of dexmedetomidine during the perioperative period of liver transplantation can reduce the incidence of EAD and primary graft non-function (PNF). At the same time, the effects of dexmedetomidine application on perioperative renal function and lung function were studied. Acute kidney injury (AKI) occurs in 12-94% of patients undergoing LT (depending on the definition of AKI used) and is associated with increased morbidity and mortality [30, 31] . The etiology is multifactorial and is likely to involve renal I/R injury following renal hypoperfusion as a result of perioperative hypotension, intestinal endotoxemia induced by inferior vena cava (IVC) occlusion during surgery, and remote kidney damage induced by hepatic I/R injury [32, 33] . EAD has been shown to be an independent risk factor for AKI [34] . Perioperative interventions to reduce incidence are currently limited to supportive therapies and include volume expansion and vasopressors to optimize renal perfusion. Early renal replacement therapy is indicated if these measures fail with 4.5-21% of LT patients requiring support [31] . Other pharmacological interventions such as dopamine, mannitol, and diuretics have not been shown to have any benefit. Preclinical studies have widely reported the renoprotective effects of DEX following renal ischemia-reperfusion [18, [35] [36] [37] [38] . In the context of LT, both Yu et al. and Yao et al. have demonstrated that pre-treatment with DEX reduces AKI following orthotopic autologous LT in rats by suppressing TLR4/NF-κB pathway activation [22] and by enhancing antioxidant levels through activation of nuclear factor erythroid 2-related factor 2 [23] . Acute respiratory distress syndrome (ARDS) is a common complication following LT with an incidence up to 42% [39] . ARDS is one of the major causes of death following LT. Hepatic I/R injury, and the subsequent systemic release of inflammatory mediators has again been implicated in the etiology of postoperative pulmonary injury [40] . A number of studies have demonstrated that DEX has cytoprotective effects in the lungs: Cui et al. have shown that DEX protects against bilirubin-induced lung alveolar epithelial cell death in vitro and in vivo [20] . Gu et al. reported that DEX attenuates remote lung injury induced by renal I/R injury in mice [24] . And, most relevant to this study, Chi et al. have shown that DEX ameliorates lung injury following orthotopic autologous LT in rats by inhibiting the TLR4/NF-κB pathway [25] . Given these preclinical findings, it is important that the impact of DEX on postoperative renal and pulmonary function in patients undergoing LT be studied in clinical trials. DSA-OLT is a single-center, randomized, double-blind, placebo-controlled, parallel-group study. We plan to enroll 200 adult participants scheduled for liver transplantation surgery to evaluate the impact of dexmedetomidine on allograft function and survival following cadaveric liver transplantation. This trial is registered at www.clinicalTrials.gov with a registration number of NCT03770130. The primary endpoint is the incidence of EAD following surgery. Participants will be considered for inclusion if they meet the following criteria: 1). Age ≥ 18 years and < 65 2). Scheduled to undergo allogenic liver transplant surgery under general anesthesia 3). Participants should meet the UCSF criteria [41] (single tumor diameter ≤ 6.5 cm; multiple tumors ≤ 3, maximum diameter ≤ 4.5 cm; cumulative diameter ≤ 8 cm; without large vessel infiltration and extrahepatic metastasis) 4). Agree to participate and give written informed consent Exclusion criteria 1). Severe renal dysfunction (undergoing renal replacement therapy before surgery) 2). Severe pulmonary dysfunction (severe pre-existing chronic lung disease) 3). Severe circulatory instability (severe coronary artery disease, unstable angina, left ventricular ejection fraction < 30%, sick sinus syndrome, severe sinus bradycardia [< 50 bpm], second-degree or greater atrioventricular block) 4). Known allergy or intolerance to trial medication 5). Participation in other clinical trials within 30 days prior to randomization 6). Retransplantation 7). Multiple organ transplantation 8). Other reasons that are considered unsuitable for study participation by the responsible surgeon or anesthetist (reasons must be documented in the case report form [CRF]) Drop out criteria 1). Withdrawal of consent by the participants or their legal representative 2). Loss to follow-up For drop out cases, the detailed reason will be recorded and the primary therapeutic effects last recorded will be regarded as the final results. The CRFs of these cases will be preserved for future reference. Enrolled cases who meet any of the following criteria will be excluded from per protocol analysis: 1). Anesthesia not performed according to the protocol 2). No study record For rejected cases, the detailed reasons will be documented. However, subsequent study procedure will be performed according to the protocol and the CRFs will be preserved for future reference. These cases will be included in the intention-to-treat analysis. The trial will be suspended if: 1) Serious safety issues occur during the study 2) Serious errors are found in the study protocol 3) Funding or management issues for the researchers occur 4) The study is canceled by executive Study termination may be short-lived or permanent. If the study is terminated early, a written report should be submitted to the Ethics Committee. All CRFs and recorded files should be kept for reference. The resumption of research will require the approval of an ethics committee. Incidence of EAD following surgery [42] . 4). Incidence of graft failure and retransplantation rate during 3-year follow-up period. 5). All-cause mortality in the 3-year follow-up period. Ethical approval is obtained from the ethics committee of Renji Hospital, Shanghai Jiaotong University School of Medicine (project number: 2018-022). The principal investigator will submit a research progress report to the Ethics Committee on a regular basis. For every potential participant, investigators should explain in detail the purpose, procedures, and potential benefits and risks of the study in a written informed manner. They must let every potential participant know that he/she has the right to withdraw his/her consent at any time during the study period. We will inform the participants about the study as soon as possible after receiving the operation notice, though every potential participant may do not have enough time for careful consideration. Every participant or the authorized surrogate of the participant must sign the consent before they can be enrolled in the study. Written informed consents will be kept as a part of the clinical trial documents. Personal information of all participants will be confidentially kept. All related documents will be locked up. For each participant, all data collected during the study period will be identified by a serial number and a name acronym in the CRF. Results of the study will be published in the form of publication(s) without personal information (including name, age, etc.). An independent statistician will generate a random sequence of 0 s and 1 s in a 1:1 fashion correspondent to numbers from 1 to 330. The results of allocation will be stored in the electronic system until the end of the study period. An independent pharmacist who will not participate in the rest of the study will be noticed and also receive the results of randomization to provide the trial drugs to the participating centers in sequentially numbered, sealed, identical boxes according to the allocation sequence. Participants who consent to enter the trial will be sequentially assigned to the random number based on the order of surgery time and receive either dexmedetomidine or placebo (normal saline). Postoperative follow-up will be performed by investigators who do not participate in participants' care and who have been trained prior to the study. Both anesthesiologist(s) and investigator(s) do not communicate while collecting and analyzing results. Study personnel, healthcare team members, and participants will be blinded to the treatment group allocation throughout the study period. No pre-anesthesia medication will be administered. Thoracic epidural anesthesia will not be sited before or after induction of anesthesia. Intraoperative monitoring will be instituted to include electrocardiogram (ECG), non-invasive and invasive blood pressure monitoring, pulse oximetry, central venous pressure, bispectral index (BIS), end-tidal gas analysis, nasopharyngeal temperature, and urine output. Thermodilution cardiac output monitoring (measured via a pulmonary artery catheter or PICCO system) or perioperative transesophageal echocardiography may be used when necessary. Anesthesia will be induced with midazolam (0.015-0.3 mg/kg), remifentanil/sufentanil/ fentanyl, propofol, and rocuronium/cisatracurium. For participants with predicted difficult airway, succinylcholine may be used for rapid sequence induction. Awake fiberscope intubation may be performed. Dexamethasone (4-8 mg) may be administered to prevent postoperative nausea and vomiting. Anesthesia will be maintained with sevoflurane inhalation, of which the concentration will be adjusted to maintain the BIS value between 40 and 60. Muscle relaxation will be maintained with rocuronium or cisatracurium. Analgesia will be maintained with remifentanil (administered via continuous infusion), sufentanil (administered via continuous infusion or intermittent injection), or fentanyl (administered via intermittent injection). In addition to this, participants will receive an initial loading dose of dexmedetomidine of 1 μg/kg over 10 min after the induction of anesthesia followed by a continuous infusion of 0.5 μg/kg/h until the end of surgery. Participants in the placebo arm receive a corresponding amount of saline instead of DEX. Mechanical ventilation will be performed with a tidal volume between 6 and 8 ml/kg, a positive end expiratory pressure of 5 cmH20, a plateau pressure of less than 30 cmH20, a frequency between 10 and 16 per minute, and a 1:1 air-oxygen mixture. Intraoperative fluid therapy will be managed according to routine practice. Packed red blood cells will be transfused to maintain hemoglobin levels within the range 7-10 g/L. Plasma, platelets, and anti-fibrinolytics will be used to manage coagulopathic states. Vasopressors/inotropes will be administered where necessary to maintain systolic blood pressure within 20% of baseline. Intravenous steroids will be administered before reperfusion of the new liver as per normal protocol. Towards the end of surgery, analgesia will be optimized with intravenous fentanyl/sufentanyl according to requirement. 5-HT3 antagonists may be administered for the prevention of postoperative nausea and vomiting. Sevoflurane inhalation concentration will be decreased or ceased, and muscle relaxation may not be antagonized with neostigmine or sugammadex. The treatment or control infusion will be stopped at the end of surgery. If the participant's condition warrants a delayed emergence from anesthesia, then anesthesia will be maintained and the participant will be transferred to the intensive care unit. Postoperative analgesia in the first 3 days will be provided with intravenous bolus administration of nonsteroidal antiinflammatory drugs (flurbiprofen or coxibs, etc.) in ICU. Intravenous opioids may also be administered in participants with severe pain. PCA technique will not be recommended in post-transplantation participants in our center. The day before surgery (or Friday for participants who will undergo surgery on the next Monday), investigators who have been trained for the study and are authorized by the principal investigator will screen potential participants according to the inclusion and exclusion criteria. Participants who meet the inclusion/exclusion criteria will be invited for study participation. Baseline data will be collected after obtaining written informed consent. . Duration of surgery, type of liver grafts (cadaveric or living), operating method 2). Duration of anesthesia and doses of anesthetic drugs given 3). Fluid balance during surgery, including estimated bleeding, type and volume of blood products transfused (document duration of storage before transfusion), and type and volume of fluid infusion 4). Variations of blood pressure and BIS during anesthesia/surgery 5). Duration of cold and warm ischemia times Data collection immediately after surgery Participants will be followed up twice daily during the first 7 days following surgery and then weekly until the 30th day after surgery (by telephone for those discharged from hospital). 3). Incidence of AKI during postoperative days 1-7. 4). Incidence of ARDS during postoperative days 1-7. 5). Medication (including sedatives, analgesics, anticholinergics, and glucocorticoids) used during postoperative days 1-7 will be recorded. 6). Length of stay in ICU and hospital after surgery. 7). All-cause 30-day mortality. Participants will be followed up (by telephone) at 3, 6, 12, 24, and 36 months after surgery. 1). Incidence of graft failure and retransplantation rates between 30 days and 36 months after the initial surgery 2). Status of survival. For participants who died after surgery, the date of death will be recorded. All participants will be followed up until the end of the 3rd year (36th month) after LT, or if they die within 3 years they will be followed up to death. The study design is illustrated in the flow chart in Fig. 1 , and the study schedule is presented in Fig. 2 . In the present study, the drug under investigation is commonly used during daily anesthetic practice at a similar dose. Therefore, our study is unlikely to produce additional risk to participants. However, adverse events may occur even during routine anesthesia. In such case, anesthesiologists will manage participants according to routine practice. During the present study, the occurrence of adverse events/severe adverse events will be monitored; any adverse events/severe adverse events will be managed, followed up, and documented. Adverse events These include anesthesia-related adverse event, general anesthesia-related adverse events, and perioperative analgesia-related adverse events. The occurrence of adverse events will be monitored from the beginning of anesthesia until 24 h after surgery. Any adverse events should be treated promptly according to routine practice and should be followed up until it has completely resolved. Any adverse event should be documented, including time of occurrence, diagnosis, time of diagnosis, management, duration, sequelae, and severity. The severity of adverse events can be classified into the following 3 classes: Mild: signs and symptoms are mild and transient, do not affect daily activity, do not need treatment, and usually recover after rest. Moderate: signs and symptoms last longer, mildly affect daily activity, and recover after simple treatment. Severe: signs and symptoms last even longer, significantly affect daily activity and life, and do not recover after simple treatment. Any severe adverse events should be treated immediately according to routine practice and must be followed up until it is completely resolved or when therapy is ended. Any severe adverse event should be documented, including time of occurrence, diagnosis, time of diagnosis, management, duration of persistence, and sequelae. In case of any severe adverse event, apart from active treatment and documentation as above, the principal investigator and the Ethics Committee will be informed within 24 h in written report. In case of study drug-related death, immediately stop the clinical trial, report the event to the Ethics Committee as soon as possible, record in detail, and carefully preserve the related documents. Restart of the study will be decided by the Ethics Committee. In an emergency (e.g., rapid, unexpected deterioration in the participant's clinical status), the anesthesiologist can request unmasking of the treatment allocation, or adjust or interrupt the study drug infusion if necessary. Likewise, the team leading postoperative care can request unmasking of treatment allocation in the interests of participant care. The detailed reasons for such events will be documented. These cases will be included in the intention-to-treat analysis. Fig. 1 Flow chart of the trial. The present study is a randomized controlled Anesthesiology trial. Three hundred thirty LT participants will be included and randomized equally to two groups. After surgery, each participant will be followed up. Whether DEX can reduce the incidence of early postoperative EAD and PNF and even improve the postoperative survival and outcome of orthotopic liver transplantation recipients will be analyzed after data collection When it is necessary to unmask, the biostatistician who generated the allocation list can be connected at any time and can open the electronic system to unmask. All analyses will be conducted based on intention-totreat principle. Statistical analysis includes analysis of numeric variables, categorical variables, and time-toevent variables. Numeric variables including postoperative laboratory results will be presented as mean (standard deviation) or median (minimum, maximum; or interquartile range). Categorical variables including the incidence of EAD, PNF, AKI, and ARDS after LT will be presented as number of cases (percentage). Difference of numeric variables between groups will be analyzed using independent sample t test, and that of categorical variables will be analyzed using chi-square test. Cox proportional hazard regression will be used to estimate average effect sizes for each treatment. Results are reported as hazard ratios and 95% confidence intervals. Two-tailed tests will be used in all statistical analysis, and p values of less than 0.05 will be considered to be of statistical significance. The sample size was calculated from the assumption that the incidence of EAD is 35% [43] and 20% of the DEX group were expected to develop EAD. One hundred thirty-six participants in each group are required to have an 80% power at the two-sided 0.05 significance level. With an anticipated 20% dropout rate, we concluded that a total of 165 participants for each group are required. After calculation, the effect size is 0.31, which is also in line with the general recommendations to detect a medium effect size. Paper Case Report Form (CRF) will be used to record all data during the study. Investigators should promptly, completely, and accurately record data in the CRFs according to original observation. Supervisor(s)/study coordinator(s) will monitor the conduct of the study. The completed CRFs, after having been signed by the supervisor, will be sent to Renji Clinical Research Institute who are responsible for data entry and management. Data entry will be performed two times by two persons using the EpiData3.10 database system. A data manager will perform database check out using the SAS9.2 software. Data queries will be answered by investigators. After data entry and database check out are completed and all problems encountered during the procedure solved, the database will be locked. The decision to lock database will be made by the principal investigator, the database manager, and a statistician who is responsible for statistical analysis. The informed consent and examination will be conducted after recruitment. Then, participants will be randomized into two groups. Adverse events will be recorded in the case report form at any time during the study. Postoperative graft evaluation includes EAD, PNF, AKI, and ARDS Training programs will be organized for all investigators before the study. A study coordinator who is assigned by the principal investigator will be responsible to conduct the training programs and to keep the records of the training programs. Prior to the study, the investigators involved in the study will also need to complete training in the following items: the study protocol, the related standard operating procedure, and the working plan of the study; the instruction and contents of the CRF; and the considerations during conduct of the study (such as recording of adverse events and complications, etc.). Trial-related training will be provided throughout the whole period of the study. The principal investigator and the study coordinator will organize new training program according to the progress of the study, such as training programs for new investigators, revised study protocol, or other reasons. Supervisor(s)/study coordinator(s) will monitor the conduct of the study. The trial protocol must be strictly adhered throughout the trial period. All expected and unexpected findings will be documented promptly and accurately in order to guarantee the reliability of the values. An independent auditor at the Renji Hospital Clinical Research Institute will conduct an audit of the study. The DAS-OLT trial is a long-term single-center interventional study of 330 participants aged between 18 and 65 years old undergoing liver transplantation. This study will provide characterization of this surgical population and depict whether DEX reduce the incidence of EAD on allograft cadaveric liver transplantation. Findings from this study will no doubt provide important information for anesthesia management in adult LT surgeries. This study is special because, firstly, being one of the largest liver transplant centers in the world, our center has a mature surgical and anesthetic team that will decrease heterogeneity of medical care that participants receive. Secondly, the long time frame will help better evaluate the influence of DEX, especially on participants' long-term survival and graft survival. However, our study may face a number of difficulties. Because of the nature of donor liver transplantation, liver transplantation is often performed in an emergency. Therefore, the anesthesiologist performing the anesthesia is not known in advance. Knowing the infeasibility of pre-assigning an anesthesiologist for all participants, and in an effort to reduce the differences of anesthesia administration given by different anesthesiologists, we will assign 3 anesthesiologists for each included participant, and anesthesia will be conducted by anyone of them. In addition, since most of the participants are non-natives to our center, they are more likely to be followed up in their local hospitals, which may cause great difficulties to our followup survey. Designated staff will be responsible for giving phone calls to these participants and acquiring follow-up data. Lastly, the single-center nature impacts on the generalizability of this trial's conclusions. A great percentage of participants undergoing LT in our institution suffer from hepatitis B infection or hepatocellular cancer, which is quite different from the scenario in other regions. In the USA, the most common indications for liver transplantation are hepatitis C virus (30%) and alcoholic liver disease (18%) [44] . The strengths of this study are as follows: first, this is a parallel-group, randomized, controlled trial which will be used for the first time to provide clinical evidence for the potential benefit of dexmedetomidine in improving outcomes of liver transplantation. Second, all laboratory tests will be performed at specific time (1, 3, 7, 14, 30 days after surgery), and the incidence of EAD, PNF, AKI, and ARDS will be determined accordingly. Third, this study will be followed up for 3 years after surgery and is long enough to observe the function of the new liver. The trial is currently in the participant recruitment stage. With reference to the amount of surgery last year, the number of operations for adult liver transplantation in 2018 is more than 300, of which more than 90% met the conditions of this trial. The trial began recruitment on 14 January 2019 and is expected to complete the recruitment on 30 June 2020. Protocol version number: DAS-OLT 3.0. Date: 31 October 2018. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study Global, regional, and national life expectancy, all-cause mortality, and causespecific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR) Liver transplantation in Australia and New Zealand The utility of marginal donors in liver transplantation Safely expanding the donor pool: brain dead donors with history of temporary cardiac arrest Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors Should a lower quality organ go to the least sick patient? Model for endstage liver disease score and donor risk index as predictors of early allograft dysfunction Effect of early allograft dysfunction on outcomes following liver transplantation Primary graft dysfunction after liver transplantation Early allograft dysfunction after liver transplantation: an intermediate outcome measure for targeted improvements A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial Precondition effects of dexmedetomidine on myocardial ischemia/reperfusion injury in rats Effect of dexmedetomidine on ischemia-reperfusion injury in rat kidney: a histopathologic study Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-kappaB pathway Dexmedetomidine attenuates bilirubin-induced lung alveolar epithelial cell death in vitro and in vivo Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon Dexmedetomidine inhibits TLR4/NF-kappaB activation and reduces acute kidney injury after orthotopic autologous liver transplantation in rats Dexmedetomidine pretreatment attenuates kidney injury and oxidative stress during orthotopic autologous liver transplantation in rats Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice Dexmedetomidine ameliorates acute lung injury following orthotopic autologous liver transplantation in rats probably by inhibiting Toll-like receptor 4-nuclear factor kappa B signaling Dexmedetomidine protects rat liver against ischemia-reperfusion injury partly by the alpha2A-adrenoceptor subtype and the mechanism is associated with the TLR4/NF-kappaB pathway Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice Dexmedetomidine reduces intestinal and hepatic injury after hepatectomy with inflow occlusion under general anaesthesia: a randomized controlled trial Effect of dexmedetomidine on hepatic ischemia-reperfusion injury in the setting of adult living donor liver transplantation Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes Hepatic ischemia/reperfusion injury associates with acute kidney injury in liver transplantation: prospective cohort study Acute kidney injury after hepatic ischemia and reperfusion injury in mice Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation after brain death liver transplantation Early allograft dysfunction after liver transplantation is associated with short-and long-term kidney function impairment Dexmedetomidine preconditioning inhibits the long term inflammation induced by renal ischemia/reperfusion injury in rats Protective effects of dexmedetomidine and remote ischemic preconditioning on renal ischemia reperfusion injury in rats Dexmedetomidine protects against cisplatin-induced acute kidney injury in mice through regulating apoptosis and inflammation Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the P38-MAPK/TXNIP signaling activation in streptozotocin induced diabetic rats Early respiratory complications after liver transplantation Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group, KDIGO clinical practice guidelines for acute kidney injury Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival Acute respiratory distress syndrome: the Berlin Definition Primary graft dysfunction of the liver: definitions, diagnostic criteria and risk factors. Einstein (Sao Paulo, Brazil) Not applicable. Everyone that has significantly contributed to this work has been listed as co-author. All authors have participated in the conceptualization of the study and design. JM designed the main part of the trial. LY and DM are the leaders of the trial. CN, BQ, WY, YY, CC, and LY are the executor of the trial. CN, LZ, and SY are going to follow up each case. YJ is responsible for database creation. All participants were involved in the development of the trial. The decisions regarding scientific issues were made within the committees, brought to discussion in the scientific committee, and submitted to a vote from all PI. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.