Study settings
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.
Study population
Inclusion criteria
Participants will be considered for inclusion if they meet the following criteria:
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1).
Age ≥ 18 years and < 65
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2).
Scheduled to undergo allogenic liver transplant surgery under general anesthesia
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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)
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4).
Agree to participate and give written informed consent
Exclusion criteria
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1).
Severe renal dysfunction (undergoing renal replacement therapy before surgery)
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2).
Severe pulmonary dysfunction (severe pre-existing chronic lung disease)
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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)
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4).
Known allergy or intolerance to trial medication
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5).
Participation in other clinical trials within 30 days prior to randomization
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6).
Retransplantation
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7).
Multiple organ transplantation
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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
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1).
Withdrawal of consent by the participants or their legal representative
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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.
Rejection criteria
Enrolled cases who meet any of the following criteria will be excluded from per protocol analysis:
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1).
Anesthesia not performed according to the protocol
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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.
Termination criteria
The trial will be suspended if:
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1)
Serious safety issues occur during the study
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2)
Serious errors are found in the study protocol
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3)
Funding or management issues for the researchers occur
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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.
Purposes of the study
Primary outcomes
Incidence of EAD following surgery
Secondary outcomes
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1).
Incidence of PNF
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Defined as graft loss, retransplantation, or participant death due to graft non-function in first 30 days (excluding non-function secondary to hepatic artery thrombosis, biliary complications, or recurrent hepatic disease)
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2).
Incidence of postoperative AKI during postoperative days 1–7
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3).
Incidence of ARDS during postoperative days 1–7
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4).
Incidence of graft failure and retransplantation rate during 3-year follow-up period.
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5).
All-cause mortality in the 3-year follow-up period.
Ethics issues
Ethics committee
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.
Written informed consent
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.
Privacy protection
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.).
Randomization and blinding
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.
Description of study treatment
Premedication
No pre-anesthesia medication will be administered. Thoracic epidural anesthesia will not be sited before or after induction of anesthesia.
Intraoperative monitoring
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.
Induction of anesthesia
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.
Maintenance of anesthesia
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1).
Dexmedetomidine treatment group
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.
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2).
Control group
Participants in the placebo arm receive a corresponding amount of saline instead of DEX.
Intraoperative management
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.
Emergence from anesthesia
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
Postoperative analgesia in the first 3 days will be provided with intravenous bolus administration of non-steroidal 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.
Study procedure and data collection
Participant screening
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.
Data collection before surgery
Baseline data will be collected after obtaining written informed consent.
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1).
Demographic data: gender, date of birth, height, weight, and body mass index (BMI)
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2).
Medical data: diagnosis (reason for LT), comorbidities, concomitant medication, non-drug therapies, history of smoking and drinking, history of food or drug allergy, and history of anesthesia and surgery
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3).
Results of physical examinations
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4).
Baseline laboratory investigations (to calculate model for end-stage liver disease [MELD] score)
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5).
Donor characteristics: age, height, weight, BMI, cause of death, and virology status
Data collection during surgery
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1).
Duration of surgery, type of liver grafts (cadaveric or living), operating method
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2).
Duration of anesthesia and doses of anesthetic drugs given
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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
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4).
Variations of blood pressure and BIS during anesthesia/surgery
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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).
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1).
Incidence of EAD.
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2).
Incidence of PNF.
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3).
Incidence of AKI during postoperative days 1–7.
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4).
Incidence of ARDS during postoperative days 1–7.
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5).
Medication (including sedatives, analgesics, anticholinergics, and glucocorticoids) used during postoperative days 1–7 will be recorded.
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6).
Length of stay in ICU and hospital after surgery.
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7).
All-cause 30-day mortality.
Long-term data collection
Participants will be followed up (by telephone) at 3, 6, 12, 24, and 36 months after surgery.
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1).
Incidence of graft failure and retransplantation rates between 30 days and 36 months after the initial surgery
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2).
Status of survival. For participants who died after surgery, the date of death will be recorded.
End of follow-up
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.
Safety considerations
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
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1).
Possible adverse events during the study
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.
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2).
Management and documentation of adverse effects
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:
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Mild: signs and symptoms are mild and transient, do not affect daily activity, do not need treatment, and usually recover after rest.
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Moderate: signs and symptoms last longer, mildly affect daily activity, and recover after simple treatment.
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Severe: signs and symptoms last even longer, significantly affect daily activity and life, and do not recover after simple treatment.
Severe adverse events
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.
Emergency unmasking
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.
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.
Statistics and data management
Statistical analysis
All analyses will be conducted based on intention-to-treat principle. Statistical analysis includes analysis of numeric variables, categorical variables, and time-to-event 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.
Sample size calculation
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.
Data management
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.
Quality control
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.