The authors would like to thank Dr. Jos&#233; A. Diaz, Jamie Adcock, Mary Susan Fultz and the S.R. Light Laboratory at Vanderbilt University Medical Center for their assistance and support. 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.

The protocol received approval from 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, weighing approximately 40-45 kg, were utilized in this experiment. The animals were obtained from a commercial source (see Table of Materials). The current practice does not involve screening for any pre-existing medical conditions in t...

Oleic Acid&amp;#45;Induced Acute Respiratory Decompensation in Pigs

<ol>
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A provisional patent on intellectual property associated with respiratory non-invasive venous waveform analysis has been filed by the authors (BA, CB, and KH).

The key element in this protocol is to closely monitor the hemodynamic condition of the pig during the administration of oleic acid to induce respiratory distress15. It is of the utmost importance for researchers to take the necessary time to appropriately position the hemodynamic monitoring devices. One specific drawback of this model is the potential hemodynamic instability that may arise as a result of inflammation and injury to the respiratory vasculature8,<s...

The utilization of porcine models in translational research holds significant importance in advancing our understanding of human medicine1. Porcine models, due to their physiological and anatomical similarities to humans, provide a valuable platform for studying complex diseases and therapeutic interventions1. In the context of acute respiratory failure, porcine models offer a unique opportunity to investigate the pathophysiological mechanisms, evaluate treatment strategies, and assess potential interventions1,2,3. The ability to replicate key aspects of human respiratory physiology and responses to various stimuli in porcine models allows for a comprehensive evaluation of therapeutic modalities before progressing to human trials1,2,3. This research paradigm enables researchers to bridge the gap between preclinical investigations and clinical application, facilitating the development of novel therapies and improving patient outcomes1. Therefore, the establishment of an efficient, effective, and reproducible acute respiratory failure porcine model serves as a crucial tool in advancing the knowledge of respiratory diseases and guiding the development of effective interventions in human medicine1.
Respiratory distress, a critical medical condition, has witnessed limited advancements in its diagnosis and management over the past three decades4. The currently employed evaluation and triage metrics, which include subjective symptoms, physical examination findings, SpO2, and respiratory rate, often exhibit limitations in detecting acute pulmonary conditions at an early stage5,6,7. This inadequacy not only hampers efficient triage and resource allocation but also fails to provide effective, quantitative monitoring of disease progression and treatment response in patients with chronic pulmonary diseases. The emerging landscape of chronic respiratory conditions, such as long COVID, along with the burden of acute respiratory insufficiencies on hospital resources, underscores the urgent need to expand translational research and foster innovation in respiratory disease management.
The direct infusion of oleic acid into a pig&#39;s bloodstream has been recognized as a robust method to induce acute respiratory distress8. Oleic acid, a monounsaturated fatty acid, has demonstrated the ability to trigger significant pulmonary injury and compromise respiratory function when introduced into the pulmonary circulation8. Upon infusion, oleic acid provokes vasoconstriction, resulting in increased pulmonary arterial pressure and resistance, leading to impaired gas exchange and oxygenation9. Furthermore, oleic acid promotes the activation of inflammatory pathways, including the release of pro-inflammatory mediators and recruitment of immune cells, which contribute to the development of lung injury and respiratory distress10. All of this results in severe hypoxemia, increases in pulmonary arterial pressures, and the accumulation of extravascular lung water11. Histological evaluation of the lung parenchyma has demonstrated injury that is indistinguishable from human acute respiratory distress9.
This article details a method involving the direct administration of oleic acid into the pulmonary artery to induce acute respiratory distress, avoiding untreatable, severe hemodynamic compromise. The described method is anticipated to be a valuable tool for future researchers exploring the underlying pathophysiological mechanisms of acute respiratory failure and assessing potential therapeutic interventions and innovations.

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	<tbody>
		<tr>
			<td>1% Isoflurane</td>
			<td>Primal, Boston, MA, USA</td>
			<td>26675-46-7</td>
			<td>https://www.sigmaaldrich.com/US/en/product/aldrich/792632?gclid=Cj0KCQjw9fqnBhDSARIsAHl 
			cQYS_W-q6tS2s6LQw2Qn7Roa3T 
			GIpTLPf52351vrhgp44foEcRozPqt 
			YaAtvfEALw_wcB</td>
		</tr>
		<tr>
			<td>Arterial Catheter</td>
			<td>Merit Medical, South Jordan, UT, USA</td>
			<td>MAK401</td>
			<td>MAK Mini Access Kit 4F</td>
		</tr>
		<tr>
			<td>Blood Pressure Amp</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>FE117</td>
			<td>https://www.adinstruments.com/products/bp-blood-pressure-amp</td>
		</tr>
		<tr>
			<td>Central Venous Catheter</td>
			<td>Arrow International, Cleveland, OH, USA</td>
			<td>AK-09800</td>
			<td>8.5 Fr. x 4&#34; (10 cm) Arrow-Flex</td>
		</tr>
		<tr>
			<td>Disposable Pressure Transducers</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>MLT0670</td>
			<td>https://www.adinstruments.com/products/disposable-bp-transducers</td>
		</tr>
		<tr>
			<td>Edwards Lifesciences Triple Stage Venous Cannulas</td>
			<td>Edwards Life Sciences, Irvine, CA</td>
			<td>TF293702</td>
			<td>https://www.graylinemedical.com/products/edwards-lifesciences-triple-stage-venous-cannulas-venous-dual-stage-cannula-tf293702?variant=31851942576185&#38;gad=1&#38; 
			gclid=Cj0KCQiAr8eqBhD3ARIsAIe 
			-buNdmkzavUBaIx-1be7boWn2kW 
			hbUR6QCjaobB08uuK9qJW66JvY 
			TM4aAufGEALw_wcB</td>
		</tr>
		<tr>
			<td>Kelly Scissors</td>
			<td>MPM Medical Supply, Freehold, NJ 07728</td>
			<td>104-5516</td>
			<td>https://www.mpmmedicalsupply.com/products/kelly-scissors</td>
		</tr>
		<tr>
			<td>Kendall 930 FoamElectrodes</td>
			<td>Covidien, Mansfield, MA, USA</td>
			<td>22935</td>
			<td>https://www.cardinalhealth.com/en/product-solutions/medical/patient-monitoring/electrocardiography/monitoring-ecg-electrodes/radiolucent-electrodes/kendall-930-series-radiolucent-foam-electrodes.html</td>
		</tr>
		<tr>
			<td>Ketamine Hydrochloride 100 mg/mL, Injectable Solution, 10 mL</td>
			<td>Patterson Veterinary, Loveland, CO 80538</td>
			<td>07-894-8462</td>
			<td>https://www.pattersonvet.com/ProductItem/078948462?omni=ketamine</td>
		</tr>
		<tr>
			<td>LabChart 8 software</td>
			<td>AD Instruments, Colorado Springs, CO, USA</td>
			<td>N/A</td>
			<td>https://www.adinstruments.com/products/labchart</td>
		</tr>
		<tr>
			<td>Lahey Retractor</td>
			<td>BOSS Instruments LTD, Gordonsville, VA 22942</td>
			<td>18-1210</td>
			<td>https://bossinstruments.com/product/7-3-4-lahey-thyroid-retractor-6mmx28mm/</td>
		</tr>
		<tr>
			<td>Oleic Acid</td>
			<td>Sigma-Aldrich, Merck, Darmstadt, Germany</td>
			<td>O1008</td>
			<td>https://www.sigmaaldrich.com/US/en/product/sial/o1008?gclid=CjwKCAjwzJmlBhBBEiwAEJy 
			Lu2047wRpXqF_Z2BegUyhgZJ 
			_WygsWfErhgrGCIyMp8PxwNH 
			sTZ8qARoCl1QQAvD_BwE&#38;gcl 
			src=aw.ds</td>
		</tr>
		<tr>
			<td>Peripheral IV Catheter Angiocath 18-24 G 1.16 inch</td>
			<td>McKesson, Irving, TX, USA</td>
			<td>329830</td>
			<td>https://mms.mckesson.com/product/329830/Becton-Dickinson-381144</td>
		</tr>
		<tr>
			<td>Piezoelectrode</td>
			<td>MuRata Manuractoring Co, Ltd., Nagaokakyo, Kyoto, Japan</td>
			<td>7BB-12-9</td>
			<td>https://www.murata.com/en-us/products/productdetail?partno=7BB-12-9</td>
		</tr>
		<tr>
			<td>PlasmaLyte</td>
			<td>Baxter International, Deerfield, IL, USA</td>
			<td>2B2544X</td>
			<td>https://www.ciamedical.com/baxter-2b2544x-each-solution-plasma-lyte-a-inj-ph-7-4-1000ml</td>
		</tr>
		<tr>
			<td>Pulmonary Artery Catheter</td>
			<td>Edwards Life Sciences, Irvine, CA</td>
			<td>131F7</td>
			<td>Swan Ganz 7F x 110cm&#160;</td>
		</tr>
		<tr>
			<td>Standard Endotracheal Tubes</td>
			<td>Teleflex, Morrisville, NC 27560</td>
			<td>5-10313</td>
			<td>https://www.teleflex.com/usa/en/product-areas/anesthesia/airway-management/endotracheal-tubes/standard-tubes/index.html</td>
		</tr>
		<tr>
			<td>SurgiVet Clearview Foley Catheter, 8 Fr, 55 cm Silicone</td>
			<td>Penn Veterinary Supply, Inc, West Rendering, PN 13971</td>
			<td>SVCFC1030</td>
			<td>https://www.pennvet.com/customer/portal/catalog/home?urile=wcm:path%3APennVet+Catalog/Super+Sku+Catalog/SS0672/Surgivet+Clearview+Silicone+Foley+Catheters</td>
		</tr>
		<tr>
			<td>Telazol (Tiletamine HCl and Zolazepam HCl), Injectable Solution, 5 mL</td>
			<td>Patterson Veterinary, Loveland, CO 80538</td>
			<td>07-801-4969</td>
			<td>https://www.pattersonvet.com/ProductItem/078014969?omni=telazol</td>
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			<td>Welch Allyn E-MacIntosh Standard Laryngoscope Blade</td>
			<td>MFIMedical, San Diego, CA 92131</td>
			<td>WLA-69242</td>
			<td>https://mfimedical.com/products/welch-allyn-e-macintosh-standard-laryngoscope-blade?variant=12965771870285&#38;currency 
			=USD&#38;utm_medium=product_sync 
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			=sag_organic&#38;utm_campaign=sag 
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			<td>Xylazine HCl 100 mg/mL, Injectable Solution, 50 mL</td>
			<td>Patterson Veterinary, Loveland, CO 80538</td>
			<td>07-894-5244</td>
			<td>https://www.pattersonvet.com/ProductItem/078945244</td>
		</tr>
		<tr>
			<td>Yorkshire Pigs</td>
			<td>Oak Hill Genetics, Ewing, IL, USA</td>
			<td>138274</td>
			<td>Female/Male Swine- Yorkshire/Landrace 81-100lbs</td>
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a porcine model of acute respiratory failure with a continuous infusion of oleic acid

This protocol outlines an acute respiratory distress model utilizing centrally administered oleic acid infusion in Yorkshire pigs. Prior to experimentation, each pig underwent general anesthesia, endotracheal intubation, and mechanical ventilation, and was equipped with bilateral&#160;jugular vein central vascular access catheters. Oleic acid was administered through a dedicated pulmonary artery catheter at a rate of 0.2 mL/kg/h. The infusion lasted for 60-120 min, inducing respiratory distress. Throughout the experiment, various parameters including heart rate, respiratory rate, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, end-tidal carbon dioxide, peak airway pressures, and plateau pressures were monitored. Around the 60 min mark, decreases in partial arterial oxygen pressure (PaO2) and fraction of oxygen-saturated hemoglobin (SpO2) were observed. Periodic hemodynamic instability, accompanied by acute increases in pulmonary artery pressures, occurred during the infusion. Post-infusion, histological analysis of the lung parenchyma revealed changes indicative of parenchymal damage and acute disease processes, confirming the effectiveness of the model in simulating acute respiratory decompensation.

Author Spotlight: Exploring Venous Waveforms for Non&amp;#45;Invasive Respiratory Monitoring in Pigs

A Porcine Model of Acute Respiratory Failure with a Continuous Infusion of Oleic Acid

Our team's translational research is in how vascular waveforms, specifically the low-frequency venous waveform, change in various volume and respiratory states. We are trying to better understand the venous waveform and how the respiratory system influences them. Our research shows that analyzing the fundamental frequencies of respiratory and pulse rates to calculate the RIVA-RI ratio can help in quantitatively monitoring patients'oxygen therapy needs correlating with PaO2.This could lead to a noninvasive tool for triaging patients with acute respiratory insufficiency, worsening asthma, COPD, emphysema, or idiopathic pulmonary fibrosis. Given the novel nature of our research, obtaining these venous waveforms in humans is a big challenge and just not practical in a lot of instances. That is why porcine models such as this one are so important to what we do and what we hope to achieve.The significant findings of our research is that waveforms from the venous side, a traditionally ignored field, hold a vast amount of information. We have found that these venous signals are very sensitive to changes in both volume status and the respiratory condition. This discovery offers hope for enhancing noninvasive respiratory monitoring in humans.

Early single pig, pilot data demonstrates an increase in RIVA-RI prior to changes in other respiratory monitoring measures (RR and SpO2), in line with changes in PaO2 (Figure 3). The drop in PaO2 is the &#34;positive&#34; result this model intends to achieve. Preliminary data also shows that RIVA-RI increases and the PaO2 decreases with disease progression starting at the 30-min&#160;mark (Figure 3; red arrow). PaO<sub...

Watch this Scientific Journal Video about Author Spotlight: Exploring Venous Waveforms for Non-Invasive Respiratory Monitoring in Pigs at JoVE.com

Infusing oleic acid continuously into the pulmonary artery of an anesthetized adult pig induces acute respiratory failure, enabling controlled experimentation during acute respiratory decompensation.

This protocol outlines an acute respiratory distress model utilizing centrally administered oleic acid infusion in Yorkshire pigs. Prior to ...

a-porcine-model-acute-respiratory-failure-with-continuous-infusion

Research

JoVE Journal

Medicine

Cannulation and Integrated Hemodynamic Monitoring in Swine for Oleic Acid&#45;Induced Pulmonary Injury Studies

To begin, disinfect the entire anterior neck of an anesthetized pig with a 2%chlorhexidine scrub solution, followed by a spray of 5%povidone iodine solution. With a number 23 blade, make a vertical incision immediately lateral to the trachea on either side of the sternum to expose the right and left external jugular veins and internal carotid arteries. Next, use Kelly tissue scissors, and Lahey retractors to dissect the strap muscles and tracked as needed.Expose the common carotid artery, internal jugular and external jugular veins on both the right and left side. Using the Seldinger technique, place an arterial line in the right carotid artery for invasive blood pressure monitoring. Monitor heart rate using telemetry leads.Connect a pressure transducer to the carotid artery catheter and monitor the systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Using the Seldinger technique, place two 8.5 French cannulas into the right and left internal jugular veins. Place two pulmonary artery catheters, one through the right 8.5 French cannula, and the other through the left 8.5 French cannula.Using an independent pressure transducer and amplifier system set up monitor mean pulmonary artery pressure and central venous pressure. Prepare 16%oleic acid in normal saline for infusion. Prime the oleic acid into an IV fluid line and add dimethyl sulf oxide to prevent separation.Connect it to the distal port of the left internal jugular pulmonary artery catheter. Start the oleic acid infusion and mark the start time. Immediately after starting an infusion, adjust ventilator settings to mimic room air conditions.Monitor the heart rate, fraction of oxygen saturated hemoglobin, respiratory rate, and tidal carbon dioxide, central venous pressure, systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure variability, and mean pulmonary artery pressure. Measure the cardiac output and pulmonary capillary wedge pressure every 30 minutes over the first 60 to 90 minutes, and then every 15 minutes thereafter until the pig is sacrificed. Record peak airway pressure, plateau pressure, and partial arterial oxygen pressure.

221 Views.  Vanderbilt University Medical Center.  Infusing oleic acid continuously into the pulmonary artery of an anesthetized adult pig induces acute respiratory failure, enabling controlled experimentation during acute respiratory decompensation.

Oleic Acid-Induced Acute Respiratory Decompensation in Pigs

Summary