The effects of standardized intravenous Treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure

The effects of standardized intravenous Treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effects of standardized intravenous Treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure Xiaofeng Wang, Shilin Wang, Ruihuan Shen, Zhongyuan Lu, Xu Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4169877/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Oct, 2024 Read the published version in European Journal of Medical Research → Version 1 posted 9 You are reading this latest preprint version Abstract Objective Total cavo-pulmonary connection (TCPC) is a palliative treatment for single ventricular malformations. For high-risk patients (preoperative mean pulmonary arterial pressure, mPAP > 15 mmHg), between the inhaled and oral targeted medications, the application of intravenous Treprostinil as a bridge therapy to achieve "seamless" management is core postoperative treatment. This study intends to explore the effect of different administration regimens on early postoperative recovery. Methods This was a retrospective cohort study. High-risk pediatric patients (age ≤ 14 years) who underwent TCPC procedure in Fu Wai Hospital from 2015 to 2022 were included. Since the regimen of Treprostinil was standardized in our center in 2021, the patients in 2020 and before were included in group 1, patients in 2021 and 2022 were included in group 2. The hemodynamic parameters were compared before and after the maintenance dose of Treprostinil. The differences of demographic characteristics, surgical data and postoperative recovery were compared between the two groups. Results A total of 51 pediatric patients was included. The group 1 included 35 patients who received Treprostinil at 1–3 post-operative days and an average dose of 12 ± 4 ng/(kg·min). The group 2 included 16 patients who received Treprostinil within postoperative 1 day and an average dose of 22 ± 7 ng/(kg·min). There were no significant differences between the two groups in terms of age, weight, preoperative percutaneous oxygen saturation and mPAP, heterotaxia syndrome, TCPC procedure type, other concurrent procedure, cardiopulmonary bypass time and aortic cross clamp proportion (p > 0.05). After 24 hours of Treprostinil treatment, the mPAP in group 1 reduced from 17 ± 3 mmHg to 15 ± 2mmHg (p < 0.001), and in group 2 from 17 ± 2 mmHg to 14 ± 2mmHg (p < 0.001), with no difference between groups. In the postoperative recovery, patients in Group 2 exhibited a reduced duration of mechanical ventilation, 19 (11, 25) hours vs 69 (23, 189) hours, p = 0.001; a shorter stay in the ICU, 8 (6,12) days vs 16 (9,26) days, p = 0.006; and a shorter postoperative length of stay, 27 (17,55) days vs 39 (29,58) days, p = 0.032. Patients in group 2 also exhibited a lower incidence of thromboembolic events, 0 (0/26) vs 26% (9/35), p = 0.043; and the need for renal replacement therapy, 0 (0/26) vs 31% (11/35), p = 0.011. Conclusion After TCPC procedure, the standardized application of Treprostinil can improve the postoperative recovery, reduce the incidence of important complications and benefit the early postoperative recovery. Single ventricle Pulmonary hypertension Total cavo-pulmonary connection Treprostinil Introduction The total cavopulmonary connection (TCPC) is a classic palliative surgery for the treatment of single ventricle anomalies. Pulmonary arterial hypertension (PAH) is one of the common complications of single ventricle anomalies and is also a key determinant of the success of TCPC surgery [1] . With the gradual improvement in perioperative management, postoperative complications have decreased gradually, leading to a significant improvement in patient prognosis [2] . However, for high-risk patients with concomitant pulmonary hypertension, the surgical prognosis remains unsatisfactory, particularly as early postoperative complications can lead to delayed recovery or even increased risk of mortality. In patients with single ventricle anomalies, unlike the commonly used criterion of mean pulmonary arterial pressure (mPAP) >20mmHg [3] , the criterion for single ventricle-associated PAH is mPAP >15 mmHg [4] . Due to the lack of pulsatile blood flow in the pulmonary artery post-TCPC surgery, even mild increases in pulmonary artery pressure can lead to a significant reduction in pulmonary circulation. Therefore, the application of targeted PAH medications to reduce pulmonary vascular resistance is essential in the post-TCPC treatment regimen. Currently, numerous studies focus on the specific effects of targeted drug therapy on post-TCPC patients. Goldberg et al. conducted a randomized, double-blind, placebo-controlled crossover study involving 28 patients, demonstrating that oral sildenafil improved ventilatory efficiency during cardiopulmonary exercise testing [5] . Similarly, Rhodes et al. employed the same study design and demonstrated, through a study of 18 patients, that inhaled iloprost improved pulse oxygen saturation and maximal oxygen consumption during cardiopulmonary exercise testing [6] . Hebert et al. conducted a randomized, double-blind, placebo-controlled study involving 74 patients, with 37 receiving oral bosentan treatment and 37 receiving oral placebo for a duration of 14 weeks, demonstrating the ability of bosentan to improve cardiopulmonary exercise capacity, exercise endurance, and functional class [7]. Constantine et al. conducted a retrospective analysis of 1538 patients from 10 hospitals in the UK, of which only 76 (4.9%) received targeted drug therapy. After matching, analysis of 108 patients revealed that targeted drug therapy could improve patients' NYHA functional class [8]. However, these studies still have certain limitations. Primarily, they mainly include patients receiving outpatient medications and follow-up after discharge from surgery, most of whom undergo oral medication therapy. The methods used to evaluate efficacy also tend to focus more on tests of exercise capacity. However, in the early post-TCPC period, due to increased central venous pressure in patients leading to gastrointestinal congestion and poor drug absorption, clinicians often prefer drugs administered via inhalation or intravenous/subcutaneous infusion routes. Moreover, in terms of efficacy, greater attention is placed on the impact on hemodynamics and important postoperative recovery indicators. Treprostinil is a targeted medication within the prostacyclin pathway and its analogs, which can be administered via intravenous/subcutaneous infusion pumps. Currently, this medication is considered the first-line and essential therapy for patients with severe PAH (WHO functional class III-IV) [9]. For high-risk single-ventricle patients undergoing TCPC surgery, intravenous Treprostinil infusion can serve as a bridging therapy between inhaled nitric oxide and oral targeted medications, aiming at achieve seamless management of targeted drug therapy. There are already small-sample self-controlled studies supporting the effectiveness and safety of Treprostinil l in high-risk single-ventricle postoperative patients [10,11]. However, there is a lack of research supporting the timing and maintenance dose of medication administration. This study aims at explore whether standardized timing and dosing of Treprostinil administration can further improve hemodynamic status and postoperative recovery indicators in high-risk single-ventricle patients after TCPC surgery, using a retrospective cohort study approach. Data and Methods 1.1 Patient Inclusion and Grouping Criteria This retrospective study analyzed pediatric patients (≤ 14 years old) who underwent TCPC surgery and were hospitalized at Fuwai Hospital from 2015 to 2022. Inclusion criteria: 1. Preoperative right heart catheterization showing mPAP > 15mmHg; 2. Postoperative initiation of intravenous Treprostinil therapy in the intensive care unit. Exclusion criteria: Receipt of extracorporeal membrane oxygenation support postoperatively. Since our center standardized the use of Treprostinil in 2021, patients undergoing surgery from 2015 to 2020 were assigned to Group 1, while patients undergoing surgery in 2021 and 2022 were assigned to Group 2. 1.2 Treprostinil and Other Targeted Medication Administration Strategies For high-risk TCPC postoperative patients, blood pressure stability is initially maintained using vasopressors and fluid therapy. Inhalation of 20 ppm nitric oxide via a ventilator is used to reduce pulmonary vascular resistance, gradually tapering off nitric oxide concentration before planned extubation, and sildenafil (Pfizer Inc., Puerto Rico) is added at a dose of 0.5 mg/kg, up to a maximum of 20 mg per dose, three times daily. Once the patient's blood pressure stabilizes, intravenous Treprostinil (Zhaoke Pharmaceutical (Hefei) Co., LTD., China) therapy is initiated. Due to initial limited experience with Treprostinil, the starting dose is 4 ng/(kg·min), with increments every 2 hours of 2–4 ng/(kg·min) until the symptom improvement is observed (reduction in central venous pressure, improved fluid intake requirements, gradual resolution of tachycardia), maintaining therapy at the current dose. Since standardization of Treprostinil therapy began in 2021, administration starts as soon as circulatory stability is achieved postoperatively, with an initial dose of 5 ng/(kg·min), increments every 30 minutes of 5 ng/(kg·min) until reaching the maximum tolerated dose (when blood pressure fluctuates), then transitioning to maintenance therapy. Once gastrointestinal function recovers in all patients, oral medication therapy is initiated, with bosentan (Actelion Pharmaceuticals Ltd., Switzerland) at a dose of 2 mg/kg per dose, up to a maximum of 125 mg per dose, twice daily, in combination with oral sildenafil therapy. Patients continue oral targeted medication therapy after discharge from the intensive care unit. Following initiation of oral targeted medication therapy in pediatric patients, intravenous Treprostinil is gradually discontinued without conversion to subcutaneous administration. 1.3 Data Collection Data from both groups of pediatric patients were recorded preoperatively, intraoperatively, and postoperatively. Preoperative data primarily included: age, gender, weight, transcutaneous oxygen saturation, hemoglobin concentration, presence of heterotaxy syndrome, and preoperative mPAP. Intraoperative data mainly included: TCPC procedure, whether concomitant atrioventricular valve repair/replacement, pulmonary vein stenosis correction, extracorporeal circulation time, whether aortic clamping was performed, and whether a window was created. Postoperative data mainly included: maintenance dose and duration of Treprostinil. Hemodynamic parameters were recorded in both groups of patients before and at 6, 12, 18, and 24 hours after initiation of intravenous Treprostinil, including: mPAP (superior vena cava pressure) and vasopressor score, where the vasopressor score = dopamine [µg/(kg·min)] + dobutamine [µg/(kg·min)] + milrinone [µg/(kg·min)] × 10 + adrenaline [µg/(kg·min)] × 100 + vasopressin [U/(kg·min)] × 10,000. Other recorded parameters included: duration of mechanical ventilation, length of stay in the intensive care unit, postoperative hospital stay, occurrence of tachyarrhythmias, volume of chest drainage, duration of chest tube placement, occurrence of thromboembolic events, receipt of renal replacement therapy, need for multiple endotracheal intubations, need for tracheostomy, and in-hospital mortality rate. 1.4 Statistical Analysis Statistical analysis was performed using SPSS version 25.0 (IBM Corporation, USA). The Shapiro-Wilk test was utilized to assess the normality of continuous variables. Normally distributed continuous variables were described as mean ± standard deviation, while non-normally distributed continuous variables were described as median (interquartile range), and categorical variables were described as frequency (percentage). For comparisons of changes in hemodynamic parameters before and after Treprostinil infusion and between groups, a one-way repeated measures analysis of variance (ANOVA) was conducted. The assumption of sphericity was assessed using Mauchly's test of sphericity or Greenhouse-Geisser correction as appropriate. Continuous variables between groups were compared using independent samples t-tests or Wilcoxon rank-sum tests depending on the normality of the data distribution. Categorical variables were compared using chi-square tests, continuity correction, or Fisher's exact test as appropriate. Expectation maximization was utilized to estimate missing values. A significance level of P ≤ 0.05 was considered statistically significant. 1.5 Ethical Support This study has been reviewed and approved by the Ethics Committee of Fuwai Hospital, with ID: 2022 − 1859. Due to its retrospective nature, informed consent was waived. The ethical principles outlined in the 1964 Helsinki Declaration were adhered to throughout the study. Results Out of a total of 829 patients, 53 patients met the inclusion criteria. After excluding 2 patients who received extracorporeal membrane oxygenation support, a total of 51 patients were included. Among them, 35 patients were included in Group 1, initiating maintenance Treprostinil therapy within 1–3 days postoperatively, with an average dose of 12 ± 4 ng/(kg·min). Group 2 included 16 patients, starting maintenance Treprostinil therapy within 1 day postoperatively, with an average dose of 22 ± 7 ng/(kg·min). The demographic characteristics of patients in both groups are shown in Table 1 , with no statistically significant differences between the two groups (p > 0.05). The surgical data of patients in both groups are presented in Table 2 , with no statistically significant differences between the two groups (p > 0.05). Table 1 Demographic Characteristics of the Two Patient Groups Variable Group 1 (n = 35) Group 2 (n = 16) p-value Age (years) 4.6(3.6, 7) 5.8(4.2,12) 0.127 Gender (n, %) Male Female 17(49) 18(51) 10(62) 6(38) 0.355 Weight (kg) 16(14, 23) 19(15, 33) 0.242 Peripheral oxygen saturation (%) 79 ± 6 79 ± 7 0.98 Hemoglobin concentration (g/L) 175 ± 26 172 ± 26 0.757 Visceral ectopia syndrome (n, %) 11(31) 2(13) 0.274 mPAP(mmHg) 17 ± 2 17 ± 3 0.289 Table 2 Surgical data of the Two Patient Groups Group 1 (n = 35) Group 2 (n = 16) p-value TCPC Procedure (n, %) Side-to-side tunnel Extra-cardiac conduit 5(14) 30(86) 2(13) 14(87) 1.0 Concomitant Procedures (n, %) 18(51) 7(44) 0.611 Atrial fenestration (n, %) 28(80) 12(75) 0.971 Cardiopulmonary Bypass Time (minutes) 166 ± 52 146 ± 47 0.181 Aortic Cross-Clamp (n, %) 23(66) 8(50) 0.286 Regarding hemodynamic changes after Treprostinil infusion, the mPAP gradually decreased at each observation point after maintenance infusion in both groups. In Group 1, the mPAP decreased from 17 ± 3 mmHg to 15 ± 2 mmHg (p < 0.001), and in Group 2, it decreased from 17 ± 2 mmHg to 14 ± 2 mmHg (p < 0.001). However, there was no statistically significant difference in mPAP changes between the two groups (p = 0.18). The changes in vasoactive inotropic score in both Group 1 and Group 2 were not statistically significant, and there was no statistically significant difference in changes between the two groups (p > 0.05), as shown in Table 3 . Table 3 Hemodynamic changes of two groups of patients Baseline 6 Hours 12 Hours 18 Hours 24 Hours p-value mPAP (mmHg) Group1 Group 2 Inter-group 17 ± 3 17 ± 2 16 ± 3 15 ± 2 16 ± 2 15 ± 1 16 ± 2 14 ± 1 15 ± 2 14 ± 2 < 0.001 < 0.001 0.18 VIS Group1 Group 2 Inter-group 10 (7,15) 9 (5, 15) 9 (7, 15) 7 (3, 14) 10 (6, 14) 7 (3, 15) 10 (6, 13) 8 (3, 14) 9 (6, 13) 8 (3, 14) 0.114 0.247 0.473 VIS: Vasoactive inotropic score Regarding postoperative recovery indicators, patients in Group 2 had significantly shorter mechanical ventilation time compared to those in Group 1 (19 [11, 25] hours vs 69 [23, 189] hours, p = 0.001). Similarly, ICU stay (8 [ 6 , 12 ] days vs 16 [9, 26] days, p = 0.006) and postoperative hospital stay (27 [17, 55] days vs 39 [29, 58] days, p = 0.032) were shorter in Group 2 compared to Group 1. Additionally, the proportion of patients with thromboembolic events (0 [0/26] vs 26% [9/35], p = 0.043) and requiring renal replacement therapy (0 [0/26] vs 31% [11/35], p = 0.011) was lower in Group 2 compared to Group 1. Specific details are presented in Table 4 . Table 4 Postoperative Recovery Indicators for Two Patient Groups Group 1 (n = 35) Group 2 (n = 16) p-value Mechanical Ventilation Duration (hours) 69 (23, 189) 19 (11, 25) 0.001 ICU Length of Stay (days) 16 (9, 26) 8(6, 12) 0.006 Postoperative Length of Stay (days) 39 (29, 58) 27(17, 55) 0.032 Duration of Chest Tube Drainage (days) 34(20, 47) 23(14, 36) 0.113 Chest Tube Drainage Volume (ml/kg) 261(163, 484) 152(94, 316) 0.054 Thromboembolic Events (n, %) 9(26) 0(0) 0.043 Supraventricular Arrhythmias (n, %) 14(40) 3(19) 0.241 Renal Replacement Therapy (n, %) 11(31) 0(0) 0.011 Neurological Complications (n, %) 5(14) 0(0) 0.167 Multiple Endotracheal Intubations 6(17) 1(6) 0.542 Tracheostomy 5(14) 0(0) 0.167 Mortality 0(0) 0(0) NA Discussion In pediatric patients post-TCPC surgery, the absence of a subpulmonary ventricle makes minimizing pulmonary artery pressure a crucial factor determining pulmonary circulation. Even mild increases in pulmonary artery pressure can decrease cardiac output and increase central venous pressure, which is unfavorable for Fontan circulation. Therefore, the application of targeted PAH medications to reduce pulmonary artery pressure becomes pivotal for the success of the surgery [ 12 ]. Currently, commonly used targeted medications include nitric oxide pathway agents, endothelin pathway agents, and prostacyclin pathway agents [ 13 ]. In China, apart from inhaled nitric oxide and intravenous/subcutaneous Treprostinil, all other medications are administered orally. However, in the early post-TCPC period, gastrointestinal function has not yet recovered, and the efficacy of oral medications depends on gastrointestinal absorption, which may delay achieving stable therapeutic effects. Although inhaled nitric oxide has proven efficacy, its administration depends on ventilator support and is only suitable for use during mechanical ventilation. Therefore, the use of intravenous Treprostinil as a bridging therapy between inhaled and oral targeted medications, achieving seamless management of targeted drug therapy post-TCPC surgery, is theoretically feasible and represents a promising treatment strategy. The application of Treprostinil in the treatment of single ventricle with concomitant PAH patients is currently supported by limited research in both quantity and level of evidence. Chen X and colleagues reported on a self-controlled study of 8 patients (5 post-Glenn procedure, 3 post-TCPC procedure) who received early postoperative intravenous Treprostinil. Following an average treatment dosage of 55 ng/(kg·min) of Treprostinil, significant improvements were observed in mPAP, pulmonary/systemic pressure ratio, and arterial oxygen partial pressure/inhaled oxygen concentration [ 9 ]. Sullivan RT and colleagues reported a self-controlled study of 17 patients who received long-term subcutaneous Treprostinil infusion at 20–30 ng/(kg·min) to improve hemodynamic parameters in high-risk single ventricle patients and facilitate surgical opportunities. The study found that Treprostinil not only reduced pulmonary vascular resistance but also demonstrated that in most patients, pulmonary vascular resistance did not rebound after discontinuation. Regarding the pursuit of surgical opportunities, among 11 patients undergoing stage I (palliative shunt) procedures, 9 (82%) gained the opportunity for Glenn procedure, while among 6 patients post-Glenn procedure, 3 (50%) gained the opportunity for TCPC procedure [ 10 ]. Since 2015, our center has been employing Treprostinil to treat high-risk TCPC postoperative patients with concomitant PAH. Initially, due to insufficient experience and concerns regarding the passive pulmonary circulation following TCPC, compounded by inadequate effective circulating blood volume in the early postoperative period [ 14 ], the dosage escalation of Treprostinil was cautious, with a slow titration rate and maintenance dosage selection based on the drug's effectiveness. Subsequently, no further dose escalation was pursued. With increasing experience, a standardized approach was initiated in 2021, with expedited dosage escalation and maintenance dose selection based on the maximum tolerated dose by patients. The primary aim of this study is to compare these two distinct dosing strategies and their impact on improving patients' hemodynamic parameters and postoperative recovery indicators. Regarding the hemodynamic improvement, observations made 24 hours after medication administration revealed that Treprostinil effectively and steadily reduced pulmonary arterial pressure in TCPC postoperative patients in both Group 1 and Group 2, suggesting that targeted pharmacotherapy remains effective in reducing pulmonary arterial pressure in single ventricle patients with concomitant PAH. Although patients in Group 2 exhibited a greater reduction in pulmonary arterial pressure compared to Group 1, no statistically significant difference was found. In terms of circulatory stability, given the varying target blood pressures for children of different ages, this study did not directly compare absolute blood pressure values. Instead, it analyzed the change in vasoactive inotropic score required to maintain satisfactory blood pressure, thereby assessing the effectiveness and safety of drug therapy. In both Group 1 and Group 2 patients, no statistically significant difference was observed in the change in vasopressor score following Treprostinil administration, indicating minimal impact on systemic blood pressure under the maintenance dosage used in this study, thus suggesting a higher level of safety. In terms of improving postoperative recovery indicators, patients in Group 2 exhibited significant advantages over those in Group 1 in mechanical ventilation time, ICU length of stay, postoperative hospital stay, incidence of thromboembolic events, and need for renal replacement therapy. Regarding the underlying reasons, although there was no statistically significant difference in the reduction of pulmonary arterial pressure between the two groups following Treprostinil treatment, Treprostinil 's pharmacological effects extend beyond reducing pulmonary vascular resistance. It includes reducing systemic ventricular afterload, inhibiting platelet aggregation, and suppressing smooth muscle cell proliferation. It is plausible that the higher dosage of Treprostinil in Group 2 exerted its comprehensive pharmacological effects, thereby improving patients' surgical outcomes. Furthermore, the superior postoperative recovery indicators in Group 2 patients further underscore the safety and efficacy of standardized Treprostinil treatment. Nevertheless, this study has several limitations. Firstly, the small sample size may have led to a lack of statistical power to detect clinically significant differences. Future studies should aim at expand the sample size or conduct multicenter research to address this limitation. Secondly, due to the retrospective nature of this analysis, the evidence level remains suboptimal. Future research should consider conducting randomized controlled trials (RCTs) or matched cohort studies to strengthen the evidence base. Thirdly, since our center's surgeons do not routinely insert atrial pressure monitoring catheters, the hemodynamic parameters in this study were not comprehensive. Future studies could consider utilizing monitoring systems such as PICCO to refine hemodynamic parameters. Conclusion In patients with single ventricle and concomitant PAH undergoing TCPC surgery, the use of Treprostinil can reduce pulmonary arterial pressure. Standardized Treprostinil administration (achieving the maintenance dosage within 24 hours postoperatively, i.e., the maximum tolerated dose) can expedite postoperative recovery, reduce the incidence of major complications, and facilitate early postoperative recovery. Declarations Conflicts of Interest: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest. Source of Funding: This study was supported by the Clinical Research Foundation of the National Health Commission of the People’s Republic of China (grant number 2022-GSP-GG-32 and 2022-GSP-QN-13). Data sharing statement All data collected for the study, including individual participant data, a data dictionary defining each field in the set, and related documents such as the study protocol and statistical analysis results, will be made available to others with publication by email addresses with the consent of the corresponding author. Author contributions Xiaofeng Wang and Shilin Wang contributed to the article writing, data collection, and statistical analysis. Ruihuan Shen and Zhongyuan Lu drafted and critically reviewed the manuscript. Xu Wang contributed to the study design and the review of the final article. All authors contributed to the manuscript and approved the submitted version. References Becker K, Uebing A, Hansen JH. 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Cite Share Download PDF Status: Published Journal Publication published 01 Oct, 2024 Read the published version in European Journal of Medical Research → Version 1 posted Editorial decision: Revision requested 20 May, 2024 Reviews received at journal 22 Apr, 2024 Reviews received at journal 15 Apr, 2024 Reviewers agreed at journal 03 Apr, 2024 Reviewers agreed at journal 01 Apr, 2024 Reviewers invited by journal 30 Mar, 2024 Editor assigned by journal 27 Mar, 2024 Submission checks completed at journal 27 Mar, 2024 First submitted to journal 26 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4169877","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":284518644,"identity":"8acadf24-a460-4b4b-9b09-54b38dc07b95","order_by":0,"name":"Xiaofeng Wang","email":"","orcid":"","institution":"National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiaofeng","middleName":"","lastName":"Wang","suffix":""},{"id":284518645,"identity":"acc1846f-4fdc-4d2f-9172-e287b09a4894","order_by":1,"name":"Shilin Wang","email":"","orcid":"","institution":"National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Shilin","middleName":"","lastName":"Wang","suffix":""},{"id":284518646,"identity":"b9937938-fa25-432b-96fd-e8841b12e608","order_by":2,"name":"Ruihuan Shen","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ruihuan","middleName":"","lastName":"Shen","suffix":""},{"id":284518647,"identity":"52908522-b5a0-4777-8581-395c984737cf","order_by":3,"name":"Zhongyuan Lu","email":"","orcid":"","institution":"National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zhongyuan","middleName":"","lastName":"Lu","suffix":""},{"id":284518648,"identity":"2b0b572d-5bd7-4fd8-9091-4554102e8dea","order_by":4,"name":"Xu Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqklEQVRIiWNgGAWjYBAC9gYGhgMMDDY8/PwNRGrhOQDWkiYjOeMACVqA4LCNQUMCsVokcg8e+Nl2nseA4QDjh485RGnJSzjY23abx5y5gVly5jYitNhL5xgcZgRqsWw4wMbMS4wWHoiWczwGBxJI03KAFC3y7xIO9pxL5pGccbCZOL/w8Jw9/OFHmZ09P3/zwQ8fidEC1ARjMDYQpR5ZyygYBaNgFIwCHAAAjlk13dowlg0AAAAASUVORK5CYII=","orcid":"","institution":"National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Xu","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-03-26 12:38:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4169877/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4169877/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-024-02077-y","type":"published","date":"2024-10-01T15:57:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66096940,"identity":"b1e66f17-a378-4010-b2e7-b5fb0fd7ed54","added_by":"auto","created_at":"2024-10-07 16:11:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":410112,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4169877/v1/62dc51e0-143b-428b-8f01-4f2c1062b58e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effects of standardized intravenous Treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe total cavopulmonary connection (TCPC) is a classic palliative surgery for the treatment of single ventricle anomalies. Pulmonary arterial hypertension (PAH) is one of the common complications of single ventricle anomalies and is also a key determinant of the success of TCPC surgery \u003csup\u003e[1]\u003c/sup\u003e. With the gradual improvement in perioperative management, postoperative complications have decreased gradually, leading to a significant improvement in patient prognosis \u003csup\u003e[2]\u003c/sup\u003e. However, for high-risk patients with concomitant pulmonary hypertension, the surgical prognosis remains unsatisfactory, particularly as early postoperative complications can lead to delayed recovery or even increased risk of mortality. In patients with single ventricle anomalies, unlike the commonly used criterion of mean pulmonary arterial pressure (mPAP) \u0026gt;20mmHg \u003csup\u003e[3]\u003c/sup\u003e, the criterion for single ventricle-associated PAH is mPAP \u0026gt;15 mmHg \u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDue to the lack of pulsatile blood flow in the pulmonary artery post-TCPC surgery, even mild increases in pulmonary artery pressure can lead to a significant reduction in pulmonary circulation. Therefore, the application of targeted PAH medications to reduce pulmonary vascular resistance is essential in the post-TCPC treatment regimen. Currently, numerous studies focus on the specific effects of targeted drug therapy on post-TCPC patients. Goldberg et al. conducted a randomized, double-blind, placebo-controlled crossover study involving 28 patients, demonstrating that oral sildenafil improved ventilatory efficiency during cardiopulmonary exercise testing \u003csup\u003e[5]\u003c/sup\u003e. Similarly, Rhodes et al. employed the same study design and demonstrated, through a study of 18 patients, that inhaled iloprost improved pulse oxygen saturation and maximal oxygen consumption during cardiopulmonary exercise testing \u003csup\u003e[6]\u003c/sup\u003e. Hebert et al. conducted a randomized, double-blind, placebo-controlled study involving 74 patients, with 37 receiving oral bosentan treatment and 37 receiving oral placebo for a duration of 14 weeks, demonstrating the ability of bosentan to improve cardiopulmonary exercise capacity, exercise endurance, and functional class [7]. Constantine et al. conducted a retrospective analysis of 1538 patients from 10 hospitals in the UK, of which only 76 (4.9%) received targeted drug therapy. After matching, analysis of 108 patients revealed that targeted drug therapy could improve patients\u0026apos; NYHA functional class [8].\u003c/p\u003e\n\u003cp\u003eHowever, these studies still have certain limitations. Primarily, they mainly include patients receiving outpatient medications and follow-up after discharge from surgery, most of whom undergo oral medication therapy. The methods used to evaluate efficacy also tend to focus more on tests of exercise capacity. However, in the early post-TCPC period, due to increased central venous pressure in patients leading to gastrointestinal congestion and poor drug absorption, clinicians often prefer drugs administered via inhalation or intravenous/subcutaneous infusion routes. Moreover, in terms of efficacy, greater attention is placed on the impact on hemodynamics and important postoperative recovery indicators.\u003c/p\u003e\n\u003cp\u003eTreprostinil is a targeted medication within the prostacyclin pathway and its analogs, which can be administered via intravenous/subcutaneous infusion pumps. Currently, this medication is considered the first-line and essential therapy for patients with severe PAH (WHO functional class III-IV) [9]. For high-risk single-ventricle patients undergoing TCPC surgery, intravenous Treprostinil infusion can serve as a bridging therapy between inhaled nitric oxide and oral targeted medications, aiming at achieve seamless management of targeted drug therapy. There are already small-sample self-controlled studies supporting the effectiveness and safety of Treprostinil l in high-risk single-ventricle postoperative patients [10,11]. However, there is a lack of research supporting the timing and maintenance dose of medication administration. This study aims at explore whether standardized timing and dosing of Treprostinil administration can further improve hemodynamic status and postoperative recovery indicators in high-risk single-ventricle patients after TCPC surgery, using a retrospective cohort study approach.\u003c/p\u003e"},{"header":"Data and Methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Patient Inclusion and Grouping Criteria\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed pediatric patients (\u0026le;\u0026thinsp;14 years old) who underwent TCPC surgery and were hospitalized at Fuwai Hospital from 2015 to 2022. Inclusion criteria: 1. Preoperative right heart catheterization showing mPAP\u0026thinsp;\u0026gt;\u0026thinsp;15mmHg; 2. Postoperative initiation of intravenous Treprostinil therapy in the intensive care unit. Exclusion criteria: Receipt of extracorporeal membrane oxygenation support postoperatively.\u003c/p\u003e \u003cp\u003eSince our center standardized the use of Treprostinil in 2021, patients undergoing surgery from 2015 to 2020 were assigned to Group 1, while patients undergoing surgery in 2021 and 2022 were assigned to Group 2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Treprostinil and Other Targeted Medication Administration Strategies\u003c/h2\u003e \u003cp\u003eFor high-risk TCPC postoperative patients, blood pressure stability is initially maintained using vasopressors and fluid therapy. Inhalation of 20 ppm nitric oxide via a ventilator is used to reduce pulmonary vascular resistance, gradually tapering off nitric oxide concentration before planned extubation, and sildenafil (Pfizer Inc., Puerto Rico) is added at a dose of 0.5 mg/kg, up to a maximum of 20 mg per dose, three times daily. Once the patient's blood pressure stabilizes, intravenous Treprostinil (Zhaoke Pharmaceutical (Hefei) Co., LTD., China) therapy is initiated. Due to initial limited experience with Treprostinil, the starting dose is 4 ng/(kg\u0026middot;min), with increments every 2 hours of 2\u0026ndash;4 ng/(kg\u0026middot;min) until the symptom improvement is observed (reduction in central venous pressure, improved fluid intake requirements, gradual resolution of tachycardia), maintaining therapy at the current dose. Since standardization of Treprostinil therapy began in 2021, administration starts as soon as circulatory stability is achieved postoperatively, with an initial dose of 5 ng/(kg\u0026middot;min), increments every 30 minutes of 5 ng/(kg\u0026middot;min) until reaching the maximum tolerated dose (when blood pressure fluctuates), then transitioning to maintenance therapy. Once gastrointestinal function recovers in all patients, oral medication therapy is initiated, with bosentan (Actelion Pharmaceuticals Ltd., Switzerland) at a dose of 2 mg/kg per dose, up to a maximum of 125 mg per dose, twice daily, in combination with oral sildenafil therapy. Patients continue oral targeted medication therapy after discharge from the intensive care unit. Following initiation of oral targeted medication therapy in pediatric patients, intravenous Treprostinil is gradually discontinued without conversion to subcutaneous administration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Data Collection\u003c/h2\u003e \u003cp\u003eData from both groups of pediatric patients were recorded preoperatively, intraoperatively, and postoperatively. Preoperative data primarily included: age, gender, weight, transcutaneous oxygen saturation, hemoglobin concentration, presence of heterotaxy syndrome, and preoperative mPAP. Intraoperative data mainly included: TCPC procedure, whether concomitant atrioventricular valve repair/replacement, pulmonary vein stenosis correction, extracorporeal circulation time, whether aortic clamping was performed, and whether a window was created. Postoperative data mainly included: maintenance dose and duration of Treprostinil. Hemodynamic parameters were recorded in both groups of patients before and at 6, 12, 18, and 24 hours after initiation of intravenous Treprostinil, including: mPAP (superior vena cava pressure) and vasopressor score, where the vasopressor score\u0026thinsp;=\u0026thinsp;dopamine [\u0026micro;g/(kg\u0026middot;min)]\u0026thinsp;+\u0026thinsp;dobutamine [\u0026micro;g/(kg\u0026middot;min)]\u0026thinsp;+\u0026thinsp;milrinone [\u0026micro;g/(kg\u0026middot;min)] \u0026times; 10\u0026thinsp;+\u0026thinsp;adrenaline [\u0026micro;g/(kg\u0026middot;min)] \u0026times; 100\u0026thinsp;+\u0026thinsp;vasopressin [U/(kg\u0026middot;min)] \u0026times; 10,000. Other recorded parameters included: duration of mechanical ventilation, length of stay in the intensive care unit, postoperative hospital stay, occurrence of tachyarrhythmias, volume of chest drainage, duration of chest tube placement, occurrence of thromboembolic events, receipt of renal replacement therapy, need for multiple endotracheal intubations, need for tracheostomy, and in-hospital mortality rate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS version 25.0 (IBM Corporation, USA). The Shapiro-Wilk test was utilized to assess the normality of continuous variables. Normally distributed continuous variables were described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, while non-normally distributed continuous variables were described as median (interquartile range), and categorical variables were described as frequency (percentage). For comparisons of changes in hemodynamic parameters before and after Treprostinil infusion and between groups, a one-way repeated measures analysis of variance (ANOVA) was conducted. The assumption of sphericity was assessed using Mauchly's test of sphericity or Greenhouse-Geisser correction as appropriate. Continuous variables between groups were compared using independent samples t-tests or Wilcoxon rank-sum tests depending on the normality of the data distribution. Categorical variables were compared using chi-square tests, continuity correction, or Fisher's exact test as appropriate. Expectation maximization was utilized to estimate missing values. A significance level of P\u0026thinsp;\u0026le;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.5 Ethical Support\u003c/h2\u003e \u003cp\u003e This study has been reviewed and approved by the Ethics Committee of Fuwai Hospital, with ID: 2022\u0026thinsp;\u0026minus;\u0026thinsp;1859. Due to its retrospective nature, informed consent was waived. The ethical principles outlined in the 1964 Helsinki Declaration were adhered to throughout the study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOut of a total of 829 patients, 53 patients met the inclusion criteria. After excluding 2 patients who received extracorporeal membrane oxygenation support, a total of 51 patients were included. Among them, 35 patients were included in Group 1, initiating maintenance Treprostinil therapy within 1\u0026ndash;3 days postoperatively, with an average dose of 12\u0026thinsp;\u0026plusmn;\u0026thinsp;4 ng/(kg\u0026middot;min). Group 2 included 16 patients, starting maintenance Treprostinil therapy within 1 day postoperatively, with an average dose of 22\u0026thinsp;\u0026plusmn;\u0026thinsp;7 ng/(kg\u0026middot;min).\u003c/p\u003e \u003cp\u003eThe demographic characteristics of patients in both groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, with no statistically significant differences between the two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The surgical data of patients in both groups are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, with no statistically significant differences between the two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic Characteristics of the Two Patient Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1 (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2 (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6(3.6, 7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.8(4.2,12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (n, %)\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(49)\u003c/p\u003e \u003cp\u003e18(51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(62)\u003c/p\u003e \u003cp\u003e6(38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.355\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(14, 23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(15, 33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.242\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral oxygen saturation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin concentration (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e175\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e172\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.757\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisceral ectopia syndrome (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emPAP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurgical data of the Two Patient Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1 (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2 (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCPC Procedure (n, %)\u003c/p\u003e \u003cp\u003eSide-to-side tunnel\u003c/p\u003e \u003cp\u003eExtra-cardiac conduit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(14)\u003c/p\u003e \u003cp\u003e30(86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(13)\u003c/p\u003e \u003cp\u003e14(87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant Procedures (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18(51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fenestration (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.971\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiopulmonary Bypass Time (minutes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e166\u0026thinsp;\u0026plusmn;\u0026thinsp;52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146\u0026thinsp;\u0026plusmn;\u0026thinsp;47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.181\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAortic Cross-Clamp (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.286\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding hemodynamic changes after Treprostinil infusion, the mPAP gradually decreased at each observation point after maintenance infusion in both groups. In Group 1, the mPAP decreased from 17\u0026thinsp;\u0026plusmn;\u0026thinsp;3 mmHg to 15\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mmHg (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and in Group 2, it decreased from 17\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mmHg to 14\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mmHg (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, there was no statistically significant difference in mPAP changes between the two groups (p\u0026thinsp;=\u0026thinsp;0.18). The changes in vasoactive inotropic score in both Group 1 and Group 2 were not statistically significant, and there was no statistically significant difference in changes between the two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemodynamic changes of two groups of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 Hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 Hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 Hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 Hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emPAP (mmHg)\u003c/p\u003e \u003cp\u003eGroup1\u003c/p\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003cp\u003eInter-group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVIS\u003c/p\u003e \u003cp\u003eGroup1\u003c/p\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003cp\u003eInter-group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (7,15)\u003c/p\u003e \u003cp\u003e9 (5, 15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7, 15)\u003c/p\u003e \u003cp\u003e7 (3, 14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (6, 14)\u003c/p\u003e \u003cp\u003e7 (3, 15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (6, 13)\u003c/p\u003e \u003cp\u003e8 (3, 14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9 (6, 13)\u003c/p\u003e \u003cp\u003e8 (3, 14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003cp\u003e0.247\u003c/p\u003e \u003cp\u003e0.473\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eVIS: Vasoactive inotropic score\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding postoperative recovery indicators, patients in Group 2 had significantly shorter mechanical ventilation time compared to those in Group 1 (19 [11, 25] hours vs 69 [23, 189] hours, p\u0026thinsp;=\u0026thinsp;0.001). Similarly, ICU stay (8 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] days vs 16 [9, 26] days, p\u0026thinsp;=\u0026thinsp;0.006) and postoperative hospital stay (27 [17, 55] days vs 39 [29, 58] days, p\u0026thinsp;=\u0026thinsp;0.032) were shorter in Group 2 compared to Group 1. Additionally, the proportion of patients with thromboembolic events (0 [0/26] vs 26% [9/35], p\u0026thinsp;=\u0026thinsp;0.043) and requiring renal replacement therapy (0 [0/26] vs 31% [11/35], p\u0026thinsp;=\u0026thinsp;0.011) was lower in Group 2 compared to Group 1. Specific details are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative Recovery Indicators for Two Patient Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1 (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2 (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical Ventilation Duration (hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (23, 189)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (11, 25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU Length of Stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (9, 26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(6, 12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative Length of Stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (29, 58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(17, 55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of Chest Tube Drainage (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34(20, 47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(14, 36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest Tube Drainage Volume (ml/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e261(163, 484)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e152(94, 316)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThromboembolic Events (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupraventricular Arrhythmias (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal Replacement Therapy (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological Complications (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple Endotracheal Intubations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTracheostomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn pediatric patients post-TCPC surgery, the absence of a subpulmonary ventricle makes minimizing pulmonary artery pressure a crucial factor determining pulmonary circulation. Even mild increases in pulmonary artery pressure can decrease cardiac output and increase central venous pressure, which is unfavorable for Fontan circulation. Therefore, the application of targeted PAH medications to reduce pulmonary artery pressure becomes pivotal for the success of the surgery [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, commonly used targeted medications include nitric oxide pathway agents, endothelin pathway agents, and prostacyclin pathway agents [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In China, apart from inhaled nitric oxide and intravenous/subcutaneous Treprostinil, all other medications are administered orally. However, in the early post-TCPC period, gastrointestinal function has not yet recovered, and the efficacy of oral medications depends on gastrointestinal absorption, which may delay achieving stable therapeutic effects. Although inhaled nitric oxide has proven efficacy, its administration depends on ventilator support and is only suitable for use during mechanical ventilation. Therefore, the use of intravenous Treprostinil as a bridging therapy between inhaled and oral targeted medications, achieving seamless management of targeted drug therapy post-TCPC surgery, is theoretically feasible and represents a promising treatment strategy.\u003c/p\u003e \u003cp\u003eThe application of Treprostinil in the treatment of single ventricle with concomitant PAH patients is currently supported by limited research in both quantity and level of evidence. Chen X and colleagues reported on a self-controlled study of 8 patients (5 post-Glenn procedure, 3 post-TCPC procedure) who received early postoperative intravenous Treprostinil. Following an average treatment dosage of 55 ng/(kg\u0026middot;min) of Treprostinil, significant improvements were observed in mPAP, pulmonary/systemic pressure ratio, and arterial oxygen partial pressure/inhaled oxygen concentration [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Sullivan RT and colleagues reported a self-controlled study of 17 patients who received long-term subcutaneous Treprostinil infusion at 20\u0026ndash;30 ng/(kg\u0026middot;min) to improve hemodynamic parameters in high-risk single ventricle patients and facilitate surgical opportunities. The study found that Treprostinil not only reduced pulmonary vascular resistance but also demonstrated that in most patients, pulmonary vascular resistance did not rebound after discontinuation. Regarding the pursuit of surgical opportunities, among 11 patients undergoing stage I (palliative shunt) procedures, 9 (82%) gained the opportunity for Glenn procedure, while among 6 patients post-Glenn procedure, 3 (50%) gained the opportunity for TCPC procedure [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince 2015, our center has been employing Treprostinil to treat high-risk TCPC postoperative patients with concomitant PAH. Initially, due to insufficient experience and concerns regarding the passive pulmonary circulation following TCPC, compounded by inadequate effective circulating blood volume in the early postoperative period [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], the dosage escalation of Treprostinil was cautious, with a slow titration rate and maintenance dosage selection based on the drug's effectiveness. Subsequently, no further dose escalation was pursued. With increasing experience, a standardized approach was initiated in 2021, with expedited dosage escalation and maintenance dose selection based on the maximum tolerated dose by patients. The primary aim of this study is to compare these two distinct dosing strategies and their impact on improving patients' hemodynamic parameters and postoperative recovery indicators.\u003c/p\u003e \u003cp\u003eRegarding the hemodynamic improvement, observations made 24 hours after medication administration revealed that Treprostinil effectively and steadily reduced pulmonary arterial pressure in TCPC postoperative patients in both Group 1 and Group 2, suggesting that targeted pharmacotherapy remains effective in reducing pulmonary arterial pressure in single ventricle patients with concomitant PAH. Although patients in Group 2 exhibited a greater reduction in pulmonary arterial pressure compared to Group 1, no statistically significant difference was found. In terms of circulatory stability, given the varying target blood pressures for children of different ages, this study did not directly compare absolute blood pressure values. Instead, it analyzed the change in vasoactive inotropic score required to maintain satisfactory blood pressure, thereby assessing the effectiveness and safety of drug therapy. In both Group 1 and Group 2 patients, no statistically significant difference was observed in the change in vasopressor score following Treprostinil administration, indicating minimal impact on systemic blood pressure under the maintenance dosage used in this study, thus suggesting a higher level of safety.\u003c/p\u003e \u003cp\u003eIn terms of improving postoperative recovery indicators, patients in Group 2 exhibited significant advantages over those in Group 1 in mechanical ventilation time, ICU length of stay, postoperative hospital stay, incidence of thromboembolic events, and need for renal replacement therapy. Regarding the underlying reasons, although there was no statistically significant difference in the reduction of pulmonary arterial pressure between the two groups following Treprostinil treatment, Treprostinil 's pharmacological effects extend beyond reducing pulmonary vascular resistance. It includes reducing systemic ventricular afterload, inhibiting platelet aggregation, and suppressing smooth muscle cell proliferation. It is plausible that the higher dosage of Treprostinil in Group 2 exerted its comprehensive pharmacological effects, thereby improving patients' surgical outcomes. Furthermore, the superior postoperative recovery indicators in Group 2 patients further underscore the safety and efficacy of standardized Treprostinil treatment.\u003c/p\u003e \u003cp\u003eNevertheless, this study has several limitations. Firstly, the small sample size may have led to a lack of statistical power to detect clinically significant differences. Future studies should aim at expand the sample size or conduct multicenter research to address this limitation. Secondly, due to the retrospective nature of this analysis, the evidence level remains suboptimal. Future research should consider conducting randomized controlled trials (RCTs) or matched cohort studies to strengthen the evidence base. Thirdly, since our center's surgeons do not routinely insert atrial pressure monitoring catheters, the hemodynamic parameters in this study were not comprehensive. Future studies could consider utilizing monitoring systems such as PICCO to refine hemodynamic parameters.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with single ventricle and concomitant PAH undergoing TCPC surgery, the use of Treprostinil can reduce pulmonary arterial pressure. Standardized Treprostinil administration (achieving the maintenance dosage within 24 hours postoperatively, i.e., the maximum tolerated dose) can expedite postoperative recovery, reduce the incidence of major complications, and facilitate early postoperative recovery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflicts of Interest: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Source of Funding: This study was supported by the Clinical Research Foundation of the National Health Commission of the People\u0026rsquo;s Republic of China (grant number 2022-GSP-GG-32 and 2022-GSP-QN-13).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Data sharing statement\u003c/p\u003e\n\u003cp\u003eAll data collected for the study, including individual participant data, a data dictionary defining each field in the set, and related documents such as the study protocol and statistical analysis results, will be made available to others with publication by email addresses with the consent of the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Author contributions\u003c/p\u003e\n\u003cp\u003eXiaofeng Wang and Shilin Wang contributed to the article writing, data collection, and statistical analysis. Ruihuan Shen and Zhongyuan Lu drafted and critically reviewed the manuscript. Xu Wang contributed to the study design and the review of the final article. All authors contributed to the manuscript and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBecker K, Uebing A, Hansen JH. Pulmonary vascular disease in Fontan circulation-is there a rationale for pulmonary vasodilator therapies? Cardiovasc Diagn Ther. 2021 Aug;11(4):1111-1121.\u003c/li\u003e\n\u003cli\u003eAl-Shawk M, Banjoko A, Axiaq A, Amin K, Harky A. Perioperative and long-term management of Fontan patients. Cardiol Young. 2021 May;31(5):775-785.\u003c/li\u003e\n\u003cli\u003eSimonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis\u003csup\u003e \u003c/sup\u003eMA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019 Jan 24;53(1):1801913.\u003c/li\u003e\n\u003cli\u003eBaumgartner H, De Backer J, Babu-Narayan SV, Budts W, Chessa M, Diller GP, et al. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J. 2021 Feb 11;42(6):563-645.\u003c/li\u003e\n\u003cli\u003eGoldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011;123:1185\u0026ndash;1193.\u003c/li\u003e\n\u003cli\u003eRhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, Milliren CE, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 2013;168:2435\u0026ndash;2440.\u003c/li\u003e\n\u003cli\u003eHebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, et al. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation. 2014;130:2021\u0026ndash;2030.\u003c/li\u003e\n\u003cli\u003eConstantine A, Dimopoulos K, Jenkins P, Tulloh RMR, Condliffe R, Jansen K, et al. Use of Pulmonary Arterial Hypertension Therapies in Patients with a Fontan Circulation: Current Practice Across the United Kingdom. J Am Heart Assoc. 2022 Jan 4;11(1):e023035.\u003c/li\u003e\n\u003cli\u003eAblonczy L, Tordas D, Kis E, Szatm\u0026aacute;ri A. Use of subcutaneous Treprostinil in pediatric pulmonary arterial hypertension-Bridge-to-transplant or long-term treatment? Pediatr Transplant. 2018 Mar;22(2).\u003c/li\u003e\n\u003cli\u003eChen X, Cai XM, Zhang MJ, Xu JH, Li H, Xu ZM. Pharmacokinetics of Treprostinil in children with functional single-ventricle pulmonary arterial hypertension: a randomized controlled trial. Ann Transl Med. 2021 Jul;9(14):1163.\u003c/li\u003e\n\u003cli\u003eSullivan RT, Handler SS, Feinstein JA, Ogawa M, Liu E, Ma M, et al. Subcutaneous Treprostinil Improves Surgical Candidacy for Next Stage Palliation in Single Ventricle Patients With High-Risk Hemodynamics. Semin Thorac Cardiovasc Surg. 2022 Aug 2:S1043-0679(22)00191-5.\u003c/li\u003e\n\u003cli\u003eJeremiasen I, Tran-Lundmark K, Idris N, Tran PK, Moledina S. Pulmonary Vasodilator Therapy in Children with Single Ventricle Physiology: Effects on Saturation and Pulmonary Arterial Pressure. Pediatr Cardiol. 2020 Dec;41(8):1651-1659.\u003c/li\u003e\n\u003cli\u003eRuopp NF, Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA. 2022 Apr 12;327(14):1379-1391.\u003c/li\u003e\n\u003cli\u003eSiddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017 Jul;92(1):37-46.\u003c/li\u003e\n\u003cli\u003eSkoro-Sajer N, Lang I, Naeije R. Treprostinil for pulmonary hypertension. Vasc Health Risk Manag. 2008;4(3):507-13.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Single ventricle, Pulmonary hypertension, Total cavo-pulmonary connection, Treprostinil","lastPublishedDoi":"10.21203/rs.3.rs-4169877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4169877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal cavo-pulmonary connection (TCPC) is a palliative treatment for single ventricular malformations. For high-risk patients (preoperative mean pulmonary arterial pressure, mPAP \u0026gt; 15 mmHg), between the inhaled and oral targeted medications, the application of intravenous Treprostinil as a bridge therapy to achieve \"seamless\" management is core postoperative treatment. This study intends to explore the effect of different administration regimens on early postoperative recovery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a retrospective cohort study. High-risk pediatric patients (age ≤ 14 years) who underwent TCPC procedure in Fu Wai Hospital from 2015 to 2022 were included. Since the regimen of Treprostinil was standardized in our center in 2021, the patients in 2020 and before were included in group 1, patients in 2021 and 2022 were included in group 2. The hemodynamic parameters were compared before and after the maintenance dose of Treprostinil. The differences of demographic characteristics, surgical data and postoperative recovery were compared between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 51 pediatric patients was included. The group 1 included 35 patients who received Treprostinil at 1–3 post-operative days and an average dose of 12 ± 4 ng/(kg·min). The group 2 included 16 patients who received Treprostinil within postoperative 1 day and an average dose of 22 ± 7 ng/(kg·min). There were no significant differences between the two groups in terms of age, weight, preoperative percutaneous oxygen saturation and mPAP, heterotaxia syndrome, TCPC procedure type, other concurrent procedure, cardiopulmonary bypass time and aortic cross clamp proportion (p \u0026gt; 0.05). After 24 hours of Treprostinil treatment, the mPAP in group 1 reduced from 17 ± 3 mmHg to 15 ± 2mmHg (p \u0026lt; 0.001), and in group 2 from 17 ± 2 mmHg to 14 ± 2mmHg (p \u0026lt; 0.001), with no difference between groups. In the postoperative recovery, patients in Group 2 exhibited a reduced duration of mechanical ventilation, 19 (11, 25) hours vs 69 (23, 189) hours, p = 0.001; a shorter stay in the ICU, 8 (6,12) days vs 16 (9,26) days, p = 0.006; and a shorter postoperative length of stay, 27 (17,55) days vs 39 (29,58) days, p = 0.032. Patients in group 2 also exhibited a lower incidence of thromboembolic events, 0 (0/26) vs 26% (9/35), p = 0.043; and the need for renal replacement therapy, 0 (0/26) vs 31% (11/35), p = 0.011.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter TCPC procedure, the standardized application of Treprostinil can improve the postoperative recovery, reduce the incidence of important complications and benefit the early postoperative recovery.\u003c/p\u003e","manuscriptTitle":"The effects of standardized intravenous Treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 17:40:43","doi":"10.21203/rs.3.rs-4169877/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-20T13:31:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-22T05:05:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-15T12:54:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"cffedabe-858e-4c52-ac1d-8229907f479f","date":"2024-04-03T10:58:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"1c884c0d-9bce-4dcd-ab9f-ae1b95d9423a","date":"2024-04-01T12:53:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-30T10:38:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-27T08:55:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-27T07:20:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2024-03-26T12:37:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e9f60610-ab5d-4de4-bbb8-fa029d499048","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T16:03:47+00:00","versionOfRecord":{"articleIdentity":"rs-4169877","link":"https://doi.org/10.1186/s40001-024-02077-y","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2024-10-01 15:57:57","publishedOnDateReadable":"October 1st, 2024"},"versionCreatedAt":"2024-03-29 17:40:43","video":"","vorDoi":"10.1186/s40001-024-02077-y","vorDoiUrl":"https://doi.org/10.1186/s40001-024-02077-y","workflowStages":[]},"version":"v1","identity":"rs-4169877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4169877","identity":"rs-4169877","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}