Effect of Heart Rate Control with Esmolol on Oxygen Metabolism and Clinical Outcomes in VVECMO patients: a Multicenter, Prospective, Randomized Controlled Study

Effect of Heart Rate Control with Esmolol on Oxygen Metabolism and Clinical Outcomes in VVECMO patients: a Multicenter, Prospective, Randomized Controlled Study | 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 Study protocol Effect of Heart Rate Control with Esmolol on Oxygen Metabolism and Clinical Outcomes in VVECMO patients: a Multicenter, Prospective, Randomized Controlled Study Wenxiong Hu, Liusheng Hou, Zhanyuan Zhao, Ting Yang, Shiyong Zeng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8231264/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Veno-venous extracorporeal membrane oxygenation (VV ECMO) has been widely used in patients with respiratory failure. For patients with refractory hypoxemia treated with VV ECMO, β-blockers can improve oxygenation by reducing cardiac output (CO) and increasing ECMO flow /CO ratio. However, it has been suggested that β-blockers aggravate tissue hypoxia by reducing systemic oxygen delivery (DO2) by controlling heart rate. Therefore, the effect of heart rate control by esmolol on oxygen metabolism and clinical outcomes in VV ECMO patients is still controversial and needs further study. Methods This study was a randomized (1:1), prospective, multi-center, parallel controlled clinical study. Patients with acute respiratory distress syndrome (ARDS) were treated with VV ECMO. After signing the informed consent form and meeting the inclusion/exclusion criteria, patients will be randomly assigned to the esmolol group or the control group, with 60 patients in each group, for a total of 120 patients to be recruited. The primary endpoint was 28-day survival. Secondary endpoints included oxygen metabolism, ventilator parameters (lung-protective ventilation), norepinephrine equivalent, duration of mechanical ventilation, length of ICU stay, and length of hospital stay. Discussion 1. To investigate the effect of heart rate control by β-blocker on 28-day survival rate in VV ECMO patients; 2. To investigate the effect of heart rate control by β-blockers on circulation in VV ECMO patients and whether lowering DO2 causes tissue hypoxia. Figures Figure 1 Figure 2 Background Veno-venous extracorporeal membrane oxygenation (VV ECMO) is increasingly used to treat the optimal ventilator strategy (FiO2 > 80%, VT to 6ml/kg, PEEP ≥ 10) [ 1 ] ineffective patients with severe, acute and reversible respiratory failure [ 2 ] . VV ECMO can significantly improve the survival rate for ARDS patients [ 1 ] . The purpose of VV ECMO treatment is to achieve systemic oxygenation through extracorporeal circulation, remove carbon dioxide, promote lung rest, reduce ventilator-induced lung injury (VILI), and reduce harmful complications [ 2 , 3 ] . In addition, VV ECMO can reduce the need for sedative drugs and promote safe spontaneous breathing in patients [ 4 , 5 ] . Clinical studies have found that some ARDS patients with severe inflammatory response may still have refractory hypoxemia after receiving VVECMO treatment [ 6 ] . In order to solve refractory hypoxemia after VVECMO, the following measures are usually taken: 1. Measures such as routine raising of hemoglobin levels, sedation, mild hypothermia, and management of recirculation usually have limited effectiveness [ 7 ] . 2. Increasing the oxygen concentration provided by the ventilator (FIO2) and more aggressive ventilator strategies, such as the use of lung recruitment, high PEEP and high driving pressure, can help to improve oxygenation, but can increase the risk of lung overexpansion and aggravate ventilator-induced lung injury [ 8 – 11 ] . Studies have shown that β-blockers can improve hemodynamic parameters and clinical prognosis of patients with sepsis by controlling heart rate [12]. Professor Vincent's study showed that intravenous β-blockers can increase PaO2 levels in patients with acute hypoxemia [13]. In the hyperhemodynamic state caused by high sepsis, cardiac output (CO) can be significantly higher than ECMO flow. When the ECMO flow /CO ratio is 0.6, VV ECMO can provide adequate oxygen supply [ 11 ] . By reducing CO in patients, β-blockers increase the ECMO flow /CO ratio, thereby improving the oxygenation of patients [ 14 – 17 ] . Studies have shown that β-blockers can improve hemodynamic parameters and clinical prognosis of patients with sepsis by controlling heart rate [ 12 ] . Professor Vincent's research shows that intravenous β-blockers can increase PaO2 levels in patients with acute hypoxemia [ 13 ] . Therefore, β-blockers are used as a treatment in patients with refractory hypoxemia treated with VV ECMO [ 1 ] . Beta blockers improve the oxygenation status of patients by reducing CO in patients, thereby increasing the ECMO flow/CO ratio [ 14 – 17 ] . Studies have shown that VV ECMO can provide adequate oxygen supply when the ECMO/CO ratio is > 0.6 [ 11 ] . In the hyper-hemodynamic state caused by high sepsis, the cardiac output (CO) can be significantly higher than the ECMO flow when the ECMO flow/CO ratio is < 0. 6. Excessive deoxygenated blood is mixed with oxygenated blood from ECMO, resulting in the reduction of SVO2 and SPO2 oxygen saturation [ 7 , 11 ] . Studies have pointed out that β-blockers reduce cardiac output (CO) by controlling the heart rate, which may lead to the decrease of systemic oxygen supply (DO2), thus aggravating the condition of tissue hypoxia and increasing the anaerobic metabolic process [ 7 ] . Studies have shown that β-blockers can improve oxygenation in ARDS patients undergoing VV ECMO. However, there is still uncertainty about whether β-blockers improve 28-day survival, and whether β-blockers affect circulation and cause tissue hypoxia, so the aim of this study is to investigate these issues. Method This clinical study was a randomized (1:1), prospective, multi-center, parallel controlled clinical study. Patients with acute respiratory distress syndrome (ARDS) treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) were enrolled. After signing the informed consent from, patients who met the inclusion/exclusion criteria were randomly assigned to receive treatment in the esmolol group or the control group, with a planned enrollment of 120 patients (Fig. 1 ). The study protocol was approved by the site ethics committee on February 25, 2025 (version 4.1 - November 9, 2024). Approval from the local ethics committee was required before trial initiation at each participating site. Prior to the initiation of the clinical trial, the investigator will provide each patient with detailed clinical trial information and obtain their informed consent..Patients who were unable to provide informed consent at enrollment were offered the option of delaying consent. The investigator will provide the patient or their legally designated representative with information about the study and obtain informed consent. Patients who did not consent to participate were clearly informed of their right to refuse the use of data obtained from clinical trials. Setting This study was led by the Department of Critical Care Medicine of Zhongshan People's Hospital, and Southern Hospital of Southern Medical University, Foshan Shunde People's Hospital, Dongwan People's Hospital, Guiyang Medical University First Affiliated Hospital and Guangxi Liuzhou Workers' Hospital were jointly completed as participants. The study plan included approximately 20 patients in each study center (Fig. 2 ); Eligibility Inclusion criteria: 1.ARDS patients were treated with VV ECMO for less than 48 hours; 2.HR ≥ 100 beats/min; 3. After adequate fluid resuscitation (PCWP ≥ 12mmhg, CVP ≥ 8mmhg); 4. The family voluntarily signs an informed consent form; Exclusion criteria: 1. Age 70 years old, 2. In pregnancy or breastfeeding; 3. End-stage chronic lung disease; 4. Irreversible ARDS or lung function cannot be restored; 5. Contraindications to beta blockers (asthma, pathological bradycardia); 6. The researchers judged that it was not suitable for participating in this study. (Fig. 1 ) Randomization In this study, patients meeting the inclusion/exclusion criteria will be randomly assigned to the esmolol group or the control group in a 1:1 ratio. For example, the central randomization method can be expressed as follows: the randomization method is central randomization, and the safety network-based system uses the minimization method for randomization. Intervention Esmolol group Participants randomly assigned to the experimental group will receive esmolol treatment. The initial dose of treatment was 25 mg × h − 1, followed by increments of 50 mg × h − 1 every 20 minutes until the target threshold was reached after 12 hours. Thereafter, esmolol treatment was continued to maintain heart rate stability, with a maximum dose not exceeding 2000 mg×h − 1. Control group Patients who were randomly assigned to the control group were not to receive esmolol unless tachycardia developed or beta-blocker use was clearly indicated, in which case clinicians could withdraw from the study at their discretion. The experimental group and the control group jointly intervene Both groups were required to receive invasive blood pressure, central venous pressure and cardiac output monitoring; The circulatory management criteria of the two groups were MAP ≥ 65mmHg and CI > 2.2 L/min/m2; Volume management strategies of the two groups: in the early stage, the main strategy was to maintain the stability of circulation and ECMO flow. After reaching a stable state, the fluid load could be reduced to reduce the risk of pulmonary edema. Anticoagulation therapy (heparin, argatroban, bivalirudin, etc.) aimed at minimizing the risk of bleeding and thrombosis Carbon dioxide management in both groups: CO2 was gradually reduced to the normal range (35-45mmHg); Patients in both groups received sedation and analgesia: deep sedation could be implemented within 24–48 hours of VV ECMO treatment, and temporary use of muscle relaxant if necessary. RASS score could be controlled from 0 to -1 after 24–48 hours of VV ECMO treatment; Patients in the two groups followed the VV ECMO management guidelines or Red Book guidelines issued by ELSO in 2021, such as renal insufficiency, identification of infectious pathogens, prevention and control of nosocomial infection, blood glucose management, and prevention of stress ulcer. Weaning plan: Reference Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO) and the Red Book guide. Stop Rules Criteria for termination of the trial (the trial should be terminated immediately if any of the following conditions are met) : 1) Serious safety issues occurred during the trial; 2) Major errors in the clinical trial protocol were identified during the trial; 3) The applicant for drug registration requests to terminate the test; 4) The ethics committee recommended that the trial be stopped; 5) The drug regulatory department instructed to terminate the trial. Follow-up ends The enrolled patients were subjected to a 60-day follow-up observation Endpoint Primary endpoint : 1. 28-day survival study of VVECMO patients(Table 2 ); Secondary endpoints : 1. The ventilator parameters, norepinephrine equivalent dose, mechanical ventilation time, ICU time, and hospital stay of the two groups of patients under the lung-protective ventilation strategy; 2. Analysis of organ and tissue metabolic status in the two groups(Table 2 ). Data management All subjects were required to complete the corresponding screening period before enrollment in the study, and were strictly screened according to the inclusion and exclusion criteria. (1) Informed consent was signed (2) Record demographic information: including date of birth, gender, and abbreviation; (3) Medical history collection and physical examination: gender, age, height, weight, underlying diseases, and APACHEII score (4) Other laboratory examination categories: heart rate, oxygenation index, norepinephrine equivalent dose, lactate level, functional status of each organ (liver, kidney, heart, lung, coagulation system), ARDS etiology, tracheal intubation to VVECMO start time, ventilator parameters, etc. (Table 1 ); Table 1 Baseline Characteristics of the Study Patient Esmolol group Control group P value Age,median(IQR),Y Men,NO(%) Body mass index,median(IQR),Y Preexisting conditions, No. (%) Coronary artery disease Congestive heart failure Chronic kidney disease Chronic obstructive pulmonary disease APACHEII score, median (IQR) Etiology of VVECMO Heart rate median(IQR) /min PaO2/FIO2, median (IQR), mm Hg Norepinephrine equivalent dosage, median(IQR), ug/kg/min Lactic Acid(mmol/L) Organ function assessment(SOFA) Ventilation parameters,median (IQR) FIO2 Positive end-expiratory pressure, cm H2O Tidal volume, mL/kg of predicted body weight Respiratory rate, /min Plateau pressure, cm H2O Respiratory system compliance, mL/cm H2O SOFA: Sequential Organ Failure Score FIO2: Fraction of Inspired Oxygen Table 2 Primary and Secondary End Points Outcomes/events Esmolol group Control group P value Primary outcome Successful VV ECMO weaning by day 28, No. (%) Competing events Death before ECMO weaning, No. (%) ECMO weaning failure, No. (%)b Secondary outcomes Heart rate median(IQR) /min Norepinephrine equivalent dosage, median(IQR), ug/kg/min Organ function assessment(SOFA) median (IQR) Lactic Acid(mmol/L) median (IQR) DO2 VO2 ECMO weaning time median (IQR) lung-protective ventilation strategy Ventilation parameters,median (IQR) FIO2 Positive end-expiratory pressure, cm H2O Tidal volume, mL/kg of predicted body weight Respiratory rate, /min Plateau pressure, cm H2O Respiratory system compliance, mL/cm H2O mechanical ventilation time median (IQR) ICU time median (IQR) hospital stay median (IQR) DO2: Oxygen Delivery VO2༚Oxygen Consumption (5) The following data were recorded throughout the study: the indicators of the two groups of patients, including heart rate, blood pressure, oxygenation index, norepinephrine-effective dose, lactate level, functional status of each organ (liver, kidney, heart, lung, coagulation system), ventilator parameter changes (FiO2, platform pressure, drive pressure, PEEP), QECMO, QCO, DO2, VO2, VVECMO withdrawal time, mechanical ventilation time, ICU time, hospital stay and survival status (Table 2 ); (6) Follow-up evaluation 60 days after discharge; Validity and safety evaluation Effectiveness evaluation 1. Comparison of survival rate between the two groups; 2. The differences of mechanical ventilation time, ICU time and hospital stay between the two groups; Safety evaluation 1. Esmolol may trigger a negative inotropic effect and has the risk of reducing blood pressure. During the use of esmolol, vasoactive drugs such as norepinephrine were used to maintain blood pressure, and the equivalent dose of norepinephrine was compared between the two groups; 2. In patients with VV ECMO, reduction of heart rate with esmolol can lead to a decrease in cardiac output, thereby affecting oxygen delivery. Therefore, it is necessary to evaluate the lactate level and the hypoxia status of various organs and tissues. Statistical Analysis Sample size The type of study design, such as a parallel controlled study, was described, and the sample size was scientifically estimated based on the main indicators. On the basis of statistical principles, the number of cases needed to achieve the intended goal of the trial was calculated. Statistical analysis Continuous variables were described as mean ± standard deviation, and categorical variables were described as absolute numbers (percentage). Normally distributed continuous variables were analyzed by Student t test, and non-normally distributed continuous variables were analyzed by Wilcoxon 2-sample test. Categorical variables were analyzed using the χ2 test or Fisher's exact test. Normality tests for continuous variables were performed using the Shapiro-Wilk method. Kaplan-Meier curves were constructed to compare the 60-day survival rates between the two groups. For the comparison of survival discharge rates, a multivariate Cox proportional hazards model was developed, including all variables that were significant in the univariate analysis and those that were considered clinically relevant. A P value of less than 0.05 was considered statistically significant. Research Organization The study was initiated by Liang Hongkai, chief physician of Zhongshan People's Hospital, and the study protocol was designed by Hou Liusheng, deputy chief physician and Hu Wenxiong, attending physician. The research partners included Nanfang Hospital of Southern Medical University, Shunde People's Hospital of Foshan City, Dongguan People's Hospital, the First Affiliated Hospital of Guiyang Medical University, and Liuzhou Workers' Hospital of Guangxi Province. Each participating center will appoint a local investigator to lead the study.The principal investigators were responsible for administrative management and communication with local investigators and helped the participating clinical sites with trial administration, record-keeping, and data management. The study will be conducted with financial support from Qilu Pharmaceutical Co., LTD. The funders assume no responsibility in the decision to analyze and interpret the results of the study or to submit the report for publication. Local investigators vouch for the integrity of data collection.All adverse events will be reported to the drug registration applicant, the National Medical Products Administration, the provincial Food and Drug Administration, the ethics committee of the corresponding clinical trial center and the Medical Department of the Medical Administration Bureau of the Health Commission within 24 hours, and to the ethics committee of the team leader's unit in a timely manner. Insurance will be granted to selected patients to cover all unanticipated adverse events arising from the study intervention. Discussion This study was a randomized (1:1), prospective, multi-center, parallel controlled clinical trial. To evaluate the efficacy and safety of esmolol in reducing heart rate and increasing ECMO/CO ratio in ARDS patients with refractory hypoxemia after VVECMO treatment. Some studies have suggested that β-blockers can improve the hemodynamic indexes and clinical prognosis of patients with sepsis by controlling the ventricular rate [ 12 ] . For ARDS patients with refractory hypoxemia after VVECMO treatment, esmolol is used to control the heart rate and reduce the cardiac output (CO) of patients, thereby increasing the ECMO flow /CO ratio and helping to improve oxygenation [ 14 – 17 ] . This method is conducive to the implementation of lung protective ventilation strategy, reduce ventilator-induced lung injury (VILI), and reduce the incidence of harmful complications [ 2 , 3 ] , so as to compare the 28-day survival rate and 60-day follow-up survival rate between the two groups. Ventilator parameters (lung protective ventilation), duration of mechanical ventilation, length of ICU stay, length of hospital stay and other key indicators were evaluated to evaluate the feasibility of this treatment strategy for VV ECMO patients. Some studies believe that reducing CO by controlling heart rate through β-blockers will lead to decreased systemic oxygen supply (DO2), thereby aggravating tissue hypoxia and increasing anaerobic metabolism [ 7 ] , so as to evaluate the metabolism of tissues and organs of patients and evaluate the safety of the study for VVECMO patients. Studies have pointed out that β-blockers control heart rate and reduce cardiac output (CO), which will lead to a decrease in systemic oxygen supply (DO2), thereby aggravating tissue hypoxia and increasing anaerobic metabolism [ 7 ] . Therefore, the aim of this study was to evaluate the metabolic status of tissues and organs in patients to assess their potential impact on the safety of patients undergoing veno-venous extracorporeal membrane oxygenation (VVECMO). β-blockers have negative inotropic effects, and esmolol may cause a decrease in blood pressure in patients. The safety of heart rate control by esmolol on VV ECMO was evaluated by comparing the equivalent dose of norepinephrine and hemodynamic parameters (HR, MAP, CVP, PCWP, CI) between the two groups. The aim of this study is to evaluate the survival rate of VVECMO patients by controlling heart rate with esmolol, and to observe the lung protective ventilation strategy, mechanical ventilation time, ICU time, and hospital stay, and to evaluate the feasibility of the experiment. At the same time, the tissue metabolic status, including blood lactate level and sequential organ failure assessment (SOFA) score, norepinephrine equivalent dose and hemodynamics (HR, MAP, CVP, PCWP, CI) were evaluated in the two groups to evaluate the safety of the study. Research Endpoint The aim of this study was to investigate the effect of heart rate control by esmolol on survival in VV ECMO patients. The control of heart rate by esmolol can improve the ECMO flow /CO ratio, thereby improving the oxygenation status of patients and providing favorable conditions for the implementation of lung-protective ventilation strategy, which may improve the survival rate of patients. The primary end point was 28-day survival with VV ECMO. Secondary end points included: 1. Ventilator parameters, norepinephrine equivalent dose, mechanical ventilation time, ICU time, and hospital stay were compared between the two groups under the lung-protective ventilation strategy. 2. Metabolic status of organs and tissues in the two groups. Research Advantages and Limitations The advantage of our study are the randomized (1:1), prospective, multicenter, parallel-controlled clinical design. In the experimental group, the dose of esmolol was prescribed according to a defined protocol, which helped to control the heart rate in the target range. For VV ECMO patient management, this study refers to Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guidelines for treatment from the Extracorporeal Life Support Organization (ELSO). However, the limitation of this study is that blinding is not possible due to the nature of the intervention. In addition, patients treated with VVECMO are usually critically ill patients, and complications such as infection and bleeding may have an impact on the study results. Current status The study protocol is currently in the recruitment phase. The protocol was approved by the ethics review board on February 25, 2025. The study was planned to be conducted at our center and to recruit patients who met the inclusion criteria. Abbreviations VVECMO Veno-Venous Extracorporeal Membrane Oxygenation FiO2 Fraction of Inspired Oxygen PEEP Positive End-Expiratory Pressure VT Tidal Volume PaO2 Partial Pressure of Oxygen PaO2/FiO2 Index of Oxygenation VILI Ventilator Induced Lung Injury ARDS Acute Respiratory Distress Syndrome CO Cardiac Output QECMO ECMO Flow QCO CO Flow DO2 Oxygen Delivery VO2 Oxygen Consumption CVP Central Venous Pressure PCWP Pulmonary Capillary Wedge Pressure ICU Intensive Care Unit Lac Lactic Acid SOFA Sequential Organ Failure Score APACHEII Acute Physiology And Chronic Health Score II MAP Mean Arterial Pressure HR Heart Rate RR Respiration Rate Declarations Acknowledgements We would like to thank all the participant centers of the trial Ancillary and post-trial care The trial insurance to cover for non-negligent harm associated with the protocol. This will include cover for additional health care, compensation, or damages. Dissemination The results of the study will be disseminated through international peer-reviewed journals and medical conferences. There is no intention to use the services of professional writers. Funds The funding for the trial was provided by Qilu Pharmaceutical Co., LTD.The sponsor and funder are responsible for the development and dissemination of the project. Author information Department of Critical Care Medicine, Zhongshan People's Hospital,zhongshan,guangdong,Chnia Wenxiong Hu，Liusheng Hou ，Zhanyuan Zhao ,Ting Yang , Shiyong Zeng ,Hongkai Liang Contributions LSH, WXH and HKL participated in the intervention of the study. LSH and WXH participated in the study design. ZYZ, TY and SYZ drafted and revised this manuscript. LSH and WXH are the principal investigators and conceived the study. The authors read and approved the final manuscript. Corresponding author Correspondence to Hongkai liang Ethics approval and consent to participate Ethical review, protocol (version 5.1, February 25, 2025), and related documents have been approved by the Ethics Committee of Zhongshan People's Hospital (approval number: K2024-068-2). Clinical trial number: not applicable.Any major modification to the protocol requires approval from the ethics committee prior to implementation. Informed consent and written consent forms of patients are mandatory before study participation. After the participant has been assessed as eligible, they or their guardians will be invited by the treating physicians to discuss the details and sign the informed consent. Additional consent provisions for use of participant data in ancillary studies are required. This trial does not involve collecting biological specimens for storage. Consent for publication Written informed consent was obtained from the participants to publish this manuscript and accompanying images. Competing interests The authors declare that they have no competing interests. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. References Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome [J]. The New England journal of medicine, 2018, 378(21): 1965–75. Tonna J E, Abrams D, Brodie D, et al. Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO) [J]. 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Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults [J]. Intensive care medicine, 2013, 39(5): 838–46. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial [J]. Jama, 2013, 310(16): 1683–91. Vincent J L, Lignian H, Gillet J B, et al. Increase in PaO2 following intravenous administration of propranolol in acutely hypoxemic patients [J]. Chest, 1985, 88(4): 558–62. Guarracino F, Zangrillo A, Ruggeri L, et al. β-Blockers to optimize peripheral oxygenation during extracorporeal membrane oxygenation: a case series [J]. Journal of cardiothoracic and vascular anesthesia, 2012, 26(1): 58–63. Pappalardo F, Zangrillo A, Pieri M, et al. Esmolol administration in patients with VV ECMO: why not? [J]. Journal of cardiothoracic and vascular anesthesia, 2013, 27(4): e40. Pinto B B, Siegenthaler N, Tassaux D, et al. VV-ECMO and brave heart: A subtle competition? [J]. International journal of cardiology, 2015, 186: 45–7. Bunge J J H, Diaby S, Valle A L, et al. Safety and efficacy of beta-blockers to improve oxygenation in patients on veno-venous ECMO [J]. Journal of critical care, 2019, 53: 248–52. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8231264","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":578407710,"identity":"e1e88d6d-eaf8-43e5-bc65-fc4aa1bbf55d","order_by":0,"name":"Wenxiong Hu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wenxiong","middleName":"","lastName":"Hu","suffix":""},{"id":578407715,"identity":"4efaa077-21c4-4a57-9688-d221e0e7fc10","order_by":1,"name":"Liusheng 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14:23:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8231264/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8231264/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101205898,"identity":"7d17c4b7-b268-4e54-b11b-1861fba52a58","added_by":"auto","created_at":"2026-01-27 09:50:30","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":334587,"visible":true,"origin":"","legend":"","description":"","filename":"EffectofHeartRateControlwithEsmololonOxygenMetabolismandClinicalOutcomesinVVECMOpatientsaMulticenterProspectiveRandomizedControlledStudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/70c98315af1c3b1f05e6adad.docx"},{"id":101205866,"identity":"24d39049-82e3-40f6-8da0-0ba605897d90","added_by":"auto","created_at":"2026-01-27 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01:31:42","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69303,"visible":true,"origin":"","legend":"","description":"","filename":"e5d38cef4b4c463bb67df0f157ceab2c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/3fc41a1da6fed3e81b56ef6f.xml"},{"id":101100506,"identity":"03c7b671-ee78-4f46-b7ad-6987bb4020b5","added_by":"auto","created_at":"2026-01-26 01:31:42","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80449,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/cb47bc966f87bc6218495f45.html"},{"id":101100500,"identity":"ec8b94a4-0925-48db-9aef-7d342c946018","added_by":"auto","created_at":"2026-01-26 01:31:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":314479,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram VVECMO：Veno-venous extracorporeal membrane oxygenation PCWP：Pulmonary Capillary Wedge Pressure CVP：Central Venous Pressure\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/aaa0bb7a4d4b40925aa71d14.png"},{"id":101206445,"identity":"da2cd78e-57a4-40a3-ab77-87c2be00128d","added_by":"auto","created_at":"2026-01-27 09:56:14","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":385298,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/d2cafdae56f48ff030908789.jpeg"},{"id":108170803,"identity":"b0c1ef27-432e-4f59-9030-e43b23a5b223","added_by":"auto","created_at":"2026-04-30 06:56:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":986048,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8231264/v1/66e0fcd1-2377-40f9-9706-3f4cad60d6df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Heart Rate Control with Esmolol on Oxygen Metabolism and Clinical Outcomes in VVECMO patients: a Multicenter, Prospective, Randomized Controlled Study","fulltext":[{"header":"Background","content":"\u003cp\u003eVeno-venous extracorporeal membrane oxygenation (VV ECMO) is increasingly used to treat the optimal ventilator strategy (FiO2\u0026thinsp;\u0026gt;\u0026thinsp;80%, VT to 6ml/kg, PEEP\u0026thinsp;\u0026ge;\u0026thinsp;10) \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e ineffective patients with severe, acute and reversible respiratory failure \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. VV ECMO can significantly improve the survival rate for ARDS patients \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe purpose of VV ECMO treatment is to achieve systemic oxygenation through extracorporeal circulation, remove carbon dioxide, promote lung rest, reduce ventilator-induced lung injury (VILI), and reduce harmful complications \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In addition, VV ECMO can reduce the need for sedative drugs and promote safe spontaneous breathing in patients \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eClinical studies have found that some ARDS patients with severe inflammatory response may still have refractory hypoxemia after receiving VVECMO treatment \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. In order to solve refractory hypoxemia after VVECMO, the following measures are usually taken: 1. Measures such as routine raising of hemoglobin levels, sedation, mild hypothermia, and management of recirculation usually have limited effectiveness \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. 2. Increasing the oxygen concentration provided by the ventilator (FIO2) and more aggressive ventilator strategies, such as the use of lung recruitment, high PEEP and high driving pressure, can help to improve oxygenation, but can increase the risk of lung overexpansion and aggravate ventilator-induced lung injury \u003csup\u003e[\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies have shown that β-blockers can improve hemodynamic parameters and clinical prognosis of patients with sepsis by controlling heart rate [12]. Professor Vincent's study showed that intravenous β-blockers can increase PaO2 levels in patients with acute hypoxemia [13].\u003c/p\u003e \u003cp\u003eIn the hyperhemodynamic state caused by high sepsis, cardiac output (CO) can be significantly higher than ECMO flow. When the ECMO flow /CO ratio is \u0026lt;\u0026thinsp;0.6, excessive deoxygenated blood is mixed with oxygenated blood from ECMO, resulting in a decrease in SPO2 \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. When the ECMO/CO ratio is \u0026gt;\u0026thinsp;0.6, VV ECMO can provide adequate oxygen supply \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. By reducing CO in patients, β-blockers increase the ECMO flow /CO ratio, thereby improving the oxygenation of patients \u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies have shown that β-blockers can improve hemodynamic parameters and clinical prognosis of patients with sepsis by controlling heart rate \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Professor Vincent's research shows that intravenous β-blockers can increase PaO2 levels in patients with acute hypoxemia \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Therefore, β-blockers are used as a treatment in patients with refractory hypoxemia treated with VV ECMO \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Beta blockers improve the oxygenation status of patients by reducing CO in patients, thereby increasing the ECMO flow/CO ratio \u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies have shown that VV ECMO can provide adequate oxygen supply when the ECMO/CO ratio is \u0026gt;\u0026thinsp;0.6 \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In the hyper-hemodynamic state caused by high sepsis, the cardiac output (CO) can be significantly higher than the ECMO flow when the ECMO flow/CO ratio is \u0026lt;\u0026thinsp;0. 6. Excessive deoxygenated blood is mixed with oxygenated blood from ECMO, resulting in the reduction of SVO2 and SPO2 oxygen saturation \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies have pointed out that β-blockers reduce cardiac output (CO) by controlling the heart rate, which may lead to the decrease of systemic oxygen supply (DO2), thus aggravating the condition of tissue hypoxia and increasing the anaerobic metabolic process \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies have shown that β-blockers can improve oxygenation in ARDS patients undergoing VV ECMO. However, there is still uncertainty about whether β-blockers improve 28-day survival, and whether β-blockers affect circulation and cause tissue hypoxia, so the aim of this study is to investigate these issues.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThis clinical study was a randomized (1:1), prospective, multi-center, parallel controlled clinical study. Patients with acute respiratory distress syndrome (ARDS) treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) were enrolled. After signing the informed consent from, patients who met the inclusion/exclusion criteria were randomly assigned to receive treatment in the esmolol group or the control group, with a planned enrollment of 120 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The study protocol was approved by the site ethics committee on February 25, 2025 (version 4.1 - November 9, 2024). Approval from the local ethics committee was required before trial initiation at each participating site. Prior to the initiation of the clinical trial, the investigator will provide each patient with detailed clinical trial information and obtain their informed consent..Patients who were unable to provide informed consent at enrollment were offered the option of delaying consent. The investigator will provide the patient or their legally designated representative with information about the study and obtain informed consent. Patients who did not consent to participate were clearly informed of their right to refuse the use of data obtained from clinical trials.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSetting\u003c/h2\u003e \u003cp\u003e This study was led by the Department of Critical Care Medicine of Zhongshan People's Hospital, and Southern Hospital of Southern Medical University, Foshan Shunde People's Hospital, Dongwan People's Hospital, Guiyang Medical University First Affiliated Hospital and Guangxi Liuzhou Workers' Hospital were jointly completed as participants. The study plan included approximately 20 patients in each study center (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility\u003c/h3\u003e\n\u003cp\u003eInclusion criteria: 1.ARDS patients were treated with VV ECMO for less than 48 hours; 2.HR\u0026thinsp;\u0026ge;\u0026thinsp;100 beats/min; 3. After adequate fluid resuscitation (PCWP\u0026thinsp;\u0026ge;\u0026thinsp;12mmhg, CVP\u0026thinsp;\u0026ge;\u0026thinsp;8mmhg); 4. The family voluntarily signs an informed consent form;\u003c/p\u003e \u003cp\u003eExclusion criteria: 1. Age\u0026thinsp;\u0026lt;\u0026thinsp;18 years old or \u0026gt;\u0026thinsp;70 years old, 2. In pregnancy or breastfeeding; 3. End-stage chronic lung disease; 4. Irreversible ARDS or lung function cannot be restored; 5. Contraindications to beta blockers (asthma, pathological bradycardia); 6. The researchers judged that it was not suitable for participating in this study. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003eIn this study, patients meeting the inclusion/exclusion criteria will be randomly assigned to the esmolol group or the control group in a 1:1 ratio. For example, the central randomization method can be expressed as follows: the randomization method is central randomization, and the safety network-based system uses the minimization method for randomization.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eEsmolol group\u003c/b\u003e \u003c/p\u003e \u003cp\u003eParticipants randomly assigned to the experimental group will receive esmolol treatment. The initial dose of treatment was 25 mg \u0026times; h\u0026thinsp;\u0026minus;\u0026thinsp;1, followed by increments of 50 mg \u0026times; h\u0026thinsp;\u0026minus;\u0026thinsp;1 every 20 minutes until the target threshold was reached after 12 hours. Thereafter, esmolol treatment was continued to maintain heart rate stability, with a maximum dose not exceeding 2000 mg\u0026times;h\u0026thinsp;\u0026minus;\u0026thinsp;1.\u003c/p\u003e\n\u003ch3\u003eControl group\u003c/h3\u003e\n\u003cp\u003ePatients who were randomly assigned to the control group were not to receive esmolol unless tachycardia developed or beta-blocker use was clearly indicated, in which case clinicians could withdraw from the study at their discretion.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eThe experimental group and the control group jointly intervene\u003c/h2\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eBoth groups were required to receive invasive blood pressure, central venous pressure and cardiac output monitoring;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eThe circulatory management criteria of the two groups were MAP\u0026thinsp;\u0026ge;\u0026thinsp;65mmHg and CI\u0026thinsp;\u0026gt;\u0026thinsp;2.2 L/min/m2;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eVolume management strategies of the two groups: in the early stage, the main strategy was to maintain the stability of circulation and ECMO flow. After reaching a stable state, the fluid load could be reduced to reduce the risk of pulmonary edema.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAnticoagulation therapy (heparin, argatroban, bivalirudin, etc.) aimed at minimizing the risk of bleeding and thrombosis\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eCarbon dioxide management in both groups: CO2 was gradually reduced to the normal range (35-45mmHg);\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients in both groups received sedation and analgesia: deep sedation could be implemented within 24\u0026ndash;48 hours of VV ECMO treatment, and temporary use of muscle relaxant if necessary. RASS score could be controlled from 0 to -1 after 24\u0026ndash;48 hours of VV ECMO treatment;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients in the two groups followed the VV ECMO management guidelines or Red Book guidelines issued by ELSO in 2021, such as renal insufficiency, identification of infectious pathogens, prevention and control of nosocomial infection, blood glucose management, and prevention of stress ulcer.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eWeaning plan: Reference Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO) and the Red Book guide.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStop Rules\u003c/h3\u003e\n\u003cp\u003eCriteria for termination of the trial (the trial should be terminated immediately if any of the following conditions are met) :\u003c/p\u003e \u003cp\u003e1) Serious safety issues occurred during the trial;\u003c/p\u003e \u003cp\u003e2) Major errors in the clinical trial protocol were identified during the trial;\u003c/p\u003e \u003cp\u003e3) The applicant for drug registration requests to terminate the test;\u003c/p\u003e \u003cp\u003e4) The ethics committee recommended that the trial be stopped;\u003c/p\u003e \u003cp\u003e5) The drug regulatory department instructed to terminate the trial.\u003c/p\u003e\n\u003ch3\u003eFollow-up ends\u003c/h3\u003e\n\u003cp\u003eThe enrolled patients were subjected to a 60-day follow-up observation\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEndpoint\u003c/h2\u003e \u003cp\u003e \u003cb\u003ePrimary endpoint\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e1. 28-day survival study of VVECMO patients(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary endpoints\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e1. The ventilator parameters, norepinephrine equivalent dose, mechanical ventilation time, ICU time, and hospital stay of the two groups of patients under the lung-protective ventilation strategy; 2. Analysis of organ and tissue metabolic status in the two groups(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData management\u003c/h2\u003e \u003cp\u003eAll subjects were required to complete the corresponding screening period before enrollment in the study, and were strictly screened according to the inclusion and exclusion criteria.\u003c/p\u003e \u003cp\u003e (1) Informed consent was signed\u003c/p\u003e \u003cp\u003e(2) Record demographic information: including date of birth, gender, and abbreviation;\u003c/p\u003e \u003cp\u003e(3) Medical history collection and physical examination: gender, age, height, weight, underlying diseases, and APACHEII score\u003c/p\u003e \u003cp\u003e(4) Other laboratory examination categories: heart rate, oxygenation index, norepinephrine equivalent dose, lactate level, functional status of each organ (liver, kidney, heart, lung, coagulation system), ARDS etiology, tracheal intubation to VVECMO start time, ventilator parameters, etc. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\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 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of the Study Patient\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\u003eEsmolol group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\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,median(IQR),Y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen,NO(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index,median(IQR),Y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreexisting conditions, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronary artery disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongestive heart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic obstructive\u003c/p\u003e \u003cp\u003epulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHEII score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEtiology of VVECMO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate median(IQR) /min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaO2/FIO2, median (IQR), mm Hg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorepinephrine equivalent dosage, median(IQR), ug/kg/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactic Acid(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrgan function assessment(SOFA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVentilation parameters,median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive end-expiratory pressure, cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTidal volume, mL/kg of predicted body weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory rate, /min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlateau pressure, cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory system compliance, mL/cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSOFA: Sequential Organ Failure Score FIO2: Fraction of Inspired Oxygen\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \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 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrimary and Secondary End Points\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 \u003cp\u003eOutcomes/events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEsmolol group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\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\u003ePrimary outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccessful VV ECMO weaning by day 28, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompeting events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath before ECMO weaning, No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECMO weaning failure, No. (%)b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate median(IQR) /min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorepinephrine equivalent dosage, median(IQR), ug/kg/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrgan function assessment(SOFA) median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactic Acid(mmol/L) median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECMO weaning time median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elung-protective ventilation strategy Ventilation parameters,median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive end-expiratory pressure, cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTidal volume, mL/kg of predicted body weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory rate, /min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlateau pressure, cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory system compliance, mL/cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emechanical ventilation time median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU time median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehospital stay median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDO2: Oxygen Delivery VO2༚Oxygen Consumption\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e(5) The following data were recorded throughout the study: the indicators of the two groups of patients, including heart rate, blood pressure, oxygenation index, norepinephrine-effective dose, lactate level, functional status of each organ (liver, kidney, heart, lung, coagulation system), ventilator parameter changes (FiO2, platform pressure, drive pressure, PEEP), QECMO, QCO, DO2, VO2, VVECMO withdrawal time, mechanical ventilation time, ICU time, hospital stay and survival status (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e);\u003c/p\u003e \u003cp\u003e(6) Follow-up evaluation 60 days after discharge;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eValidity and safety evaluation\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEffectiveness evaluation\u003c/strong\u003e \u003cp\u003e1. Comparison of survival rate between the two groups; 2. The differences of mechanical ventilation time, ICU time and hospital stay between the two groups;\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSafety evaluation\u003c/strong\u003e \u003cp\u003e1. Esmolol may trigger a negative inotropic effect and has the risk of reducing blood pressure. During the use of esmolol, vasoactive drugs such as norepinephrine were used to maintain blood pressure, and the equivalent dose of norepinephrine was compared between the two groups; 2. In patients with VV ECMO, reduction of heart rate with esmolol can lead to a decrease in cardiac output, thereby affecting oxygen delivery. Therefore, it is necessary to evaluate the lactate level and the hypoxia status of various organs and tissues.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe type of study design, such as a parallel controlled study, was described, and the sample size was scientifically estimated based on the main indicators. On the basis of statistical principles, the number of cases needed to achieve the intended goal of the trial was calculated.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical variables were described as absolute numbers (percentage). Normally distributed continuous variables were analyzed by Student t test, and non-normally distributed continuous variables were analyzed by Wilcoxon 2-sample test. Categorical variables were analyzed using the χ2 test or Fisher's exact test. Normality tests for continuous variables were performed using the Shapiro-Wilk method. Kaplan-Meier curves were constructed to compare the 60-day survival rates between the two groups. For the comparison of survival discharge rates, a multivariate Cox proportional hazards model was developed, including all variables that were significant in the univariate analysis and those that were considered clinically relevant. A P value of less than 0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eResearch Organization\u003c/h2\u003e \u003cp\u003eThe study was initiated by Liang Hongkai, chief physician of Zhongshan People's Hospital, and the study protocol was designed by Hou Liusheng, deputy chief physician and Hu Wenxiong, attending physician. The research partners included Nanfang Hospital of Southern Medical University, Shunde People's Hospital of Foshan City, Dongguan People's Hospital, the First Affiliated Hospital of Guiyang Medical University, and Liuzhou Workers' Hospital of Guangxi Province. Each participating center will appoint a local investigator to lead the study.The principal investigators were responsible for administrative management and communication with local investigators and helped the participating clinical sites with trial administration, record-keeping, and data management. The study will be conducted with financial support from Qilu Pharmaceutical Co., LTD. The funders assume no responsibility in the decision to analyze and interpret the results of the study or to submit the report for publication. Local investigators vouch for the integrity of data collection.All adverse events will be reported to the drug registration applicant, the National Medical Products Administration, the provincial Food and Drug Administration, the ethics committee of the corresponding clinical trial center and the Medical Department of the Medical Administration Bureau of the Health Commission within 24 hours, and to the ethics committee of the team leader's unit in a timely manner. Insurance will be granted to selected patients to cover all unanticipated adverse events arising from the study intervention.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was a randomized (1:1), prospective, multi-center, parallel controlled clinical trial. To evaluate the efficacy and safety of esmolol in reducing heart rate and increasing ECMO/CO ratio in ARDS patients with refractory hypoxemia after VVECMO treatment.\u003c/p\u003e \u003cp\u003eSome studies have suggested that β-blockers can improve the hemodynamic indexes and clinical prognosis of patients with sepsis by controlling the ventricular rate \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. For ARDS patients with refractory hypoxemia after VVECMO treatment, esmolol is used to control the heart rate and reduce the cardiac output (CO) of patients, thereby increasing the ECMO flow /CO ratio and helping to improve oxygenation \u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This method is conducive to the implementation of lung protective ventilation strategy, reduce ventilator-induced lung injury (VILI), and reduce the incidence of harmful complications \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, so as to compare the 28-day survival rate and 60-day follow-up survival rate between the two groups. Ventilator parameters (lung protective ventilation), duration of mechanical ventilation, length of ICU stay, length of hospital stay and other key indicators were evaluated to evaluate the feasibility of this treatment strategy for VV ECMO patients.\u003c/p\u003e \u003cp\u003eSome studies believe that reducing CO by controlling heart rate through β-blockers will lead to decreased systemic oxygen supply (DO2), thereby aggravating tissue hypoxia and increasing anaerobic metabolism \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, so as to evaluate the metabolism of tissues and organs of patients and evaluate the safety of the study for VVECMO patients.\u003c/p\u003e \u003cp\u003eStudies have pointed out that β-blockers control heart rate and reduce cardiac output (CO), which will lead to a decrease in systemic oxygen supply (DO2), thereby aggravating tissue hypoxia and increasing anaerobic metabolism \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, the aim of this study was to evaluate the metabolic status of tissues and organs in patients to assess their potential impact on the safety of patients undergoing veno-venous extracorporeal membrane oxygenation (VVECMO).\u003c/p\u003e \u003cp\u003eβ-blockers have negative inotropic effects, and esmolol may cause a decrease in blood pressure in patients. The safety of heart rate control by esmolol on VV ECMO was evaluated by comparing the equivalent dose of norepinephrine and hemodynamic parameters (HR, MAP, CVP, PCWP, CI) between the two groups.\u003c/p\u003e \u003cp\u003eThe aim of this study is to evaluate the survival rate of VVECMO patients by controlling heart rate with esmolol, and to observe the lung protective ventilation strategy, mechanical ventilation time, ICU time, and hospital stay, and to evaluate the feasibility of the experiment. At the same time, the tissue metabolic status, including blood lactate level and sequential organ failure assessment (SOFA) score, norepinephrine equivalent dose and hemodynamics (HR, MAP, CVP, PCWP, CI) were evaluated in the two groups to evaluate the safety of the study.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eResearch Endpoint\u003c/h2\u003e \u003cp\u003eThe aim of this study was to investigate the effect of heart rate control by esmolol on survival in VV ECMO patients. The control of heart rate by esmolol can improve the ECMO flow /CO ratio, thereby improving the oxygenation status of patients and providing favorable conditions for the implementation of lung-protective ventilation strategy, which may improve the survival rate of patients. The primary end point was 28-day survival with VV ECMO. Secondary end points included: 1. Ventilator parameters, norepinephrine equivalent dose, mechanical ventilation time, ICU time, and hospital stay were compared between the two groups under the lung-protective ventilation strategy. 2. Metabolic status of organs and tissues in the two groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eResearch Advantages and Limitations\u003c/h2\u003e \u003cp\u003eThe advantage of our study are the randomized (1:1), prospective, multicenter, parallel-controlled clinical design. In the experimental group, the dose of esmolol was prescribed according to a defined protocol, which helped to control the heart rate in the target range. For VV ECMO patient management, this study refers to Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guidelines for treatment from the Extracorporeal Life Support Organization (ELSO).\u003c/p\u003e \u003cp\u003eHowever, the limitation of this study is that blinding is not possible due to the nature of the intervention. In addition, patients treated with VVECMO are usually critically ill patients, and complications such as infection and bleeding may have an impact on the study results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eCurrent status\u003c/h2\u003e \u003cp\u003eThe study protocol is currently in the recruitment phase. The protocol was approved by the ethics review board on February 25, 2025. The study was planned to be conducted at our center and to recruit patients who met the inclusion criteria.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVVECMO \u0026nbsp; \u0026nbsp; \u0026nbsp;Veno-Venous Extracorporeal Membrane Oxygenation\u003c/p\u003e\n\u003cp\u003eFiO2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Fraction of Inspired Oxygen\u003c/p\u003e\n\u003cp\u003ePEEP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Positive End-Expiratory Pressure\u003c/p\u003e\n\u003cp\u003eVT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Tidal Volume\u003c/p\u003e\n\u003cp\u003ePaO2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Partial Pressure of Oxygen\u003c/p\u003e\n\u003cp\u003ePaO2/FiO2 \u0026nbsp; \u0026nbsp; \u0026nbsp;Index of Oxygenation\u003c/p\u003e\n\u003cp\u003eVILI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Ventilator Induced Lung Injury\u003c/p\u003e\n\u003cp\u003eARDS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Acute Respiratory Distress Syndrome\u003c/p\u003e\n\u003cp\u003eCO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cardiac Output\u003c/p\u003e\n\u003cp\u003eQECMO \u0026nbsp; \u0026nbsp; \u0026nbsp; ECMO Flow\u003c/p\u003e\n\u003cp\u003eQCO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CO Flow\u003c/p\u003e\n\u003cp\u003eDO2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Oxygen Delivery\u003c/p\u003e\n\u003cp\u003eVO2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Oxygen Consumption\u003c/p\u003e\n\u003cp\u003eCVP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Central Venous Pressure\u003c/p\u003e\n\u003cp\u003ePCWP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pulmonary Capillary Wedge Pressure\u003c/p\u003e\n\u003cp\u003eICU \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eLac \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Lactic Acid\u003c/p\u003e\n\u003cp\u003eSOFA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Sequential Organ Failure Score\u003c/p\u003e\n\u003cp\u003eAPACHEII \u0026nbsp; \u0026nbsp;Acute Physiology And Chronic Health Score\u0026nbsp;II\u003c/p\u003e\n\u003cp\u003eMAP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Mean Arterial Pressure\u003c/p\u003e\n\u003cp\u003eHR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Heart Rate\u003c/p\u003e\n\u003cp\u003eRR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Respiration Rate\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the participant centers of the trial\u003c/p\u003e\n\u003ch3\u003eAncillary and post-trial care\u003c/h3\u003e\n\u003cp\u003eThe trial insurance to cover for non-negligent harm associated with the protocol. This will include cover for additional health care, compensation, or damages.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the study will be disseminated through international peer-reviewed journals and medical conferences. There is no intention to use the services of professional writers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funding for the trial was provided by Qilu Pharmaceutical Co., LTD.The sponsor and funder are responsible for the development and dissemination of the project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Critical Care Medicine, Zhongshan People's Hospital,zhongshan,guangdong,Chnia\u003c/p\u003e\n\u003cp\u003eWenxiong Hu，Liusheng Hou\u0026nbsp;，Zhanyuan Zhao ,Ting Yang , Shiyong Zeng ,Hongkai Liang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLSH, WXH and HKL participated in the intervention of the study. LSH and WXH participated in the study design. ZYZ, TY and SYZ drafted and revised this manuscript. LSH and WXH are the principal investigators and conceived the study. The authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to\u0026nbsp;Hongkai liang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical review, protocol (version 5.1, February 25, 2025), and related documents have been approved by the Ethics Committee of Zhongshan People's Hospital (approval number: K2024-068-2). Clinical trial number: not applicable.Any major modification to the protocol requires approval from the ethics committee prior to implementation.\u003c/p\u003e\n\u003cp\u003eInformed consent and written consent forms of patients are mandatory before study participation. After the participant has been assessed as eligible, they or their guardians will be invited by the treating physicians to discuss the details and sign the informed consent. Additional consent provisions for use of participant data in ancillary studies are required. This trial does not involve collecting biological specimens for storage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the participants to publish this manuscript and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRights and permissions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOpen Access\u003c/strong\u003e This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit \u003ca href=\"http://creativecommons.org/licenses/by/4.0/\"\u003ehttp://creativecommons.org/licenses/by/4.0/\u003c/a\u003e. The Creative Commons Public Domain Dedication waiver (\u003ca href=\"http://creativecommons.org/publicdomain/zero/1.0/\"\u003ehttp://creativecommons.org/publicdomain/zero/1.0/\u003c/a\u003e) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCombes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome [J]. The New England journal of medicine, 2018, 378(21): 1965\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTonna J E, Abrams D, Brodie D, et al. Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO) [J]. ASAIO journal (American Society for Artificial Internal Organs: 1992), 2021, 67(6): 601\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCombes A, Schmidt M, Hodgson C L, et al. Extracorporeal life support for adults with acute respiratory distress syndrome [J]. Intensive care medicine, 2020, 46(12): 2464\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrodie D, Slutsky A S, Combes A. Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review [J]. Jama, 2019, 322(6): 557\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellani G, Laffey J G, Pham T, et al. The LUNG SAFE study: a presentation of the prevalence of ARDS according to the Berlin Definition! [J]. Critical care (London, England), 2016, 20(1): 268.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy B, Taccone F S, Guarracino F. Recent developments in the management of persistent hypoxemia under veno-venous ECMO [J]. Intensive care medicine, 2015, 41(3): 508\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStaudacher D L, Wengenmayer T, Schmidt M. Beta-blockers in refractory hypoxemia on venovenous extracorporeal membrane oxygenation: a double-edged sword [J]. Critical care (London, England), 2023, 27(1): 360.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuervilly C, Hraiech S, Gariboldi V, et al. Prone positioning during veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults [J]. Minerva anestesiologica, 2014, 80(3): 307\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerpa Neto A, Schmidt M, Azevedo L C, et al. Associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a pooled individual patient data analysis: Mechanical ventilation during ECMO [J]. Intensive care medicine, 2016, 42(11): 1672\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCavalcanti A B, Suzumura \u0026Eacute; A, Laranjeira L N, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial [J]. Jama, 2017, 318(14): 1335\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt M, Tachon G, Devilliers C, et al. Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults [J]. Intensive care medicine, 2013, 39(5): 838\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial [J]. Jama, 2013, 310(16): 1683\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent J L, Lignian H, Gillet J B, et al. Increase in PaO2 following intravenous administration of propranolol in acutely hypoxemic patients [J]. Chest, 1985, 88(4): 558\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuarracino F, Zangrillo A, Ruggeri L, et al. β-Blockers to optimize peripheral oxygenation during extracorporeal membrane oxygenation: a case series [J]. Journal of cardiothoracic and vascular anesthesia, 2012, 26(1): 58\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePappalardo F, Zangrillo A, Pieri M, et al. Esmolol administration in patients with VV ECMO: why not? [J]. Journal of cardiothoracic and vascular anesthesia, 2013, 27(4): e40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePinto B B, Siegenthaler N, Tassaux D, et al. VV-ECMO and brave heart: A subtle competition? [J]. International journal of cardiology, 2015, 186: 45\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBunge J J H, Diaby S, Valle A L, et al. Safety and efficacy of beta-blockers to improve oxygenation in patients on veno-venous ECMO [J]. Journal of critical care, 2019, 53: 248\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8231264/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8231264/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eVeno-venous extracorporeal membrane oxygenation (VV ECMO) has been widely used in patients with respiratory failure. For patients with refractory hypoxemia treated with VV ECMO, β-blockers can improve oxygenation by reducing cardiac output (CO) and increasing ECMO flow /CO ratio. However, it has been suggested that β-blockers aggravate tissue hypoxia by reducing systemic oxygen delivery (DO2) by controlling heart rate. Therefore, the effect of heart rate control by esmolol on oxygen metabolism and clinical outcomes in VV ECMO patients is still controversial and needs further study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study was a randomized (1:1), prospective, multi-center, parallel controlled clinical study. Patients with acute respiratory distress syndrome (ARDS) were treated with VV ECMO. After signing the informed consent form and meeting the inclusion/exclusion criteria, patients will be randomly assigned to the esmolol group or the control group, with 60 patients in each group, for a total of 120 patients to be recruited. The primary endpoint was 28-day survival. Secondary endpoints included oxygen metabolism, ventilator parameters (lung-protective ventilation), norepinephrine equivalent, duration of mechanical ventilation, length of ICU stay, and length of hospital stay.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1. To investigate the effect of heart rate control by β-blocker on 28-day survival rate in VV ECMO patients; 2. To investigate the effect of heart rate control by β-blockers on circulation in VV ECMO patients and whether lowering DO2 causes tissue hypoxia.\u003c/p\u003e","manuscriptTitle":"Effect of Heart Rate Control with Esmolol on Oxygen Metabolism and Clinical Outcomes in VVECMO patients: a Multicenter, Prospective, Randomized Controlled Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-26 01:31:37","doi":"10.21203/rs.3.rs-8231264/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4e0a1b3f-63fc-4290-a678-cfb8fd2057e0","owner":[],"postedDate":"January 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T06:55:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-26 01:31:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8231264","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8231264","identity":"rs-8231264","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}