Modified passive leg-raising maneuver to predict fluid responsiveness by transthoracic ultrasound guidance in healthy pigs under sevoflurane anesthesia.

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Lisa Tarragona, Pablo Donati, Andrea Zaccagnini, Santiago Fuensalida, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4414423/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 This study aimed to evaluate whether the velocity-time integral of aortic blood flow (VTI Ao ) assessed by transthoracic echocardiography is significantly increased after passive leg-raising maneuver (PLRM) in anesthetized and mechanically ventilated fluid responder pigs. Eight healthy Landrace pigs were anesthetized, mechanically ventilated, and subjected to PLRM. Ultrasound-guided VTI Ao measurements were taken before and after PLRM and compared to assess changes. Fluid challenge was then performed, and changes in VTI Ao were assessed to classify pigs as fluid responders or non-responders. Following PLRM, fluid responders exhibited a significant increase in VTI Ao compared to baseline (p = 0.017). An optimal cutoff of 11.2% for ΔVTI Ao was calculated for predicting fluid responsiveness after PLRM, with an AUROC of 1.00 (95% CI not estimated – 1.00), sensitivity of 100% (95% CI 59 – 100%), specificity of 100% (95% CI 2.5–100%), positive predictive value of 100% (95% CI 59–100%), and a negative predictive value of 100% (95% CI 2.5–100%). This study demonstrates the potential of using ultrasound-guided VTI Ao measurements associated with PLRM to predict fluid responsiveness in anesthetized pigs. A ΔVTI Ao value of ≥11.2% reliably identified fluid-responsive pigs under anesthesia and mechanical ventilation, offering a non-invasive alternative to fluid challenges. Further research addressing study limitations could enhance understanding of fluid responsiveness assessment in animal models. Fluid challenge cardiac ultrasonography Frank-Starling curve porcine Figures Figure 1 Figure 2 Figure 3 Introduction Fluid therapy has been widely recommended for animals with hemodynamic instability. However, there is evidence of the deleterious effects of fluid overload associated with liberal fluid regimen (Joosten et al. 2015 ; Cavanagh et al. 2016 ; Marik et al . 2010, 2016). In an attempt to improve fluid management, in the last few decades, there has been a focus on studying the ability of various indicators to define fluid responsiveness and identify individuals who would benefit from increased stroke volume (SV) through fluid administration (Bucci et al. 2017 ; Cannesson et al. 2011 ; Carsetti et al. 2015 ; Celeita Rodriguez et al . 2019). Fluid challenges have been widely used to assess fluid responsiveness (Lakhal et al. 2017 ; Celeita et al. 2019; de Olivieira et al. 2021). However, considering the potential risk of fluid overload, its use would not be indicated in unresponsive patients. In order to avoid unnecessary fluid administration, the passive leg-raising maneuver (PLRM) has been extensively employed in human medicine, to assess fluid responsiveness (Boulain et al. 2002 ; Monnet et al. 2006 ). This test has demonstrated its ability to induce an increase in preload, causing an elevation in SV in fluid responder patients (Cavallaro et al. 2010 ). Moreover, it is considered a transient test to increase preload since its impact on SV decreases when the maneuver is suspended and can be use repeatedly for evaluating a patient's response to an elevated cardiac preload. This can be done avoiding the risks associated with fluid therapy, such as pulmonary edema, especially in cases of non-responder patients (Monnet and Teboul 2015 ). The use of modified PLRM has been reported previously in pigs and dogs (Paranjape et al. 2019 , 2023 ). However, in these studies, SV modifications were assessed by thermodilution which has been discouraged due to the difficulty of the method in detecting short-term changes in SV (Monnet and Teboul 2015 , 2017 ). Doppler echocardiography allows estimate systolic volume by calculating the velocity-time integral of aortic blood flow (VTI Ao ) and the area traversed by this flow. Since the size of the subaortic tract remains constant, changes in ultrasound-guided VTI Ao (∆VTI Ao ) were proposed as a valid measure to assess systolic volume changes (Cecconi et al. 2014 ). A previous published study performed in post-surgical human patients has showed that an increase in VTI Ao exceeding 11% during PLRM could reliably anticipate a rise in SV of at least 15% following fluid loading (El Hadouti et al. 2017 ). However, the ability of the PLRM to distinguish between responders and non-responders to fluid challenge based on changes in ultrasound-guided ∆VTI Ao in pigs has not yet been described. The primary aim of this study was to assess whether the velocity time integral of the aortic blood flow (VTI Ao ), as evaluated by transthoracic echocardiography, shows a significant increase after passive leg raising maneuver (PLRM) in pigs under anesthesia and mechanical ventilation, who are responsive to fluid administration. Additionally, as a secondary objective, we aimed to determine the optimal cutoff for the increase in VTI Ao that indicates responsiveness to fluids following PLRM. Our central hypothesis posits that VTI Ao will significantly increase after PLRM in fluid-responsive subjects. For the secondary objective, we hypothesized that the optimal threshold for the increase in VTI Ao to identify fluid responsiveness after the maneuver would resemble values previously observed in human medicine, specifically around 11%. Materials and Methods The protocol of the present study was approved by the Institutional Animal Care and Use Committee, Faculty of Veterinary Science, University of Buenos Aires (no. 2022/45). The results were reported following the Animal Research: Reporting of In Vivo Experiments guidelines ( https://arriveguidelines.org/arrive-guidelines ) (Percie du Sert et al. 2020 ). Eight young Landrace pigs (four females and four males) with a mean weight of 35 ± 5.42 kg that were part of an unrelated project that required general anesthesia and euthanasia were enrolled in this study. Eligibility criteria required them to be deemed healthy based on physical examination, hemogram, and serum biochemical evaluation results. Pigs were admitted 24 hours before general anesthesia and housed individually in separate cages, following the Association for Assessment and Accreditation guidelines of Laboratory Animal Care International (Albus 2012 ). Anesthesia protocol The pigs underwent a 12-hour fasting period with unrestricted water access before each anesthesia. Premedication included midazolam at 0.2 mg/kg (Midazolam, Richmond Vet Pharma, Buenos Aires, Argentina), xylazine at 5 mg/kg (Xilacina 100, Richmond Vet Pharma, Buenos Aires, Argentina), and ketamine at 10 mg/kg (Ketonal 100, Richmond Vet Pharma, Buenos Aires, Argentina), all administered intramuscularly in a single syringe. After a 20-minute interval, a 20 G catheter was inserted into the marginal vein of both ears. Anesthesia induction was achieved with intravenous propofol to effect (Propovet, Richmond Vet Pharma, Buenos Aires, Argentina). Subsequently, tracheal intubation was performed using an appropriately sized cuffed endotracheal tube connected to a side-stream capnograph and a circle breathing system coupled to an anesthetic machine (AvanceCS2, General Electric, USA). With the animals in dorsal recumbency, femoral artery catheterization was performed to establish an arterial line. The arterial catheter was connected to a transducer positioned and zeroed at the right atrium level to measure systolic, diastolic, and mean arterial pressure directly (SAP, DAP, and MAP, respectively). An assigned anesthetist (AZ) continuously monitored anesthesia depth using end-tidal sevoflurane monitoring throughout the procedure (Bradbury and Clutton 2016 ). Anesthesia maintenance comprised sevoflurane vaporized in 40% oxygen and constant infusion of remifentanil (0.25 µg/kg/min) and rocuronium (5–10 µg/kg/min). The end-tidal sevoflurane percentage (PESEVO) was maintained between 2.0–2.5%, and the respiratory rate was adjusted to achieve a predetermined end-tidal CO 2 partial pressure (PETCO 2 ) between 35–45 mmHg. Mechanical ventilation was set to volume-controlled mode, utilizing a tidal volume of 15 mL/kg with an end-inspiratory pause of 20%, an inspiratory-to-expiratory ratio of 1:2, and 2 cmH 2 O of positive end-expiratory pressure. Lactated Ringer's solution was intravenously administered at a rate of 5 mL/kg/hour during the procedure. During the procedure, the measured variables included peripheral hemoglobin oxygen saturation (SpO 2 ) assessed via pulse oximetry probe on the tongue, heart rate (HR) obtained from lead II electrocardiography, SAP, MAP, DAP, and core body temperature, monitored using an esophageal probe with a multiparametric monitor (Digicare Lifewindow 9X, Digicare, USA). Before the experiments, the multiparametric monitor was verified according to the internal electronic protocol provided by the manufacturer. Neuromuscular function was monitored using train-of-four (Myotest Osiris, Amrra, Buenos Aires, Argentina), with a maintained ratio of < 0.3 throughout the experiment. Active heating was employed to prevent hypothermia (Amrra term HT- Sistema de normotermia, Amrra, Buenos Aires, Argentina). Anesthesia was consistently administered by the same veterinarian (AZ). Ultrasound-guided VTI Ao monitoring A single board-certified researcher (LT) performed all echocardiographic evaluations using a portable ultrasound machine (Sonosite Inc., WA, USA) with a phased array probe (1–6 MHz, Sonosite Inc). Measurements were performed by placing the pulsed Doppler gate in the left ventricular outflow tract using apical left 5-chamber ultrasound imaging through a subxiphoid view (Boon 2011 ). After achieving a clear spectral image of aortic flow, the average of three consecutive VTI Ao was recorded for further analysis. Passive leg-raising maneuver The modified PLRM consisted of placing a wooden device between the caudal part of the pig's body and the table surface with one end of the board positioned at the level of the xiphoid process. At the time of the maneuver, the free end of the board was elevated to achieve a 15° angle of elevation of the pelvic limbs and abdomen (Fig. 1 ). The head and thorax of the pig remained in the same horizontal plane as the table surface throughout the PLRM (Paranjape et al. 2019 ). Study protocol The ultrasound-guided VTI Ao measurements were taken at four specific time points: T0 (baseline), ten minutes after stabilization; T1, during the first three minutes of passive leg-raising maneuver (PLRM), with the animal in a passive leg raised position; T2, five minutes after stabilization before fluid challenge, in a horizontal position; T3, during the first three minutes after fluid challenge in a horizontal position (Fig. 2 ). No alterations were made to ventilation settings or anesthetic doses throughout the execution of the study protocol. Fluid challenge was performed using hydroxyethyl starch 130/0.4 in an isotonic sodium chloride solution (Voluven 6%, Laboratorio Fresenius Kabi, SA, Argentina), 500 mL administered over five minutes, to classify animals into responders and non-responders. Ultrasound-guided VTI Ao measurements was assessed before and after the fluid challenge (T2 and T3) to classify the included pigs as fluid responders or non-responders, with fluid responsiveness defined as a ≥ 15% increase in VTI Ao after the fluid challenge. At the end of the experiment, the animals continued as part of the unrelated project that motivated the anesthesia. Statistical analysis After recruiting the first eight pigs, a power calculation of two correlated measures was performed using the VTI Ao values obtained before and after PLRM in fluid responders. As a power of 100% was achieved, it was decided to analyze the data of the eight pigs and conclude the recruitment process. For the descriptive analysis, VTI Ao and hemodynamic variable values were reported as median [quartiles 1 and 3 (Q1–Q3)]. For comparison of VTI Ao , before and after PLRM, the Wilcoxon rank sign test was used. Area under the receiver operating characteristic curve (AUROC) analysis was used to assess the ability of variations of ΔVTI Ao to predict fluid responsiveness. Sensitivity (number of true positive results divided by the sum of true positive and false negative results) was plotted against 1–specificity (number of false-positive results divided by the sum of false-positive and true negative results) for all possible cutoff points. The optimal cutoff point was selected using Youden’s index, where the sum of sensitivity plus specificity is maximized and equal weight is given to false-positive and false-negative results. Positive predictive value (number of true positives divided by the sum of true and false-positive results) and negative predictive value (number of true negative results divided by the sum of true and false-negative results) were also calculated. Analysis was performed using professional statistical software (STATA 13.0, Stata Corporation, College Station, TX, USA). The level of significance was established at p < 0.05. Results A total of eight pigs were included in the study, with seven pigs classified as fluid responders and one as non-responders, based on ΔVTI Ao measurements after fluid challenge. The hemodynamic variables remained stable, with minimal variation, and stayed within normal ranges for the species throughout the study period (Hannon et al. 1989 ; Ido et al. 2019 ). Median values (Q1-Q3) for HR, SpO 2 , PETCO 2 , SAP, MAP, DAP and core body temperature during the study were 90 (72.5– 97.7) beats/minute, 99.5 (97.5–100) %, 46,5 (42– 53) mmHg, 94 (84.75– 115.5) mmHg, 76 (64.2– 88.5) mmHg, 65 (55.5– 73) mmHg and 37.1 (36.1– 37.4) ºC, respectively. In fluid responders, there was a significant increase in VTI Ao from baseline after the PLRM [median (Q1–Q3): 22.3 cm (17.2–25.8) versus 19.4 cm (15.4– 20.5); p = 0.017)] (Fig. 3 ). An optimal cutoff of 11.2% for ΔVTI Ao was calculated for predicting fluid responsiveness after PLRM, with an AUROC of 1.00 (95% CI not estimated – 1.00), sensitivity of 100% (95% CI 59–100%), specificity of 100% (95% CI 2.5–100%), positive predictive value of 100% (95% CI 59–100%), and a negative predictive value of 100% (95% CI 2.5–100%). Discussion This study showed a significant increase in VTI Ao following PLRM in fluid-responsive pigs. In addition, despite the use of a small sample of animals a preliminary cutoff of a ΔVTIAo of 11.2% post-PLRM shows promise for predicting a subsequent increase in VTIAo greater than 15% after fluid challenge, which could guide the assessment of fluid responsiveness. A previous study conducted in a pig model under various hemodynamic conditions suggested that PLRM could be beneficial in identifying hemodynamically unstable animals responsive to fluid therapy. However, the authors utilized cardiac output measurement by thermodilution. Despite thermodilution being considered one of the standard techniques for cardiac output measurement, its use in conjunction with PLRM has been discouraged. Among the limitations, the method's inability to accurately detect transient and short-term changes in stroke volume is prominent (Monet and Teboul 2015, 2017). While fluid responsiveness is typically defined as an increase in stroke volume exceeding 15% following a fluid load, the increase in responders after PLRM may be less than 15%. A prior postoperative study in human patients demonstrated that an increase in VTI Ao greater than 11% following PLRM predicted fluid responsiveness with 81.8% sensitivity and 89.5% specificity (El Hadouti et al. 2017 ). These findings align with those observed in the present study. However, it is essential to consider the least significant change between two examinations, whether the procedure is performed by the same operator or two different ones. Interestingly, changes in ultrasound-guided VTI Ao measured by the same operator of less than 11% may fall within the least significant change method's inaccuracy range (Jozwiak et al. 2019 ). The preliminary cutoff value for VTI Ao obtained in the present study was slightly above the least significant change, suggesting that ultrasound-guided VTI Ao could reliably predict fluid responsiveness under the study's conditions. Despite its accuracy range, echocardiography, being noninvasive, is a recommended method for monitoring changes in cardiac output when PLRM is employed, as it provides real-time assessment (Monet and Teboul 2015). Other human medicine studies have also utilized echocardiography to confirm fluid responsiveness (Préau et al. 2010 ; Lamia et al. 2007 ). In our study, we observed a significant proportion of animals exhibiting a response to fluid administration. These results correspond with findings from other studies, which reported a considerable rate of fluid responsiveness in healthy humans and dogs (Bucci et al. 2017 ; Alves 2017 ). This study has several limitations that should be considered when interpreting the results. First, wide confidence intervals were observed, which affected the precision of the findings. This is likely due to the small sample size used in the study. Second, echocardiography is a valuable tool for assessing cardiac function. However, it has limitations, including measurement variability and the potential for errors due to operator technique. In this study, measurements were conducted by a single observer, which precluded consideration of inter-individual variability. Finally, the pigs included in the study were part of an unrelated project that required general anesthesia and euthanasia, potentially introducing bias in the sample selection process. Addressing these potential limitations in future studies could strengthen the validity and reliability of the findings and enhance the understanding of fluid responsiveness assessment techniques in animal models. This study presents a novel approach to identifying fluid-responsive animals through increased VTI Ao following PLRM. Despite the limitations, the study findings demonstrate the feasibility of assessing fluid responsiveness using ultrasound-guided VTI Ao measurements associated with a PLRM in anesthetized pigs, obviating the need for fluid challenges. This study also concludes that a preliminary ΔVTI Ao value of ≥ 11.2% reliably identified fluid-responsive pigs under anesthesia and mechanical ventilation. Statements & Declarations Statement of Animal Ethics: Institutional Animal Care and Use Committee, Faculty of Veterinary Science, University of Buenos Aires (no. 2022/45). Conflict of interest Statement: The authors declare no conflicts of interest. Funding: This study was funded by the Secretaría de Ciencia y Técnica, Universidad de Buenos Aires, Argentina (UBACyT 20020190200318BA). Author contribution: Conception and design: LT, PD, PO. Data collection: LT, PD, AZ, SF, MC, AD, NN, Analysis and interpretation: LT, PD, AZ, SF, JM, JIR, PO. 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PLoS Biol 14;18(7):e3000411. https://doi.org/10.1177/0271678X20943823 Préau S, Saulnier F, Dewavrin F, Durocher A, Chagnon JL (2010) Passive leg-raising is predictive of fluid responsiveness in spontaneously breathing patients with severe sepsis or acute pancreatitis. Critical care medicine 38, 819–825. https://doi.org/10.1097/CCM.0b013e3181c8fe7a 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4414423","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":302924560,"identity":"de8fe03b-47b5-4b29-a3a0-52b5ce2a4ba6","order_by":0,"name":"Lisa Tarragona","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBACPgST+cAHMC1BQAsbG4KZOIOBwYAkLTyGRGqRb372uaKmVs6c/czHZp6KPwwGt5sfMPzcg88WNuOZZ44dN7bsyd3YzHPGgMHgzjEDxp5neB1mzNjAdixxw4Hc7Q9ntgG13EgwYOA5gE8L+2fGhn9ALeffPGyc+Q+kJf0D4x+8WniMGRvbahI33MhhbPjYANKSY8CM35acYsbGvgPGBjeeGTZ8OGbMI3nnTMFhGTxa+JmPb2Zs+FYnZ3A++WFDQo2cHN/t9o0P3+DRAgWH4SweEEFYAwNDHRFqRsEoGAWjYMQCAGMOU4WgyRFvAAAAAElFTkSuQmCC","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":true,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Tarragona","suffix":""},{"id":302924561,"identity":"5dbac14b-a59a-4a30-8bb8-419c22ee0816","order_by":1,"name":"Pablo Donati","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Donati","suffix":""},{"id":302924562,"identity":"258feff2-0e34-4490-bc9e-9cf144dca2f7","order_by":2,"name":"Andrea Zaccagnini","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Zaccagnini","suffix":""},{"id":302924563,"identity":"d4afc1ed-cb5a-44f1-aeba-fc5ff2abb411","order_by":3,"name":"Santiago Fuensalida","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Santiago","middleName":"","lastName":"Fuensalida","suffix":""},{"id":302924565,"identity":"a6a87be9-525b-4d02-a10a-ba92c9ff7497","order_by":4,"name":"Martín Ceballos","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Martín","middleName":"","lastName":"Ceballos","suffix":""},{"id":302924567,"identity":"63d3ca78-ea2f-4058-af6c-ee8bdf2cba2c","order_by":5,"name":"Alfredo Díaz","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Alfredo","middleName":"","lastName":"Díaz","suffix":""},{"id":302924569,"identity":"b8c57a72-4cc9-495b-8bb9-e300da1a86e9","order_by":6,"name":"Néstor Nigro","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Néstor","middleName":"","lastName":"Nigro","suffix":""},{"id":302924571,"identity":"1e150c8e-22bb-4e68-a57e-770502e84e7d","order_by":7,"name":"Juan Montagne","email":"","orcid":"","institution":"Instituto Universitario Hospital Italiano","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Montagne","suffix":""},{"id":302924573,"identity":"81053b9d-f985-4b2b-bb3c-a812e1606f6b","order_by":8,"name":"José Ignacio Redondo","email":"","orcid":"","institution":"Universidad Cardenal Herrera - CEU","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Ignacio","lastName":"Redondo","suffix":""},{"id":302924575,"identity":"b0133d04-3e56-4a60-be75-79aba610645a","order_by":9,"name":"Pablo Otero","email":"","orcid":"","institution":"Facultad de Ciencias Veterinarias, Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Otero","suffix":""}],"badges":[],"createdAt":"2024-05-13 16:14:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4414423/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4414423/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56998785,"identity":"822689b1-0874-44e9-98c4-4f9a76f9b29b","added_by":"auto","created_at":"2024-05-23 08:10:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":367989,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagram depicting the implementation of the modified, passive leg-raising maneuver (PLRM) in anaesthetized and ventilated pigs. A wooden device was placed between the caudal part of the pig's body and the table surface, with one end of the board positioned at the level of the xiphoid process (a). At the time of the PLRM, the free end of the table was raised to achieve a 15° angle of elevation of the pelvic limbs and abdomen (b).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4414423/v1/f90f588946da89a3c78b534a.png"},{"id":56998786,"identity":"f30af847-8460-480e-8c6c-57355677fbb0","added_by":"auto","created_at":"2024-05-23 08:10:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":514487,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagram depicting four specific time points in anaesthetized and ventilated pigs: T0 (baseline), ten minutes after stabilization; T1, during the first three minutes of the passive leg-raising maneuver (PLRM), with the animal in passive raised leg position; T2, five minutes after stabilization before fluid challenge, in horizontal position; T3, during the first three minutes after fluid challenge in horizontal position.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4414423/v1/fc0612750f6d02845351db75.png"},{"id":56998787,"identity":"7a4cb5b9-7766-488e-b682-54a793d24000","added_by":"auto","created_at":"2024-05-23 08:10:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":166669,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBox plots represent the values of the velocity-time integral of aortic blood flow before (VTI\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003eAo\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e baseline) and after passive leg-raising maneuver (VTI\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003eAo \u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003ePLRM) in fluid-responsive anesthetized and ventilated pigs. The upper and lower margins of the box show the lower and upper quartiles, the horizontal line shows the median and the whiskers indicate the 2.5 and 97.5 percentiles.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4414423/v1/7e63bfb785f4ae8242e70545.png"},{"id":57729637,"identity":"06b10b1e-7416-482c-8b03-8e28ac90e1ad","added_by":"auto","created_at":"2024-06-04 21:53:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2187411,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4414423/v1/f6000de9-cbf9-4e27-9791-15c22da72cb3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Modified passive leg-raising maneuver to predict fluid responsiveness by transthoracic ultrasound guidance in healthy pigs under sevoflurane anesthesia.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFluid therapy has been widely recommended for animals with hemodynamic instability. However, there is evidence of the deleterious effects of fluid overload associated with liberal fluid regimen (Joosten et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Cavanagh et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Marik \u003cem\u003eet al\u003c/em\u003e. 2010, 2016). In an attempt to improve fluid management, in the last few decades, there has been a focus on studying the ability of various indicators to define fluid responsiveness and identify individuals who would benefit from increased stroke volume (SV) through fluid administration (Bucci et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Cannesson et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Carsetti et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Celeita Rodriguez \u003cem\u003eet al\u003c/em\u003e. 2019).\u003c/p\u003e \u003cp\u003eFluid challenges have been widely used to assess fluid responsiveness (Lakhal et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Celeita \u003cem\u003eet al.\u003c/em\u003e 2019; de Olivieira \u003cem\u003eet al.\u003c/em\u003e 2021). However, considering the potential risk of fluid overload, its use would not be indicated in unresponsive patients. In order to avoid unnecessary fluid administration, the passive leg-raising maneuver (PLRM) has been extensively employed in human medicine, to assess fluid responsiveness (Boulain et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Monnet et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). This test has demonstrated its ability to induce an increase in preload, causing an elevation in SV in fluid responder patients (Cavallaro et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Moreover, it is considered a transient test to increase preload since its impact on SV decreases when the maneuver is suspended and can be use repeatedly for evaluating a patient's response to an elevated cardiac preload. This can be done avoiding the risks associated with fluid therapy, such as pulmonary edema, especially in cases of non-responder patients (Monnet and Teboul \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe use of modified PLRM has been reported previously in pigs and dogs (Paranjape et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2019\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). However, in these studies, SV modifications were assessed by thermodilution which has been discouraged due to the difficulty of the method in detecting short-term changes in SV (Monnet and Teboul \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2015\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Doppler echocardiography allows estimate systolic volume by calculating the velocity-time integral of aortic blood flow (VTI\u003csub\u003eAo\u003c/sub\u003e) and the area traversed by this flow. Since the size of the subaortic tract remains constant, changes in ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e (∆VTI\u003csub\u003eAo\u003c/sub\u003e) were proposed as a valid measure to assess systolic volume changes (Cecconi et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). A previous published study performed in post-surgical human patients has showed that an increase in VTI\u003csub\u003eAo\u003c/sub\u003e exceeding 11% during PLRM could reliably anticipate a rise in SV of at least 15% following fluid loading (El Hadouti et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, the ability of the PLRM to distinguish between responders and non-responders to fluid challenge based on changes in ultrasound-guided ∆VTI\u003csub\u003eAo\u003c/sub\u003e in pigs has not yet been described.\u003c/p\u003e \u003cp\u003eThe primary aim of this study was to assess whether the velocity time integral of the aortic blood flow (VTI\u003csub\u003eAo\u003c/sub\u003e), as evaluated by transthoracic echocardiography, shows a significant increase after passive leg raising maneuver (PLRM) in pigs under anesthesia and mechanical ventilation, who are responsive to fluid administration. Additionally, as a secondary objective, we aimed to determine the optimal cutoff for the increase in VTI\u003csub\u003eAo\u003c/sub\u003e that indicates responsiveness to fluids following PLRM. Our central hypothesis posits that VTI\u003csub\u003eAo\u003c/sub\u003e will significantly increase after PLRM in fluid-responsive subjects. For the secondary objective, we hypothesized that the optimal threshold for the increase in VTI\u003csub\u003eAo\u003c/sub\u003e to identify fluid responsiveness after the maneuver would resemble values previously observed in human medicine, specifically around 11%.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e The protocol of the present study was approved by the Institutional Animal Care and Use Committee, Faculty of Veterinary Science, University of Buenos Aires (no. 2022/45). The results were reported following the Animal Research: Reporting of In Vivo Experiments guidelines (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://arriveguidelines.org/arrive-guidelines\u003c/span\u003e\u003cspan address=\"https://arriveguidelines.org/arrive-guidelines\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (Percie du Sert et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEight young Landrace pigs (four females and four males) with a mean weight of 35\u0026thinsp;\u0026plusmn;\u0026thinsp;5.42 kg that were part of an unrelated project that required general anesthesia and euthanasia were enrolled in this study. Eligibility criteria required them to be deemed healthy based on physical examination, hemogram, and serum biochemical evaluation results. Pigs were admitted 24 hours before general anesthesia and housed individually in separate cages, following the Association for Assessment and Accreditation guidelines of Laboratory Animal Care International (Albus \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnesthesia protocol\u003c/h2\u003e \u003cp\u003eThe pigs underwent a 12-hour fasting period with unrestricted water access before each anesthesia. Premedication included midazolam at 0.2 mg/kg (Midazolam, Richmond Vet Pharma, Buenos Aires, Argentina), xylazine at 5 mg/kg (Xilacina 100, Richmond Vet Pharma, Buenos Aires, Argentina), and ketamine at 10 mg/kg (Ketonal 100, Richmond Vet Pharma, Buenos Aires, Argentina), all administered intramuscularly in a single syringe. After a 20-minute interval, a 20 G catheter was inserted into the marginal vein of both ears. Anesthesia induction was achieved with intravenous propofol to effect (Propovet, Richmond Vet Pharma, Buenos Aires, Argentina). Subsequently, tracheal intubation was performed using an appropriately sized cuffed endotracheal tube connected to a side-stream capnograph and a circle breathing system coupled to an anesthetic machine (AvanceCS2, General Electric, USA). With the animals in dorsal recumbency, femoral artery catheterization was performed to establish an arterial line. The arterial catheter was connected to a transducer positioned and zeroed at the right atrium level to measure systolic, diastolic, and mean arterial pressure directly (SAP, DAP, and MAP, respectively). An assigned anesthetist (AZ) continuously monitored anesthesia depth using end-tidal sevoflurane monitoring throughout the procedure (Bradbury and Clutton \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Anesthesia maintenance comprised sevoflurane vaporized in 40% oxygen and constant infusion of remifentanil (0.25 \u0026micro;g/kg/min) and rocuronium (5\u0026ndash;10 \u0026micro;g/kg/min). The end-tidal sevoflurane percentage (PESEVO) was maintained between 2.0\u0026ndash;2.5%, and the respiratory rate was adjusted to achieve a predetermined end-tidal CO\u003csub\u003e2\u003c/sub\u003e partial pressure (PETCO\u003csub\u003e2\u003c/sub\u003e) between 35\u0026ndash;45 mmHg. Mechanical ventilation was set to volume-controlled mode, utilizing a tidal volume of 15 mL/kg with an end-inspiratory pause of 20%, an inspiratory-to-expiratory ratio of 1:2, and 2 cmH\u003csub\u003e2\u003c/sub\u003eO of positive end-expiratory pressure. Lactated Ringer's solution was intravenously administered at a rate of 5 mL/kg/hour during the procedure. During the procedure, the measured variables included peripheral hemoglobin oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) assessed via pulse oximetry probe on the tongue, heart rate (HR) obtained from lead II electrocardiography, SAP, MAP, DAP, and core body temperature, monitored using an esophageal probe with a multiparametric monitor (Digicare Lifewindow 9X, Digicare, USA). Before the experiments, the multiparametric monitor was verified according to the internal electronic protocol provided by the manufacturer. Neuromuscular function was monitored using train-of-four (Myotest Osiris, Amrra, Buenos Aires, Argentina), with a maintained ratio of \u0026lt;\u0026thinsp;0.3 throughout the experiment. Active heating was employed to prevent hypothermia (Amrra term HT- Sistema de normotermia, Amrra, Buenos Aires, Argentina). Anesthesia was consistently administered by the same veterinarian (AZ).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eUltrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e monitoring\u003c/h2\u003e \u003cp\u003eA single board-certified researcher (LT) performed all echocardiographic evaluations using a portable ultrasound machine (Sonosite Inc., WA, USA) with a phased array probe (1\u0026ndash;6 MHz, Sonosite Inc). Measurements were performed by placing the pulsed Doppler gate in the left ventricular outflow tract using apical left 5-chamber ultrasound imaging through a subxiphoid view (Boon \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). After achieving a clear spectral image of aortic flow, the average of three consecutive VTI\u003csub\u003eAo\u003c/sub\u003e was recorded for further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePassive leg-raising maneuver\u003c/h2\u003e \u003cp\u003eThe modified PLRM consisted of placing a wooden device between the caudal part of the pig's body and the table surface with one end of the board positioned at the level of the xiphoid process. At the time of the maneuver, the free end of the board was elevated to achieve a 15\u0026deg; angle of elevation of the pelvic limbs and abdomen (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The head and thorax of the pig remained in the same horizontal plane as the table surface throughout the PLRM (Paranjape et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy protocol\u003c/h2\u003e \u003cp\u003eThe ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e measurements were taken at four specific time points: T0 (baseline), ten minutes after stabilization; T1, during the first three minutes of passive leg-raising maneuver (PLRM), with the animal in a passive leg raised position; T2, five minutes after stabilization before fluid challenge, in a horizontal position; T3, during the first three minutes after fluid challenge in a horizontal position (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No alterations were made to ventilation settings or anesthetic doses throughout the execution of the study protocol.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFluid challenge was performed using hydroxyethyl starch 130/0.4 in an isotonic sodium chloride solution (Voluven 6%, Laboratorio Fresenius Kabi, SA, Argentina), 500 mL administered over five minutes, to classify animals into responders and non-responders. Ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e measurements was assessed before and after the fluid challenge (T2 and T3) to classify the included pigs as fluid responders or non-responders, with fluid responsiveness defined as a\u0026thinsp;\u0026ge;\u0026thinsp;15% increase in VTI\u003csub\u003eAo\u003c/sub\u003e after the fluid challenge. At the end of the experiment, the animals continued as part of the unrelated project that motivated the anesthesia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAfter recruiting the first eight pigs, a power calculation of two correlated measures was performed using the VTI\u003csub\u003eAo\u003c/sub\u003e values obtained before and after PLRM in fluid responders. As a power of 100% was achieved, it was decided to analyze the data of the eight pigs and conclude the recruitment process. For the descriptive analysis, VTI\u003csub\u003eAo\u003c/sub\u003e and hemodynamic variable values were reported as median [quartiles 1 and 3 (Q1\u0026ndash;Q3)]. For comparison of VTI\u003csub\u003eAo\u003c/sub\u003e, before and after PLRM, the Wilcoxon rank sign test was used.\u003c/p\u003e \u003cp\u003eArea under the receiver operating characteristic curve (AUROC) analysis was used to assess the ability of variations of ΔVTI\u003csub\u003eAo\u003c/sub\u003e to predict fluid responsiveness. Sensitivity (number of true positive results divided by the sum of true positive and false negative results) was plotted against 1\u0026ndash;specificity (number of false-positive results divided by the sum of false-positive and true negative results) for all possible cutoff points. The optimal cutoff point was selected using Youden\u0026rsquo;s index, where the sum of sensitivity plus specificity is maximized and equal weight is given to false-positive and false-negative results. Positive predictive value (number of true positives divided by the sum of true and false-positive results) and negative predictive value (number of true negative results divided by the sum of true and false-negative results) were also calculated. Analysis was performed using professional statistical software (STATA 13.0, Stata Corporation, College Station, TX, USA). The level of significance was established at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of eight pigs were included in the study, with seven pigs classified as fluid responders and one as non-responders, based on ΔVTI\u003csub\u003eAo\u003c/sub\u003e measurements after fluid challenge. The hemodynamic variables remained stable, with minimal variation, and stayed within normal ranges for the species throughout the study period (Hannon et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e1989\u003c/span\u003e; Ido et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Median values (Q1-Q3) for HR, SpO\u003csub\u003e2\u003c/sub\u003e, PETCO\u003csub\u003e2\u003c/sub\u003e, SAP, MAP, DAP and core body temperature during the study were 90 (72.5\u0026ndash; 97.7) beats/minute, 99.5 (97.5\u0026ndash;100) %, 46,5 (42\u0026ndash; 53) mmHg, 94 (84.75\u0026ndash; 115.5) mmHg, 76 (64.2\u0026ndash; 88.5) mmHg, 65 (55.5\u0026ndash; 73) mmHg and 37.1 (36.1\u0026ndash; 37.4) \u0026ordm;C, respectively.\u003c/p\u003e \u003cp\u003eIn fluid responders, there was a significant increase in VTI\u003csub\u003eAo\u003c/sub\u003e from baseline after the PLRM [median (Q1\u0026ndash;Q3): 22.3 cm (17.2\u0026ndash;25.8) \u003cem\u003eversus\u003c/em\u003e 19.4 cm (15.4\u0026ndash; 20.5); p\u0026thinsp;=\u0026thinsp;0.017)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn optimal cutoff of 11.2% for ΔVTI\u003csub\u003eAo\u003c/sub\u003e was calculated for predicting fluid responsiveness after PLRM, with an AUROC of 1.00 (95% CI not estimated \u0026ndash; 1.00), sensitivity of 100% (95% CI 59\u0026ndash;100%), specificity of 100% (95% CI 2.5\u0026ndash;100%), positive predictive value of 100% (95% CI 59\u0026ndash;100%), and a negative predictive value of 100% (95% CI 2.5\u0026ndash;100%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study showed a significant increase in VTI\u003csub\u003eAo\u003c/sub\u003e following PLRM in fluid-responsive pigs. In addition, despite the use of a small sample of animals a preliminary cutoff of a ΔVTIAo of 11.2% post-PLRM shows promise for predicting a subsequent increase in VTIAo greater than 15% after fluid challenge, which could guide the assessment of fluid responsiveness.\u003c/p\u003e \u003cp\u003eA previous study conducted in a pig model under various hemodynamic conditions suggested that PLRM could be beneficial in identifying hemodynamically unstable animals responsive to fluid therapy. However, the authors utilized cardiac output measurement by thermodilution. Despite thermodilution being considered one of the standard techniques for cardiac output measurement, its use in conjunction with PLRM has been discouraged. Among the limitations, the method's inability to accurately detect transient and short-term changes in stroke volume is prominent (Monet and Teboul 2015, 2017).\u003c/p\u003e \u003cp\u003eWhile fluid responsiveness is typically defined as an increase in stroke volume exceeding 15% following a fluid load, the increase in responders after PLRM may be less than 15%. A prior postoperative study in human patients demonstrated that an increase in VTI\u003csub\u003eAo\u003c/sub\u003e greater than 11% following PLRM predicted fluid responsiveness with 81.8% sensitivity and 89.5% specificity (El Hadouti et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). These findings align with those observed in the present study.\u003c/p\u003e \u003cp\u003eHowever, it is essential to consider the least significant change between two examinations, whether the procedure is performed by the same operator or two different ones. Interestingly, changes in ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e measured by the same operator of less than 11% may fall within the least significant change method's inaccuracy range (Jozwiak et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The preliminary cutoff value for VTI\u003csub\u003eAo\u003c/sub\u003e obtained in the present study was slightly above the least significant change, suggesting that ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e could reliably predict fluid responsiveness under the study's conditions.\u003c/p\u003e \u003cp\u003eDespite its accuracy range, echocardiography, being noninvasive, is a recommended method for monitoring changes in cardiac output when PLRM is employed, as it provides real-time assessment (Monet and Teboul 2015). Other human medicine studies have also utilized echocardiography to confirm fluid responsiveness (Pr\u0026eacute;au et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Lamia et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2007\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, we observed a significant proportion of animals exhibiting a response to fluid administration. These results correspond with findings from other studies, which reported a considerable rate of fluid responsiveness in healthy humans and dogs (Bucci et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Alves \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be considered when interpreting the results. First, wide confidence intervals were observed, which affected the precision of the findings. This is likely due to the small sample size used in the study. Second, echocardiography is a valuable tool for assessing cardiac function. However, it has limitations, including measurement variability and the potential for errors due to operator technique. In this study, measurements were conducted by a single observer, which precluded consideration of inter-individual variability. Finally, the pigs included in the study were part of an unrelated project that required general anesthesia and euthanasia, potentially introducing bias in the sample selection process. Addressing these potential limitations in future studies could strengthen the validity and reliability of the findings and enhance the understanding of fluid responsiveness assessment techniques in animal models.\u003c/p\u003e \u003cp\u003eThis study presents a novel approach to identifying fluid-responsive animals through increased VTI\u003csub\u003eAo\u003c/sub\u003e following PLRM. Despite the limitations, the study findings demonstrate the feasibility of assessing fluid responsiveness using ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e measurements associated with a PLRM in anesthetized pigs, obviating the need for fluid challenges. This study also concludes that a preliminary ΔVTI\u003csub\u003eAo\u003c/sub\u003e value of \u0026ge;\u0026thinsp;11.2% reliably identified fluid-responsive pigs under anesthesia and mechanical ventilation.\u003c/p\u003e"},{"header":"Statements \u0026 Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Animal Ethics:\u0026nbsp;\u003c/strong\u003eInstitutional Animal Care and Use Committee, Faculty of Veterinary Science, University of Buenos Aires (no. 2022/45).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest Statement:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was funded by the Secretaría de Ciencia y Técnica, Universidad de Buenos Aires, Argentina (UBACyT 20020190200318BA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u003c/strong\u003e Conception and design: LT, PD, PO. Data collection: LT, PD, AZ, SF, MC, AD, NN, Analysis and interpretation: LT, PD, AZ, SF, JM, JIR, PO. \u0026nbsp;Manuscript drafting: LT, PD, AZ, PO Critical revisions: LT, PD, SF, MC, AD, NN, JM, JIR, PO.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAlbus U (2012) Guide for the Care and Use of Laboratory Animals (8th ed). \u003cem\u003eLaboratory Animals\u003c/em\u003e 46, 267\u0026ndash;268. https://doi.org/10.1258/la.2012.150312 \u003c/li\u003e\n\u003cli\u003eAlves DR (2017) Is Fluid Responsiveness a Normal State in Human Beings? A Study in Volunteers. \u003cem\u003eAnesth Med Pract J\u003c/em\u003e G106. https://doi:10.29011/AMPJ-106/100006\u003c/li\u003e\n\u003cli\u003eBoon J (2011) \u003cem\u003eVeterinary Echocardiography\u003c/em\u003e. 2nd ed. Wiley-Blackwell \u003c/li\u003e\n\u003cli\u003eBradbury AG, Clutton RE (2016) Are neuromuscular blocking agents being misused in laboratory pigs? \u003cem\u003eBr J Anaesth\u003c/em\u003e 116, 476\u0026ndash;485. https://doi.org/10.1093/bja/aew019\u003c/li\u003e\n\u003cli\u003eBoulain T, Achard JM, Teboul JL, Richard C, Perrotin D, Ginies G (2002) Changes in BP induced by passive leg-raising predict response to fluid loading in critically ill patients. \u003cem\u003eChest\u003c/em\u003e 121,1245\u0026ndash;1252. https://doi.org/10.1378/chest.121.4.1245\u003c/li\u003e\n\u003cli\u003eBucci M, Rabozzi R, Guglielmini C, Franci P (2017) Respiratory variation in aortic blood peak velocity and caudal vena cava diameter can predict fluid responsiveness in anaesthetised and mechanically ventilated dogs. \u003cem\u003eThe\u003c/em\u003e\u003cem\u003eVeterinary Journal,\u003c/em\u003e 227, 30\u0026ndash;35. https://doi.org/10.1016/j.tvjl.2017.08.004\u003c/li\u003e\n\u003cli\u003eCannesson M, Le Manach Y, Hofer CK, Goarin JP, Lehot JJ, Vallet B, Tavernier B (2011) Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a \u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003eGray Zone\u0026rdquo; approach. \u003cem\u003eAnesthesiology\u003c/em\u003e 115, 231\u0026ndash;41. https://doi.org/10.1097/ALN.0b013e318225b80a\u003c/li\u003e\n\u003cli\u003eCarsetti A, Cecconi M, Rhodes A (2015) Fluid bolus therapy: monitoring and predicting fluid responsiveness. Curr Opin \u003cem\u003eCrit Care\u003c/em\u003e 21, 388\u0026ndash;394. https://doi.org/10.1097/MCC.0000000000000240\u003c/li\u003e\n\u003cli\u003eCavallaro F, Sandroni C, Marano C, La Torre G, Mannocci A, De Waure C, Bello G, Maviglia R, Antonelli M (2010) Diagnostic accuracy of passive leg-raising for prediction of fluid responsiveness in adults: systematic review and meta-analysis of clinical studies. \u003cem\u003eIntensive Care Med\u003c/em\u003e 36, 1475\u0026ndash;1483. https://doi.org/10.1007/s00134-010-1929-y\u003c/li\u003e\n\u003cli\u003eCavanagh AA, Sullivan LA, Hansen BD (2016) Retrospective evaluation of fluid overload and relationship to outcome in critically ill dogs. \u003cem\u003eJ Vet Emerg Crit Care\u003c/em\u003e 26, 578\u0026ndash;86. https://doi.org/10.1111/vec.12477\u003c/li\u003e\n\u003cli\u003eCecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A (2014) Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. \u003cem\u003eIntensive Care Med \u003c/em\u003e40, 1795\u0026ndash;1815. https://doi.org/10.1007/s00134-014-3525-z\u003c/li\u003e\n\u003cli\u003eCeleita-Rodr\u0026iacute;guez N, Teixeira-Neto FJ, Garofalo NA, Dalmagro TL, Girotto CH, Oliveira GCV, Santos IF (2019) Comparison of the diagnostic accuracy of dynamic and static preload indexes to predict fluid responsiveness in mechanically ventilated, isoflurane anesthetized dogs. \u003cem\u003eVet Anaesth Analg \u003c/em\u003e46, 276\u0026ndash;288. https://doi.org/10.1016/j.vaa.2018.12.004\u003c/li\u003e\n\u003cli\u003ede Oliveira GCV, Teixeira-Neto FJ, Dalmagro TL, Alfonso A, Celeita-Rodr\u0026iacute;guez N, Lobo CPC, Louren\u0026ccedil;o MLG (2021) Use of aortic flow indexes derived from transthoracic echocardiography to evaluate response to a fluid challenge in anesthetized dogs. \u003cem\u003eVet Anaesth Analg\u003c/em\u003e 48, 187\u0026ndash;197. https://doi.org/10.1016/j.vaa.2020.12.006\u003c/li\u003e\n\u003cli\u003eEl Hadouti Y, Valencia L, Becerra A, Rodr\u0026iacute;guez-P\u0026eacute;rez A, Vincent JL (2017)Echocardiography and passive leg-raising in the postoperative period. \u003cem\u003eEuropean journal of anaesthesiology\u003c/em\u003e 34, 748\u0026ndash;754. https://doi.org/10.1097/EJA.0000000000000679\u003c/li\u003e\n\u003cli\u003eHannon JP, Bossone CA, Wade CE (1989) Normal physiological values for conscious pigs used in biomedical research (pp. 0025). San Francisco, CA, USA: LAIR, \u003cem\u003eMilitary Trauma Research\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003eIdo CK, Silva PES, Silva HRA, Biteli EGF, Carneiro RL, Lopes PCF, Gering AP, Nunes N (2019) Hemodynamic variables in piglets anesthetized with isoflurane or propofol, kept under spontaneous ventilation and FIO 2 of 0.5. \u003cem\u003eArquivo Brasileiro de Medicina Veterin\u0026aacute;ria e Zootecnia\u003c/em\u003e 71, 1846\u0026ndash;1852. https://doi.org/10.1590/1678-4162-10845\u003c/li\u003e\n\u003cli\u003eJoosten A, Alexander B, Cannesson M (2015) Defining goals of resuscitation in the critically ill patient. \u003cem\u003eCrit Care Clin \u003c/em\u003e31, 113\u0026ndash;32. https://doi.org/10.1016/j.ccc.2014.08.006\u003c/li\u003e\n\u003cli\u003eJozwiak M, Mercado P, Teboul JL, Benmalek A, Gimenez J, D\u0026eacute;pret F, Richard C, Monnet X (2019) What is the lowest change in cardiac output that transthoracic echocardiography can detect? \u003cem\u003eCrit Care\u003c/em\u003e 11, 116. https://doi.org/10.1186/s13054-019-2413-x \u003c/li\u003e\n\u003cli\u003eLakhal K, Nay MA, Kamel T, Lortat-Jacob B, Ehrmann S, Rozec B, Boulain T (2017) Change in end-tidal carbon dioxide outperforms other surrogates for change in cardiac output during fluid challenge. \u003cem\u003eBr J Anaesth \u003c/em\u003e18, 355\u0026ndash;362. https://doi.org/10.1093/bja/aew478\u003c/li\u003e\n\u003cli\u003eLamia B, Ochagavia A, Monnet X, Chemla D, Richard C, \u0026amp; Teboul JL (2007)Echocardiographic prediction of volume responsiveness in critically ill patients with spontaneously breathing activity. \u003cem\u003eIntensive care medicine\u003c/em\u003e 33, 1125\u0026ndash;1132. https://doi.org/10.1007/s00134-007-0646-7\u003c/li\u003e\n\u003cli\u003eMarik PE (2010) Hemodynamic parameters to guide fluid therapy. Transfus Altern \u003cem\u003eTransfus Med\u003c/em\u003e 1, 102\u0026ndash;112. https://doi.org/10.1111/j.1778-428X.2010.01133.x\u003c/li\u003e\n\u003cli\u003eMarik P, Bellomo R (2016) A rational approach to fluid therapy in sepsis. \u003cem\u003eBr J Anaesth \u003c/em\u003e116, 339\u0026ndash;49. https://doi.org/10.1093/bja/aev349\u003c/li\u003e\n\u003cli\u003eMonnet X, Rienzo M, Osman D, Anguel N, Richard C, Pinsky MR, \u0026amp; Teboul JL (2006) Passive leg-raising predicts fluid responsiveness in the critically ill. \u003cem\u003eCritical care medicine\u003c/em\u003e 34, 1402\u0026ndash;1407. https://doi.org/10.1097/01.CCM.0000215453.11735.06 \u003c/li\u003e\n\u003cli\u003eMonnet X, Teboul JL (2015) Passive leg-raising: five rules, not a drop of fluid! \u003cem\u003eCrit Care\u003c/em\u003e 19, 18. https://doi.org/10.1186/s13054-014-0708-5\u003c/li\u003e\n\u003cli\u003eMonnet X, Teboul JL (2017) Transpulmonary thermodilution: advantages and limits. Critical Care 19, 147. https://doi.org/10.1186/s13054-017-1739-5.\u003c/li\u003e\n\u003cli\u003eParanjape VV, Shih AC, Garcia-Pereira FL (2019) Use of a modified passive leg-raising maneuver to predict fluid responsiveness during experimental induction and correction of hypovolemia in healthy isoflurane-anesthetized pigs. \u003cem\u003eAmerican Journal of Veterinary Research\u003c/em\u003e 80, 24\u0026ndash;32. https://doi.org/10.2460/ajvr.80.1.24\u003c/li\u003e\n\u003cli\u003eParanjape VV, Henao-Guerrero N, Menciotti G, Saksena S (2023) Esophageal Doppler-derived indices and arterial load variables provide useful hemodynamic information during assessment of fluid responsiveness in anesthetized dogs undergoing acute changes in blood volume. \u003cem\u003eAmerican Journal of Veterinary Research\u003c/em\u003e 84(3). https://doi.org/10.2460/ajvr.22.11.0198\u003c/li\u003e\n\u003cli\u003ePercie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Hurst V, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, W\u0026uuml;rbel H (2020) Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. \u003cem\u003ePLoS Biol\u003c/em\u003e 14;18(7):e3000411. https://doi.org/10.1177/0271678X20943823\u003c/li\u003e\n\u003cli\u003ePr\u0026eacute;au S, Saulnier F, Dewavrin F, Durocher A, Chagnon JL (2010) Passive leg-raising is predictive of fluid responsiveness in spontaneously breathing patients with severe sepsis or acute pancreatitis. \u003cem\u003eCritical care medicine\u003c/em\u003e 38, 819\u0026ndash;825. https://doi.org/10.1097/CCM.0b013e3181c8fe7a\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Fluid challenge, cardiac ultrasonography, Frank-Starling curve, porcine","lastPublishedDoi":"10.21203/rs.3.rs-4414423/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4414423/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study aimed to evaluate whether the velocity-time integral of aortic blood flow (VTI\u003csub\u003eAo\u003c/sub\u003e) assessed by transthoracic echocardiography is significantly increased after passive leg-raising maneuver (PLRM) in anesthetized and mechanically ventilated fluid responder pigs. Eight healthy Landrace pigs were anesthetized, mechanically ventilated, and subjected to PLRM. Ultrasound-guided VTI\u003csub\u003eAo\u003c/sub\u003e measurements were taken before and after PLRM and compared to assess changes. Fluid challenge was then performed, and changes in VTI\u003csub\u003eAo\u003c/sub\u003e were assessed to classify pigs as fluid responders or non-responders. Following PLRM, fluid responders exhibited a significant increase in VTI\u003csub\u003eAo\u003c/sub\u003e compared to baseline (p = 0.017). An optimal cutoff of 11.2% for ΔVTI\u003csub\u003eAo\u003c/sub\u003e was calculated for predicting fluid responsiveness after PLRM, with an AUROC of 1.00 (95% CI not estimated – 1.00), sensitivity of 100% (95% CI 59 – 100%), specificity of 100% (95% CI 2.5–100%), positive predictive value of 100% (95% CI 59–100%), and a negative predictive value of 100% (95% CI 2.5–100%).\u003c/p\u003e\n\u003cp\u003eThis study demonstrates the potential of using ultrasound-guided VTI\u003csub\u003eAo \u003c/sub\u003emeasurements associated with PLRM to predict fluid responsiveness in anesthetized pigs. A ΔVTI\u003csub\u003eAo \u003c/sub\u003evalue of ≥11.2% reliably identified fluid-responsive pigs under anesthesia and mechanical ventilation, offering a non-invasive alternative to fluid challenges. Further research addressing study limitations could enhance understanding of fluid responsiveness assessment in animal models.\u003c/p\u003e","manuscriptTitle":"Modified passive leg-raising maneuver to predict fluid responsiveness by transthoracic ultrasound guidance in healthy pigs under sevoflurane anesthesia.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 08:10:27","doi":"10.21203/rs.3.rs-4414423/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":"bd1340bc-e9fa-4c43-ae8a-ff4d1b25b4ee","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-04T21:53:34+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 08:10:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4414423","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4414423","identity":"rs-4414423","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}