Retrograde Inferior Vena Caval Perfusion for Total Aortic Arch Replacement Surgery (RIVP-TARS): A Multicenter, Randomized, Controlled, Double-Blind Trial CURRENT STATUS: ACCEPTED

Background: During total aortic arch replacement surgery (TARS) for patients with acute type A aortic dissection, organs in the lower body such as the viscera and spinal cord are at risk of ischemia even when antegrade cerebral perfusion (ACP) is performed. Combining ACP with retrograde inferior vena caval perfusion (RIVP) during TARS may improve outcomes by providing the lower body with oxygenated blood. Methods : This is a multi-center, randomized, controlled trial of 500 patients scheduled for TARS. Patients were randomly allocated to a moderate hypothermia circulatory arrest (MHCA) group, who received selective ACP with moderate hypothermia during TARS; or to an RIVP group, who received the combination of RIVP and selective ACP under moderate hypothermia during TARS. The primary outcome was a composite of early mortality and major complications, including paraplegia, postoperative renal failure, severe liver dysfunction, postoperative prolonged intubation (>48 h), and gastrointestinal complications. Discussion: This study aims to assess whether RIVP combined with selective ACP leads to superior outcomes than selective ACP alone for patients undergoing TARS under moderate hypothermia. This study seeks to provide high-quality evidence for RIVP to be used in patients with acute type A aortic dissection undergoing TARS. a heat exchanger, and two rolling pumps, bifurcate the arterial 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 and rectal temperature of 28-30 °C) will be 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.

Since lower-body circulatory arrest is needed during ACP, organs in the lower body such as the viscera and spinal cord are still at risk of ischemia. Moderate hypothermia is still required to extend the tolerance of organs to anoxia, which may prolong CPB duration for cooling and rewarming. Lowerbody circulatory arrest may therefore be a direct factor contributing to post-operative adverse events.
To reduce the risk of ischemic injury to these organs, the viscera and spinal cord should be well perfused during opening distal anastomosis.
Retrograde inferior vena caval perfusion (RIVP) is a strategy used to provide the lower body with oxygenated blood. No venous valves are present in the visceral vein[endnoteRef :29], which makes RIVP possible. Previous animal studies have revealed that RIVP may benefit the abdominal organs by maintaining continuity in circulation and providing adequate blood flow for oxygen delivery[endnoteRef :30]. However, the debate remains unsettled about the optimal RIVP pressure and the feasibility of simultaneous retrograde bi-caval perfusion at a nasopharyngeal temperature of 18 The available evidence suggests that ACP provides more physiological blood flow to the brain than RCP, while RIVP reduces the risk of lower body ischemia by providing venous-to-arterial blood flow. Therefore, we have designed a trial to test whether the combination of ACP and RIVP is feasible under moderate hypothermia during reconstruction of the aortic arch. Furthermore, we will investigate the hypothesis that combining ACP and RIVP is superior to ACP alone for TARS under moderate hypothermia.

Objective and hypothesis
The primary aim of this multicenter trial is to assess whether RIVP combined with ACP leads to better outcomes than selective ACP alone for patients undergoing TARS (Protocol no. 1.0, dated 10 January2018) under moderate hypothermia. We hypothesize that combining RIVP with ACP will lead to lower incidences of mortality, major complications and postoperative temporary neurological defects than ACP alone, as well as shorter duration of ventilation and stay in the intensive care unit (ICU). The results of this trial will serve as a foundation for future clinical recommendations regarding the application of RIVP in TARS and potentially improve treatment.

Study design
This study is designed as a multicenter, randomized, controlled, double-blind trial. 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. 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

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 comorbidity, 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.

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.

Study outcomes
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, freshfrozen 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
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. Our trial will combine ACP and RIVP during TARS using independently controlled upper-and lowerbody perfusion circuits. This trial is expected to provide up-to-date data on the safety and efficacy of RIVP in patients undergoing TARS and has the potential to reduce the incidence of circulatory arrestassociated complications and perioperative blood product transfusion of AAAD patients, ultimately improving long-and short-term prognosis.
Trial status We are currently completing the electronic CRF system. The study will open to patient recruitment on 1 January 2019. Completion of this trial is expected in December 2021.

Declarations
Hospital of Sichuan University and the National Natural Science Foundation of China (81600394 and 81570374).

Availability of data and materials
Not applicable Authors' contributions LD and JL designed the study and helped draft the manuscript. DYK assisted with statistical consideration in the study design and analyzed the data. YQG, ZW, XLH, HY, DFZ, YZ and ZXT were involved in designing the study and reviewing the manuscript. YQG, ZW, JYX, BD, XSZ, ZW, YQ and YGF will participate in patient recruitment and data collection. JL and ZXT will assist with organization of study visits and monitoring. All authors read and approved the final version of this manuscript.

Ethics approval and consent to participate
The clinical trial is being conducted in line with the Declaration of Helsinki. The study protocol has been approved by the Biological and Medical Ethics Committee of West China Hospital (2018 trial number 24). All patients must be informed about the trial and give written informed consent in order to be enrolled.

Consent for publication
Not applicable