This study is designed as a multicenter, randomized, controlled, double-blind trial. Five clinical research centers in China will participate: West China Hospital of Sichuan University, First Affiliated Hospital of the University of South China, Second Affiliated Hospital of Nanjing Medical University, First Affiliated Hospital of Wannan Medical University, First Affiliated Hospital of the University of South China, and the Second Xiangya Hospital of Central South University.
A total of 500 participants with type A aortic dissection will be randomly assigned by computer to either the MHCA (control) group or RIVP group (n = 250 in each). Patients assigned to the control group will receive selective ACP alone under moderate hypothermia, while patients in RIVP group will receive selective ACP combined with RIVP under moderate hypothermia. Details of the trial have been published elsewhere[endnoteRef:33]. Patients will be monitored during a follow-up of one year to determine outcomes of surgical treatment. All patients will be admitted to a cardiovascular ICU after surgery, where they will remain until they are considered stable enough to transfer back to a general unit. Patient enrollment is expected to start on January 2019 and to be completed within 2 years thereafter. The following members of the study will be blinded to patients' group allocation: patients themselves, investigators, outcome assessors, the data manager, and the statistician. [33: Lin J, Xiong J, Luo M,Tan Z, Wu Z, Guo Y, Du L. Combining cerebral perfusion with retrograde inferior vena caval perfusion for aortic arch surgery. Ann Thorac Surg. 2018 Oct 4. pii: S0003-4975(18)31356-0. [Epub ahead of print].]
All perfusionists and surgeons in the trial will be experienced in performing necessary procedures. Interventions will be carried out during surgery, and follow-up visits will continue for one year afterwards. In addition, patients' medical records will be reviewed for in-hospital complications and medication usage.
This protocol was designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines for interventional trials[endnoteRef:34]. The SPIRIT Checklist is shown in Additional file 1, and the SPIRIT Figure is shown in Figure 1. Participating centers will be required to sign a collaboration contract that lays out the responsibilities, intellectual property ownership, and publication processes. The funding for this trial covers only organizational costs and meetings; there is no third-party funding support for this trial. Changes to the protocol will be submitted to our ethics committee with a detailed description of the changes before going forward. All on-going severe adverse events (SAEs) will be followed up and documented until final outcomes are determined. [34: Chan AW, Tetzlaff JM, Gøtzsche PC, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586. ]
Ethics and registration
The protocol of this study follows guidelines set by the Declaration of Helsinki and is in accordance with the Medical Research Involving Human Subjects Act (WMO) as well as Good Clinical Practice guidelines[endnoteRef:35].Central ethical approval has been confirmed from the Biomedical Ethics Committee of West China Hospital (ref approval no. 201824) and we will not begin recruiting at other centers in the trial until local ethical approval has been obtained. This trial has been registered at the Clinical Trial Registry (NCT.03607786). All results will be presented with the CONSORT (Consolidated Standards of Reporting Trials) statement (Figure 2). [35: Guideline For Good Clinical Practice E6 (R1). Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 1996]
Recruitment of study population
The target study population is all patients aged 18 years or older diagnosed with AAAD and scheduled for elective or emergency TARS under CPB between January 1, 2019 and December 31, 2020. Participants will be recruited from the cardiovascular wards or ICU based on their presence on surgical lists. Eligibility will be assessed by surgeon fellows in the same hospital using thoracoabdominal enhanced computed tomography. Informed consent to participate will be obtained after a researcher has clearly explained to patients the trial and potential risks associated with RIVP. Those who meet the selection criteria and give consent will provide demographic and general medical data as described below in the section "Baseline study visit".
Patients will be excluded from the study if they are unable to understand or give informed consent, if they are pregnant, or if they are already participating in another clinical trial that might interfere with the primary or secondary outcomes of the present trial. Patients will be withdrawn from the study if they are converted to another non-TARS procedure with no requirement for circulatory arrest, or if they or their agents/guardians revoke consent. Patients who withdraw from the study will not be replaced. Withdrawals will be documented in the electronic case report form (eCRF). The investigator can decide to withdraw a participant from the study for urgent medical reasons.
Data collection and management
All data will be recorded on a paper-based case report form (CRF). After in-hospital data are recorded, a trained assessor will enter the clinical data from the paper CRF into a web-based database. All participating centers, as well as the principal investigator, will have 24-hour access to the eCRFs. If data are entered incompletely or incorrectly, the principal investigator can contact the participating centers for further clarification. All outcome parameters will be recorded by a member of the trial team at each center at the time of enrolment and throughout the follow-up period. All trial data will be stored on a secure server at the data coordinating center, kept secure and confidential, and retained for 15 years after completion of the study (defined as 365 days after follow-up of the last patient) and will be anonymized if requested by the authorities. Parameters critical to the primary aim of this trial will be monitored remotely.
Baseline study visit
As part of the baseline visit, we will collect patient information including age, height, weight, European System for Cardiac Operative Risk Evaluation (EuroSCORE II)[endnoteRef:36], smoking and drinking status, diabetes mellitus, peripheral arterial disease, lipid profile, pulmonary and cardio-cerebral co-morbidity, and pulmonary infection during the preceding 30 days. Preoperative hematology and biochemistry assessments will also be performed, including full blood count, electrolytes, liver and renal function tests, coagulation profile, thyroid function tests, and C-reactive protein. Enhanced thoracic and abdominal computed tomography and transthoracic echocardiography will be performed to confirm the preoperative diagnosis, measure left ventricular function, and detect valvular disease or other pathologies that meet the exclusion criteria. Additional clinical and study data collected at baseline, as well as at other study time points, are shown in Figure 1. [36: Nashef SA1, Roques F, Sharples LD,et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44.]
Randomization and blinding
Patients will be randomly assigned to a group after anesthesia by an independent statistician uninvolved in the trial using a computer-generated randomization list. An equal number of patients will be allocated to the control and RIVP groups at each center. The outcome of randomization will be displayed on a website accessible only to the independent statistician and the perfusionist. The allocation will be sealed in opaque envelopes prepared by an authorized trial coordinator at the coordinating center and distributed to the participating sites as needed. In cases when exclusion criteria are met after randomization (e.g. if total arch replacement is not performed), the patient will be withdrawn from the trial but will retain his or her identification code (randomization number).
Since the treatment allocation involves a surgical procedure, the surgeon, perfusionist and anesthesiologist will not be blinded to patient allocation. Physicians interacting with patients outside the operating room will be blinded to treatment allocation. The details of the randomization will be kept confidential until completion of data analysis.
Experimental intervention protocol
The CPB circuit will be set up according to a protocol described in our previous study33. Briefly, the circuit consists of a membrane oxygenator, a heat exchanger, and two rolling pumps, which can bifurcate the arterial line for both artery perfusion and inferior vena caval perfusion as necessary. For patients in the RIVP group, moderate hypothermia (defined as a nasopharyngeal temperature of 26-28 °C and rectal temperature of 28-30 °C) will be induced under CPB, then systemic perfusion will be stopped and the aorta opened. ACP and RIVP will then be performed using the two rolling pumps. ACP will be performed with a starting pump flow rate of 6-12 mL/min/kg, which will be adjusted to maintain a mean arterial pressure of 40–60 mmHg. RIVP will be performed at a flow rate of 5-12 mL/min/kg and perfusion pressure below 25 mmHg. Ascites can occur when capillary pressures are above this perfusion pressure cut-off 30. Systemic perfusion will be restored after the aortic graft is sutured to the proximal end of the descending thoracic aorta. All patients in the study will undergo transesophageal echocardiography before and after bypass to observe blood flow in the liver and kidney during RIVP.
Patients in the control group will be perfused according to previously published methods[endnoteRef:37],[endnoteRef:38]. Briefly, the patient will be cooled slowly to induce moderate hypothermia (defined as a nasopharyngeal temperature of 24-26 °C and a rectal temperature of 26-28 °C) under CPB, after which ACP will be performed using the same perfusion pressure and flow as described above. RIVP will not be performed. [37: Vallabhajosyula P, Jassar AS, Menon RS, Komlo C, Gutsche J, Desai ND, Hargrove WC, Bavaria JE, Szeto WY. Moderate Versus Deep Hypothermic Circulatory Arrest for Elective Aortic Transverse Hemiarch Reconstruction. Ann Thorac Surg.2 015; 99(5): 1511-7.] [38: Leshnower BG, Kilgo PD, Chen EP.Total arch replacement using moderate hypothermic circulatory arrest and unilateral selective antegrade cerebral perfusion. J Thorac Cardiovasc Surg. 2014;147(5):1488-92.]
The primary outcome will be combined early mortality and major complications, including paraplegia, postoperative renal failure, severe liver dysfunction, postoperative prolonged intubation (>48 h), and gastrointestinal complications. Prolonged intubation will be defined as a requirement of intubation lasting more than 48 h. Other complications will be defined according to the Society of Thoracic Surgery (https://www.sts.org/). The primary outcome will be measured throughout hospitalization (regardless of length of stay) and for up to 30 days after surgery if the patient is discharged. Early mortality will be defined as any death that occurred in the same hospital in which the surgery was performed.
Secondary outcomes will include the proportion of patients with a stroke/cerebrovascular incident, paraparesis, temporary neurologic deficit, myocardial infarction, acute kidney injury not requiring dialysis, surgical re-exploration for bleeding, and deep sternal wound infection. Tertiary outcomes include the length of ICU stay, length of hospital stay, length of endotracheal intubation, volume of perioperative blood product transfusions, as well as total hospitalization cost. The proportion of patients who develop postoperative ascites will serve as a measure of safety in this trial.
Monitoring of adverse and clinical events
Intraoperative data will include variables linked to the arterial cannulation site for cerebral perfusion (cephobranchial, internal carotid, axillary, or subcalvian artery), duration of HCA, CPB time, warming and cooling time, cross-clamp time, surgery time, temperature at the initiation of hypothermic circulatory arrest, concomitant procedures and application of cross clamp to the dissected aorta before initiation of hypothermic circulatory arrest, number of units of packed red blood cells, fresh-frozen plasma, pooled platelets and cryoprecipitate administered perioperatively, the highest lactate value during CPB, and the highest flow and pressure of RIVP.
Patients will be monitored on a daily basis for 7 days after surgery to collect data on temperature, partial pressure of oxygen (PaO2), inspiration O2 (FiO2), ventilation mode, hemoglobin and leukocyte count, and volume of chest drainage. Symptomatic cardiorespiratory complications and other secondary outcome measures (see above) will also be recorded during routine diagnostic tests. These parameters and the timing of notable events will be tracked until hospital discharge.
Patients will be instructed to visit the hospital at 30 days, 3 months, 6 months, and 12 months following discharge for postoperative data collection. If a face-to-face appointment is not possible, follow-up will be completed over the phone. During each visit, patient characteristics including mortality, cardiovascular and cerebrovascular events, postoperative renal and liver function, and gastrointestinal complications will be recorded on the CRF. In addition, radiology and electrocardiography will be performed at each visit, uploaded to the database and evaluated by outcome assessors blinded to patient allocation.
Pre- and postoperative data will be recorded by a member of the research team at each participating center who is blinded to randomization status and who is not part of the surgical team that performed the intervention. Intraoperative data will be collected by the study perfusionists and anesthesiologists.
Safety and monitoring
An independent data and safety monitoring board organized by cardiovascular surgeons, anesthesiologists and statisticians will oversee the progress and safety of the study, including adverse events and morbidity. All adverse events will be evaluated for severity. Any SAEs will be recorded on the CRF and reported within 24 h to the board and the Biological and Medical Ethics Committee of West China Hospital.
All unexpected major cardiovascular, cerebrovascular and other serious adverse events not listed in the protocol will be reported to the coordinating center within 24 h. The chief principal investigator will be responsible for all adverse event reporting. All adverse events will be closely followed until resolution or stabilization. A local investigator will review all reports of adverse events.
Data management and quality control
All CRFs will be immediately entered into a secure web-based system hosted by the data coordinating center as soon as they are received. Designated research team members will be authorized to access the allocation system and electronic CRFs by entering the patient’s unique participant identification number, initials and date of birth in an online form. If data are entered incompletely or incorrectly, the principal investigator will contact the participating centers for clarification.
To control the quality of this study, all perfusionists will receive centralized training before the trial begins. All stored records will be kept secure and confidential according to standard guidelines. A reason must be indicated whenever data are altered, and all alterations will be saved.
Sample size calculation
Based on the results of our previous study, we predict the incidence of the primary outcome to be 59.4% in the control group and 46.3% in the RIVP group. Patients will be evenly divided into two groups. The trial is planned to have 80% power with a two-sided type I error rate of 5%. Taking into consideration a dropout rate of 10% over the course of the entire study, we calculated a total sample size of 500 according the following statistical formula.
Data analysis will be performed by a statistician using SPSS 20.0 (IBM, Chicago, IL, USA). Differences associated with p < 0.05 will be considered statistically significant. Continuous variables will be expressed as mean ± standard deviation or median (interquartile range), and differences in such variables will be analyzed using an independent t test or the Wilcoxon signed-rank test, depending on whether data are normally distributed. Categorical variables will be described as numbers (percentages), and differences in such variables will be analyzed using chi-squared and Fisher's exact tests. Kaplan-Meier curves and log-rank analysis will be used to compare inter-group differences in primary and secondary outcomes. Univariate and multivariate logistic regression will be performed to determine relative risk of primary and secondary outcomes in the RIVP group compared with the control group.
Timeline 2018-2019: Development of research strategy and study protocol
2019-2020: Recruitment and treatment of patients in RIVP-TARS trial
2020-2021: Completion of follow-up and data analysis.