Adult and Pediatric Porcine Model of Acute Volume Overload

Published: January 12, 2024

doi:

Bret D. Alvis², Jenna Helmer Sobey, Lexie Vaughn, Christina Jelly, Dawson Wervey, Joyce Cheung-Flynn, Marisa Case, Colleen Brophy, Kyle Hocking³

¹Department of Anesthesiology,Vanderbilt University Medical Center, ²Department of Biomedical Engineering,Vanderbilt University, ³Department of Surgery,Vanderbilt University Medical Center, ⁴Ohio University Heritage College of Osteopathic Medicine

Summary

The protocol here shows how continuous administration of crystalloids into the central veins of a euvolemic pig/piglet allows for the appropriate investigation of the physiological effects of acute volume overload.

Abstract

This protocol describes an acute volume overload porcine model for adult Yorkshire pigs and piglets. Both swine ages undergo general anesthesia, endotracheal intubation, and mechanical ventilation. A central venous catheter and an arterial catheter are placed via surgical cutdown in the external jugular vein and carotid artery, respectively. A pulmonary artery catheter is placed through an introducer sheath of the central venous catheter. PlasmaLyte crystalloid solution is then administered at a rate of 100 mL/min in adult pigs and at 20 mL/kg boluses over 10 min in piglets. Hypervolemia is achieved either at 15% decrease in cardiac output or at 5 L in adult pigs and at 500 mL in piglets. Hemodynamic data, such as heart rate, respiratory rate, end-tidal carbon dioxide, fraction of oxygen-saturated hemoglobin, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, partial arterial oxygen pressure, lactate, pH, base excess, and pulmonary artery fraction of oxygen-saturated hemoglobin, are monitored during experimentation. Preliminary data observed with this model has demonstrated statistically significant changes and strong linear regressions between central hemodynamic parameters and acute volume overload in adult pigs. Only pulmonary capillary wedge pressure demonstrated both a linear regression and a statistical significance to acute volume overload in piglets. These models can aid scientists in the discovery of age-appropriate therapeutic and monitoring strategies to understand and prevent acute volume overload.

Introduction

Acute volume overload, a condition characterized by an abrupt and excessive increase in body fluid volume, is a critical medical concern that warrants comprehensive study¹. It is often associated with aggressive and/or inappropriate fluid resuscitation, blood transfusion, and comorbidities such as heart failure and renal failure. It can lead to severe morbidity and an increased likelihood of mortality¹^,²^,³. Despite its clinical significance, the pathophysiology of acute volume overload remains poorly understood³^,⁴. Furthermore, the lack of specific diagnostic criteria and effective monitoring strategies further underscores the need for rigorous scientific investigation. Studying acute volume overload is not only crucial for improving patient outcomes but also for advancing our understanding of human physiology. It provides a unique opportunity to explore the body's fluid homeostasis mechanisms and their responses to extreme stress¹. Studies investigating goal-directed fluid therapy (GDFT) to prevent liberal fluid resuscitation and promote a more goal-directed resuscitation approach have demonstrated improved morbidity and mortality in perioperative settings and in sepsis¹^,³^,⁴. These studies used a variety of devices to monitor the volume state, including central venous catheters with central venous pressure measurements, ScVO₂, arterial line lactate measurements, stroke volume/cardiac output measurements through transesophageal Doppler, lithium dilution cardiac output, arterial pulse contour analysis, thoracic electrical bioimpedance, and transpulmonary thermodilution¹^,³^,⁴^,⁵. The multiple approaches utilized to assess volume status, each with limitations in accuracy and usability, suggest that there is room for significant improvement in GDFT by enhancing intravascular volume assessment³^,⁴.

Porcine models have emerged as particularly valuable tools in the study of human cardiovascular physiology⁶. The anatomical and physiological similarities between porcine and human cardiovascular systems, such as heart size, coronary anatomy, and hemodynamic parameters, make pigs ideal models for translational research⁶. Furthermore, pigs exhibit a comparable response to volume overload as humans, making them excellent models for studying the pathophysiology of acute volume overload and the effectiveness of various therapeutic interventions⁷^,⁸. The use of porcine models also allows for the collection of high-quality, detailed data points, such as real-time hemodynamic measurements and tissue samples, which are often unattainable in human studies⁷. This superiority of data points provides a more comprehensive understanding of acute volume overload, which could ultimately contribute to the development of more effective monitoring and prevention strategies.

The use of piglet models in studying acute volume overload is of paramount importance, particularly given the scarcity of pediatric research in this field. Piglets, with their physiological and developmental similarities to human infants, provide an invaluable model, like their adult counterparts, for understanding the pediatric population⁹^,¹⁰^,¹¹. Despite the high incidence of volume overload conditions in pediatric patients, such as those related to congenital heart diseases or intensive care interventions, research in this area has been markedly limited, especially when it comes to animal models that accurately represent human infants⁵^,¹²^,¹³. Utilizing piglet models can help bridge this gap, offering insight into the pediatric-specific pathophysiology of acute volume overload and the efficacy of potential therapeutic strategies⁷^,¹¹.

This manuscript describes a method of using a continuous infusion of crystalloid solution directly into the external jugular vein of both adult and pediatric pigs to induce acute volume overload and to study the hemodynamic effects of such volume changes on common peripheral and central data points used in volume status monitoring. This outlined method should serve as a valuable tool to help future scientists investigate the underlying pathophysiological mechanisms of acute volume overload and evaluate potential superior monitoring modalities and innovations.

Protocol

The study protocol was approved by the Vanderbilt University Institutional Animal Care and Use Committee (protocol M1800176-00) and strictly adhered to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals. Male and Female Yorkshire pigs and piglets weighing approximately 40-45 kg and 4-10 kg are used in this experiment. The present approach does not encompass a screening for preexisting medical conditions in the ordered swine. Acknowledging that this practice could potentially influence …

Representative Results

The preliminary representative pilot data after linear regression analysis for the adult pig model demonstrated linearity to volume administration in the first eight pigs (Figure 2). While many other data points, and volume beyond 2.5 L, were measured during this experiment, these data represent the analysis to date. The two vital signs most used for volume assessment, HR (R2=0.15) and MAP (R2=0.79), both demonstrated a linear relationship during forced hypervolemia, bu…

Discussion

There are two critical steps in this protocol. First, it is imperative that time is taken to obtain appropriate cannulation and ensure the positioning of hemodynamic/volume monitoring. In both adult and piglet models, surgical cutdown is necessary to cannulate the required vessel appropriately and introduce the required catheter. Percutaneous, ultrasound guided approaches have proven challenging and traumatic around the small caliber vessels seen in pigs and piglets. Two catheters that can present a challenge are the PAC…

Declarações

The authors have nothing to disclose.

Acknowledgements

The authors would like to thank Dr. José A. Diaz, Jamie Adcock, and Mary Susan Fultz and the S.R. Light Laboratory at Vanderbilt University Medical Center for assistance and support. Another special thanks to John Poland and the rest of the Vanderbilt University Medical Center perfusionists and their students for their help with this study. This work was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (BA; R01HL148244). The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Materials

1% Isoflurane	Primal, Boston, MA, USA	26675-46-7	https://www.sigmaaldrich.com/US/en/product/aldrich/792632?gclid=Cj0KCQjw9fqnBhDSARIsAHl cQYS_W-q6tS2s6LQw2Qn7Roa3TGIpTLPf5 2351vrhgp44foEcRozPqtYaAtvfEAL w_wcB
Arterial Catheter	Merit Medical, South Jordan, UT, USA	MAK401	MAK Mini Access Kit 4F
Arterial Catheter	Cook Medical, Bloomington, IN, USA	C-PMS-300-RA/G01908	Radial Artery Catheter Set 3.0Fr./5cm
Blood Pressure Amp	AD Instruments, Colorado Springs, CO, USA	FE117	https://www.adinstruments.com/products/bp-blood-pressure-amp
Central Venous Catheter Introducer	Arrow International Inc, Reading, PA, USA	AK-09800	8.5 Fr. x 4" (10 cm) Arrow-Flex
Central Venous Catheter-Introducer	Arrow International	CP-07611-P	Super Arrow-Flex Percutaneous Sheath Introducer Kit 6Fr./7.5cm
Disposable BP Transducers	AD Instruments, Colorado Springs, CO, USA	MLT0670	https://www.adinstruments.com/products/disposable-bp-transducers
Kendall 930 FoamElectrodes	Covidien, Mansfield, MA, USA	22935	https://www.cardinalhealth.com/en/product-solutions/medical/patient-monitoring/electrocardiography/monitoring-ecg-electrodes/radiolucent-electrodes/kendall-930-series-radiolucent-foam-electrodes.html
LabChart 8 software	AD Instruments, Colorado Springs, CO, USA	N/A	https://www.adinstruments.com/products/labchart
Peripheral IV Catheter Angiocath 18-24 Gauge 1.16 inch	McKesson, Irving, TX, USA	329830	https://mms.mckesson.com/product/329830/Becton-Dickinson-381144
PlamaLyte Crystilloid Solution	Baxter International, Deerfield, IL USA	2B2544X	https://www.ciamedical.com/baxter-2b2544x-each-solution-plasma-lyte-a-inj-ph-7-4-1000ml
PowerLab	ADInstruments, Colorado Springs, CO, USA	N/A	https://www.adinstruments.com/products/powerlab/c?creative=532995768429&keyword= powerlab&matchtype=e&network= g&device=c&gclid=CjwKCAjwysipB hBXEiwApJOcu-ulfO0bfCc-j6B7PpO kOAGur8IZ4SWNkhNZ7mORGstO vKON6plWLxoCigsQAvD_BwE
Pulmonary Artery Catheter	Edwards Life Sciences, Irvine, CA, USA	TS105F5	True Size Thermodilution Catheter 24cm Proximal Port- Swan Ganz
Pulmonary Artery Catheter (7F)	Edwards Life Sciences, Irvine, CA, USA	131F7	Swan Ganz 7F x 110cm
Telazol (Tiletamine HCl and Zolazepam HCl), Injectable Solution, 5 mL	Patterson Veterinary, Loveland, CO 80538	07-801-4969	https://www.pattersonvet.com/ProductItem/078014969?omni=telazol
Terumo Sarns 8000 Roller Pump	Terumo Cardiovascular, Ann Arbor, MI, USA	16402	https://aamedicalstore.com/products/terumo-sarns%E2%84%A2-8000-roller-pump
Xylazine HCl 100 mg/mL, Injectable Solution, 50 mL	Patterson Veterinary, Loveland, CO 80538	07-894-5244	https://www.pattersonvet.com/ProductItem/078945244
Yorkshire Adult Pigs	Oak Hill Genetics, Ewing, IL, USA	N/A	Yorkshire/Landrace 81-100lbs
Yorkshire Piglets	Oak Hill Genetics	N/A	Female "piglet", specify age 5 weeks with a correlating healthy weight range (approximately 10-20lbs.)

Referências

Wise, E. S., et al. Hemodynamic parameters in the assessment of fluid status in a porcine hemorrhage and resuscitation model. Anesthesiology. 134 (4), 607-616 (2021).
Rollins, K. E., Lobo, D. N. Intraoperative goal-directed fluid therapy in elective major abdominal surgery: A meta-analysis of randomized controlled trials. Ann Surg. 263 (3), 465-476 (2016).
Som, A., Maitra, S., Bhattacharjee, S., Baidya, D. K. Goal directed fluid therapy decreases postoperative morbidity but not mortality in major non-cardiac surgery: a meta-analysis and trial sequential analysis of randomized controlled trials. J Anesth. 31 (1), 66-81 (2017).
Xu, C., et al. Goal-directed fluid therapy versus conventional fluid therapy in colorectal surgery: A meta analysis of randomized controlled trials. Int J Surg. 56, 264-273 (2018).
Hassinger, A. B., Wald, E. L., Goodman, D. M. Early postoperative fluid overload precedes acute kidney injury and is associated with higher morbidity in pediatric cardiac surgery patients. Pediatr Crit Care Med. 15 (2), 131-138 (2014).
Chen, C., et al. A global view of porcine transcriptome in three tissues from a full-sib pair with extreme phenotypes in growth and fat deposition by paired-end RNA sequencing. BMC Genomics. 12, 448 (2011).
Hou, N., Du, X., Wu, S. Advances in pig models of human diseases. Animal Model Exp Med. 5 (2), 141-152 (2022).
Spannbauer, A., et al. Large animal models of heart failure with reduced ejection fraction (HFrEF). Front Cardiovasc Med. 6, 117 (2019).
Odle, J., Lin, X., Jacobi, S. K., Kim, S. W., Stahl, C. H. The suckling piglet as an agrimedical model for the study of pediatric nutrition and metabolism. Annu Rev Anim Biosci. 2, 419-444 (2014).
Whitaker, E. E., et al. A novel, clinically relevant use of a piglet model to study the effects of anesthetics on the developing brain. Clin Transl Med. 5 (1), 2 (2016).
Gasthuys, E., et al. The potential use of piglets as human pediatric surrogate for preclinical pharmacokinetic and pharmacodynamic drug testing. Curr Pharm Des. 22 (26), 4069-4085 (2016).
Alobaidi, R., et al. Association between fluid balance and outcomes in critically ill children: A systematic review and meta-analysis. JAMA Pediatr. 172 (3), 257-268 (2018).
Soler, Y. A., Nieves-Plaza, M., Prieto, M., Garcia-De Jesus, R., Suarez-Rivera, M. Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: a prospective study. Pediatr Crit Care Med. 14 (4), e189-e195 (2013).
Alessa, M. A., et al. Porcine as a training module for head and neck microvascular reconstruction. J Vis Exp. (139), e58104 (2018).
Higgs, Z. C., Macafee, D. A., Braithwaite, B. D., Maxwell-Armstrong, C. A. The Seldinger technique: 50 years on. Lancet. 366 (9494), 1407-1409 (2005).
Cheung-Flynn, J., et al. Normal saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways. PLoS One. 14 (8), e0220893 (2019).
Canteras, M., Baptista-Silva, J. C. C., Cacione, D. G. Transverse versus longitudinal inguinotomy for femoral artery approach. Cochrane Database Syst Rev. 2018 (10), CD013153 (2018).
Katz, A. M. The descending limb of the Starling curve and the failing heart. Circulation. 32 (6), 871-875 (1965).
Ragosta, M. . Textbook of Clinical Hemodynamics. , (2017).
LaFarge, C. G., Miettinen, O. S. The estimation of oxygen consumption. Cardiovasc Res. 4 (1), 23-30 (1970).
Soto, F., Kleczka, J. F. Cardiopulmonary hemodynamics in pulmonary hypertension: Pressure tracings, waveforms, and more. Adv Pulmonary Hypertension. 7 (4), 386-393 (2008).
Helen Chum, C. P. Endotracheal intubation in swine. Lab Anim. 41 (11), 309-311 (2012).
Cavallaro, F., Sandroni, C., Antonelli, M. Functional hemodynamic monitoring and dynamic indices of fluid responsiveness. Minerva Anestesiol. 74 (4), 123-135 (2008).