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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

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 or obscure the desired results, it is essential to note that, as per the vendor's information, the likelihood of such interference is low. The limitation is acknowledged and accepted as an inherent aspect of the procedure.

1. Anesthesia and ventilation

  1. Adult porcine model
    1. Anesthetize the pig by slowly injecting ketamine (2.2 mg/kg)/xylazine (2.2 mg/kg)/telazol (4.4 mg/kg) intramuscularly (IM). Immediately after induction, an 18-24G intravenous (IV) catheter is placed in the central or marginal ear vein on the posterior side of the auricle. Secure the IV with 1-inch adhesive tape.
    2. Place the pig onto the operating room table, in the supine position. Ask an independent animal laboratory technician, responsible for overseeing specific parameters, to assess anesthesia depth determined by factors including vital signs, responsiveness to stimuli, presence or absence of movement, jaw tone laxity, fluctuations in heart rate, changes in end-tidal CO2 levels, and variations in respiratory rate. These assessments guide adjustments to the inhaled anesthetic dosage.
    3. Endotracheally intubate the pig with a 6.5 mm endotracheal tube, through direct laryngoscopy, and inflate the endotracheal cuff with 3-5 mL of air. Maintain the pig on volume-controlled ventilation with a tidal volume of 8 mL/kg, respiratory rate titrated to an end-tidal CO2 of 35-40 mmHg, and positive end-expiratory pressure of 5 cm H2O. Maintain anesthesia through the inhalation of 1% isoflurane.
    4. Place a Foley catheter in the urethra to monitor the urine output volume in female pigs and surgical place it in male pigs secondary to the anatomical difficulty of Foley placement through the urethra.
  2. Piglet model
    1. Inject anesthesia solution of ketamine (2.2 mg/kg)/xylazine (2.2 mg/kg)/telazol (4.4 mg/kg)/dexmedetomidine (0.005 mg/kg) into an approximately 5-week-old piglet (equivalent to approximately 12-month-old human) via an intramuscular (IM) injection. Then, immediately place a 22-24G IV in the best available vein, likely on the posterior side of the auricle.
    2. Place piglet on the operating room table, in the supine position.
    3. Using direct laryngoscopy, endotracheally intubate the piglet with a 4.5-5.5 mm endotracheal tube. Inflate the endotracheal tube cuff with 3-5 mL of air using a syringe without a needle attached to it. Maintain anesthesia with 1% isoflurane with or without re-administration of dexmedetomidine (0.005 - 0.01 mg/kg IV) every 2 h as needed based on the depth of anesthesia appreciated at the time of re-dose.
    4. Maintain with volume-controlled ventilation a tidal volume of 8 mL/kg, respiratory rate titrated to an end-tidal CO2 of 35-40 mmHg, and a positive end-expiratory pressure of 5 cm H2O.
    5. Place a Foley catheter in the urethra to monitor urine output volume in female piglets. Place the Foley catheter surgically in male piglets secondary to the anatomical difficulty of Foley placement through the urethra.
      ​NOTE: Additionally, buprenorphine/dexmedetomidine analgesic administration will occur via bolus administration as deemed necessary. To maintain consistency, the respiratory rate on the mechanical ventilator will be adjusted to keep the end-tidal CO2 level within the range of 35-40 mmHg throughout the experiment.

2. Cannulation and monitoring device placement

  1. Adult porcine model
    1. Disinfect the entire anterior neck with 2% chlorohexidine scrub solution and follow with a spray of 5% povidone-iodine solution14.
    2. Surgically expose both right and left external jugular (EJ) veins and internal carotid arteries (CA) with bilateral vertical incisions immediately lateral to the trachea, and dissect down to the vasculature with monopolar cautery.
    3. Dissect the strap muscles and tract as needed using Kelly tissue scissors and Lahey retractors and/or tissue forceps14. Expose bilateral EJ and CAs.
    4. Place two 8.5 French (Fr) cannula into the right EJ using the Seldinger technique15. Once cannulated, place a 7 Fr pulmonary artery catheter (PAC) through the introducer of the right EJ. Use this right EJ catheter and PAC for hemodynamic monitoring.
    5. Cannulate the left EJ with a 10 Fr cannula and connect it to a dedicated roller pump tubing primed with PlasmaLyte solution.
      NOTE: The external jugular veins tend to be of larger diameter and more appropriately angled for heart catheterization. It is for these reasons we chose to cannulate the EJ over the internal jugular (IJ) in the porcine experiments1.
    6. Using the Seldinger technique15 place a 4 Fr arterial line in the right CA for invasive blood pressure monitoring throughout the experiment.
    7. Attach the desired monitoring to pig.
      1. Monitor the heart rate (HR) with telemetry leads and the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) by connecting a pressure transducer attached to a blood pressure amplifier to the CA catheter.
      2. Monitor the mean pulmonary artery pressure (MPAP), systolic pulmonary artery pressure (SPAP), diastolic pulmonary artery pressure (DPAP), and central venous pressure (CVP) by attaching a pressure transducer attached to a blood pressure amplifier to the appropriate PAC ports.
      3. Determine pulse pressure by finding the variance between SBP and DBP. To calculate pulse pressure variability (PPV), compute the variation between peak pulse pressure levels during both inspiration and expiration throughout the respiratory cycle.
      4. Calculate PPV measurements using LabChart 8's Blood Pressure Module and running on a PowerLab system. In this setting, select 3 min of data in the Arterial Line channel where the minimum peak height is set to 10 mmHg and cycles averaged over 10 cycles. In the software's module the peaks of each pulse cycle can be automatically calculated and visually confirmed. The resulting minimum pulse pressure and maximum pulse pressure are then used to calculate PPV.
      5. Carry out thermodilution cardiac output (CO) by using device specific volume/temperature calibration. Obtain pulmonary capillary wedge pressure (PCWP) by inflating the PAC balloon with 1.5 mL of air and advancing the catheter until there is visualization of both V and A waves, representing restricted right to left blood flow. Read the PCWP at the value of the A wave at end expiration.
    8. Administer PlasmaLyte16 at a rate of approximately 100 mL/min to obtain a starting PCWP of 8-10 mmHg (euvolemia) before the initiation of acute volume overload.
      NOTE: The total volume needed to achieve euvolemia varies based on a multitude of variables covered in the Discussion. Approximately 500 mL is needed, on average, in pigs undergoing this experimental protocol at Vanderbilt University Medical Center. This model uses PlasmaLyte as the balanced buffered crystalloid solution. It is likely that any other balanced buffered crystalloid (e.g., Normosol-R, Lactated Ringer's) would offer similar results. Non-buffered, acidic normal saline is and should be avoided in this model to avoid the known loss of endothelial cell membrane integrity, endothelial dysfunction, and acidosis caused by normal saline16.
  2. Piglet model
    1. Similar to adult pigs, piglets, once anesthetized and mechanically ventilated, disinfect across their entire anterior neck with 2% chlorohexidine scrub solution and follow with a spray of 5% povidone-iodine solution14. Only cannulate the right EJ, carotid, and left femoral arteries in piglets.
    2. Surgically expose the right EJ vein and internal CA with a right sided vertical incision immediately lateral to the trachea and dissect down to the vasculature with monopolar cautery.
    3. Dissect the strap muscles and tract as needed using Kelly tissue scissors and Lahey retractors and/or tissue forceps14. Expose the right sided EJ and CA.
    4. Disinfect the lower abdomen and pubic area of the piglet with 2% chlorohexidine scrub solution and follow with a spray of 5% povidone-iodine solution. Surgically expose the left femoral artery (FA) with a classic longitudinal technique as described in17.
    5. Place a 6 Fr central venous catheter introducer into the right EJ, followed by placement of a 5 Fr PAC into the pulmonary artery.
    6. Position two 3 Fr arterial catheters: one in the right CA and the other in the left FA. Dedicate the left FA catheter to drawing blood for frequent arterial blood gas analysis. Use the open port associated with the PAC introducer for volume administration with a 60 mL syringe.
    7. Administer a PlasmaLyte16 bolus of 10 mL/kg using a 60 mL syringe at a steady push rate, stopping after each bolus to obtain a PCWP and stop once a value of 8-10 mmHg (euvolemia) is achieved.
      ​NOTE: The total volume needed to achieve euvolemia varies based on a multitude of variables covered in the Discussion of this manuscript. Approximately 50-100 mL is needed, on average, in the piglets undergoing this experimental protocol at Vanderbilt University Medical Center.

3. Volume administration

  1. Adult porcine model
    1. Once cannulation is complete and euvolemia achieved, infuse warm PlasmaLyte crystalloid solution in 500 mL increments at a rate of 100 mL/min (Figure 1).
    2. Confirm the recording of hemodynamic endpoints: HR, fraction of oxygen-saturated hemoglobin (SpO2), respiratory rate (RR), end-tidal carbon dioxide (ETCO2), CVP, SBP, DBP, MAP, PPV, SPAP, DPAP, and MPAP.
    3. Perform necessary procedures to obtain the static measures (CO and PCWP) after every 500 mL of volume until euthanasia, which will take place at 5 L total volume or until a 15% CO decrease from previous measurement exists, whichever occurs first.
      NOTE: The drop in CO represents the start of the descending limb of the Starling curve18. At this point, volume overload leads to dilation of the heart past the optimum length for muscle fiber contraction, resulting in impaired contraction and decreased CO18.
    4. At euvolemia, and at the end of total volume administration, perform an arterial blood gas analysis to obtain the partial arterial oxygen pressure (PaO2), pH, lactate, and base excess of the pig.
    5. Record the urine output (mL) after each 500 mL increment of PlasmaLyte crystalloid solution. It is advisable to zero out the urine once euvolemia is achieved. Euthanize the pig either at a total volume of 5 L or when a 15% decrease in CO is observed, whichever occurs first.
  2. Piglet model
    1. Following successful cannulation and attainment of euvolemia, administer PlasmaLyte in increments of 20 mL/kg via syringe bolus every 10 min (Figure 1).
    2. Confirm the recording of hemodynamic parameters (HR, RR, SpO2, EtCO2, CVP, SBP, DBP, MPAP, PPV, and MPAP). Measure PCWP after each 10 mL/kg bolus.
      NOTE: Owing to the volume required and the resistance created by the small internal diameter of the 5 Fr PAC, thermodilution CO is not performed in the piglets. Instead, the Fick method19,20 is employed to calculate the CO. This involves obtaining a fraction of oxygen-saturated hemoglobin from the pulmonary artery blood (SvO2), which is performed concurrently with arterial blood gas analysis.
    3. Perform arterial blood gas analysis after each 20 mL/kg volume bolus to obtain the PaO2, pH, lactate, and base excess.
      NOTE: Given the limitations of many of these invasive data points in routine clinical care, transthoracic echocardiography (TTE) is performed after each 20 mL/kg bolus in the piglet model to measure the aortic blood flow Peak Systolic Velocity (PSV) and Left Ventricular Outflow Tract (LVOT) diameters-two data points used in pediatric clinical practice to estimate a patient's volume state.
    4. Perform TTE to measure PSV and LVOT diameter data points after each 20 mL/kg bolus. Record urine output after each 20 mL/kg bolus. Euthanize the piglet either at a total volume of 500 mL or when a 15% decrease in CO is observed, whichever occurs first.

4. Euthanasia for both adult pigs and piglets

  1. Confirm maintenance of 1% isoflurane. Induce cardiac arrest by IV injection of sodium pentobarbital (125 mg/kg). Confirm lack of vital signs post injection to confirm demise.

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...

Disclosures

No disclosures specific to the topics of this report. Kyle Hocking, PhD, is Founder, CEO and President of VoluMetrix and an inventor on intellectual property in the field of venous waveform analysis assigned to Vanderbilt University and licensed to VoluMetrix. Colleen Brophy, MD, is Founder and CIO of VoluMetrix and an inventor of intellectual property in the field of venous waveform analysis assigned to Vanderbilt and licensed to VoluMetrix. Bret Alvis, MD, CMO and is an inventor on intellectual property in the field of venous waveform analysis assigned to Vanderbilt and licensed to VoluMetrix and is married to the COO of VoluMetrix. The remaining authors have no disclosures to report.

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

NameCompanyCatalog NumberComments
1% IsofluranePrimal, Boston, MA, USA26675-46-7https://www.sigmaaldrich.com/US/en/product/aldrich/792632?gclid=Cj0KCQjw9fqnBhDSARIsAHl
cQYS_W-q6tS2s6LQw2Qn7Roa3TGIpTLPf5
2351vrhgp44foEcRozPqtYaAtvfEAL
w_wcB
Arterial CatheterMerit Medical, South Jordan, UT, USAMAK401MAK Mini Access Kit 4F
Arterial CatheterCook Medical, Bloomington, IN, USAC-PMS-300-RA/G01908Radial Artery Catheter Set 3.0Fr./5cm
Blood Pressure AmpAD Instruments, Colorado Springs, CO, USAFE117https://www.adinstruments.com/products/bp-blood-pressure-amp
Central Venous Catheter IntroducerArrow International Inc, Reading, PA, USAAK-098008.5 Fr. x 4" (10 cm) Arrow-Flex
Central Venous Catheter-IntroducerArrow InternationalCP-07611-PSuper Arrow-Flex Percutaneous Sheath Introducer Kit 6Fr./7.5cm
Disposable BP TransducersAD Instruments, Colorado Springs, CO, USAMLT0670https://www.adinstruments.com/products/disposable-bp-transducers
Kendall 930 FoamElectrodesCovidien, Mansfield, MA, USA22935https://www.cardinalhealth.com/en/product-solutions/medical/patient-monitoring/electrocardiography/monitoring-ecg-electrodes/radiolucent-electrodes/kendall-930-series-radiolucent-foam-electrodes.html
LabChart 8 softwareAD Instruments, Colorado Springs, CO, USAN/Ahttps://www.adinstruments.com/products/labchart
Peripheral IV Catheter Angiocath 18-24 Gauge 1.16 inchMcKesson, Irving, TX, USA329830https://mms.mckesson.com/product/329830/Becton-Dickinson-381144
PlamaLyte Crystilloid SolutionBaxter International, Deerfield, IL USA2B2544Xhttps://www.ciamedical.com/baxter-2b2544x-each-solution-plasma-lyte-a-inj-ph-7-4-1000ml
PowerLabADInstruments, Colorado Springs, CO, USAN/Ahttps://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 CatheterEdwards Life Sciences, Irvine, CA, USATS105F5True Size Thermodilution Catheter 24cm Proximal Port- Swan Ganz 
Pulmonary Artery Catheter (7F)Edwards Life Sciences, Irvine, CA, USA131F7Swan Ganz 7F x 110cm 
Telazol (Tiletamine HCl and Zolazepam HCl), Injectable Solution, 5 mLPatterson Veterinary, Loveland, CO 8053807-801-4969https://www.pattersonvet.com/ProductItem/078014969?omni=telazol
Terumo Sarns 8000 Roller PumpTerumo Cardiovascular, Ann Arbor, MI, USA16402https://aamedicalstore.com/products/terumo-sarns%E2%84%A2-8000-roller-pump
Xylazine HCl 100 mg/mL, Injectable Solution, 50 mLPatterson Veterinary, Loveland, CO 8053807-894-5244https://www.pattersonvet.com/ProductItem/078945244
Yorkshire Adult PigsOak Hill Genetics, Ewing, IL, USAN/AYorkshire/Landrace 81-100lbs
Yorkshire PigletsOak Hill Genetics N/AFemale "piglet", specify age 5 weeks with a correlating healthy weight range (approximately 10-20lbs.)

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