Name: oleic acid-injection in pigs as a model for acute respiratory distress syndrome
Uploaded: 2018-10-26T12:30:00
Description: Watch this Scientific Journal Video about Oleic Acid-Injection in Pigs As a Model for Acute Respiratory Distress Syndrome at JoVE.com

The authors want to thank Dagmar Dirvonskis for excellent technical support.

All animal experiments described here have been approved by the institutional and state animal care committee (Landesuntersuchungsamt Rheinland-Pfalz, Koblenz, Germany; approval number G14-1-077) and were conducted in accordance with the guidelines of the European and German Society of Laboratory Animal Sciences. The experiments were conducted in anesthetized male pigs (sus scrofa domestica) of 2-3 months age, weighing 27-29 kg.
1. Anesthesia, Intubation and Mechanical Ventilation
<ol>
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<ol>
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This article describes one method of oleic acid-induced lung injury as a model for studying various aspects of severe ARDS. There are also other protocols with different emulsions, different injection sites, and different temperatures of the emulsion23,24,25,26,27,28,29. Our method offers a ...

The acute respiratory distress syndrome (ARDS) is an intensive care syndrome that has been extensively studied since its first description about 50 years ago1. This body of research led to a better understanding of the pathophysiology and causes the development of ARDS resulting in improved patient care and outcome2,3. Nevertheless, the mortality in patients suffering from ARDS remains very high with about 35-40%4,5,6. The fact that about 10% of ICU admissions and 23% of ICU patients who require mechanical ventilation is due to ARDS underscores the relevance for further research in this field.
Animal models are widely used in research to examine pathophysiologic changes and potential treatment modalities for different kinds of diseases. Due to the complexity of ARDS, there is no single animal model to mimic this disease, but different models representing different aspects7. One well-established model is oleic acid injection (OAI)-induced lung injury. This model has been used in a wide array of animals, including mice8, rats9, pigs10, dogs11, and sheep12. Oleic acid is an unsaturated fatty acid and the most common fatty acid in the body of healthy humans13. It is present in human plasma, cell membranes, and adipose tissue13. Physiologically, it is bound to albumin while it is carried through the bloodstream13. Increased levels of fatty acids in the blood stream are associated with different pathologies and the severity of some diseases correlates with serum fatty acid levels13. The oleic acid ARDS-model was developed in an attempt to reproduce ARDS caused by lipid embolism as seen in trauma patients14. Oleic acid has direct effects on innate immune receptors in the lungs13 and triggers neutrophil accumulation15, inflammatory mediator production16, and cell death13. Physiologically, oleic acid induces rapidly progressing hypoxemia, increase in pulmonary arterial pressure and accumulation of extravascular lung water. Furthermore, it induces arterial hypotension and myocardial depression7. The disadvantages of this model are the necessity for central venous access, the questionable mechanistic relevance and the potential lethal progress caused by rapid hypoxemia and cardiac depression. The advantage of this model compared to other models is the usability in small and large animals, the valid reproducibility of the pathophysiological mechanisms in ARDS, the acute onset of ARDS after injection of oleic acid, and the possibility to study isolated ARDS without systemic inflammation like in many other sepsis models7. In the following article, we give a detailed description of the oleic acid-induced lung injury in pigs and provide representative data to characterize the stability of the compromises in lung function. There are different protocols for OAI-induced lung injury. The protocol provided here is able to reliably induce acute lung injury.

<table >
	<tbody>
		<tr >
			<td >3-way-stopcock blue</td>
			<td >Becton Dickinson Infusion Therapy AB Helsingborg, Sweden</td>
			<td >394602</td>
			<td ></td>
		</tr>
		<tr >
			<td >3-way-stopcock red</td>
			<td >Becton Dickinson Infusion Therapy AB Helsingborg, Sweden</td>
			<td >394605</td>
			<td ></td>
		</tr>
		<tr >
			<td >Atracurium</td>
			<td >Hikma Pharma GmbH , Martinsried</td>
			<td>4262659</td>
			<td ></td>
		</tr>
		<tr >
			<td >Canula 20 G</td>
			<td >Becton Dickinson S.A. Carretera Mequinenza Fraga, Spain</td>
			<td >301300</td>
			<td ></td>
		</tr>
		<tr >
			<td >Datex Ohmeda S5</td>
			<td >GE Healthcare Finland Oy, Helsinki, Finland</td>
			<td></td>
			<td ></td>
		</tr>
		<tr >
			<td >Desinfection</td>
			<td >Sch&#252;lke &#38; Mayr GmbH, Germany</td>
			<td>104802</td>
			<td ></td>
		</tr>
		<tr >
			<td >Endotracheal tube</td>
			<td >Teleflex Medical Sdn. Bhd, Malaysia</td>
			<td >112482</td>
			<td ></td>
		</tr>
		<tr >
			<td >Endotracheal tube introducer</td>
			<td >R&#252;sch</td>
			<td>5033062</td>
			<td ></td>
		</tr>
		<tr >
			<td >Engstr&#246;m Carestation</td>
			<td >GE Heathcare, Madison USA</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Fentanyl</td>
			<td >Janssen-Cilag GmbH, Neuss</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Gloves</td>
			<td >Paul Hartmann, Germany</td>
			<td>9422131</td>
			<td ></td>
		</tr>
		<tr >
			<td >Incetomat-line 150 cm</td>
			<td >Fresenius, Kabi Germany GmbH</td>
			<td >9004112</td>
			<td ></td>
		</tr>
		<tr >
			<td >Ketamine</td>
			<td >Hameln Pharmaceuticals GmbH</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Laryngoscope</td>
			<td >Teleflex Medical Sdn. Bhd, Malaysia</td>
			<td >671067-000020</td>
			<td ></td>
		</tr>
		<tr >
			<td >Logical pressure monitoring system</td>
			<td >Smith- Medical Germany GmbH</td>
			<td>MX9606</td>
			<td ></td>
		</tr>
		<tr >
			<td >Logicath 7 Fr 3-lumen 30cm</td>
			<td >Smith- Medical Germany GmbH</td>
			<td>MXA233x30x70-E</td>
			<td ></td>
		</tr>
		<tr >
			<td >Masimo Radical 7</td>
			<td >Masimo Corporation Irvine, Ca 92618 USA</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Mask for ventilating dogs</td>
			<td >Henry Schein, Germany</td>
			<td >730-246</td>
			<td ></td>
		</tr>
		<tr >
			<td >Neofox Kit</td>
			<td >Ocean optics Largo, FL USA</td>
			<td>NEOFOX-KIT-PROBE</td>
			<td ></td>
		</tr>
		<tr >
			<td >Norepinephrine</td>
			<td >Sanofi- Aventis, Seutschland GmbH</td>
			<td >73016</td>
			<td ></td>
		</tr>
		<tr >
			<td >Oleic acid</td>
			<td >Applichem GmbH Darmstadt, Germany</td>
			<td>1,426,591,611</td>
			<td ></td>
		</tr>
		<tr >
			<td >Original Perfusor syringe 50ml Luer Lock</td>
			<td >B.Braun Melsungen AG, Germany</td>
			<td>8728810F</td>
			<td ></td>
		</tr>
		<tr >
			<td >PA-Katheter Swan Ganz 7,5 Fr 110cm</td>
			<td >Edwards Lifesciences LLC, Irvine CA, USA</td>
			<td>744F75</td>
			<td ></td>
		</tr>
		<tr >
			<td >Percutaneous sheath introducer set 8,5 und 9 Fr, 10 cm with integral haemostasis valve/sideport</td>
			<td >Arrow international inc. Reading, PA, USA</td>
			<td>AK-07903</td>
			<td ></td>
		</tr>
		<tr >
			<td >Perfusor FM Braun</td>
			<td >B.Braun Melsungen AG, Germany</td>
			<td>8713820</td>
			<td ></td>
		</tr>
		<tr >
			<td >Potassium chloride</td>
			<td >Fresenius, Kabi Germany GmbH</td>
			<td>6178549</td>
			<td ></td>
		</tr>
		<tr >
			<td >Propofol 2%</td>
			<td >Fresenius, Kabi Germany GmbH</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Saline</td>
			<td >B.Braun Melsungen AG, Germany</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Sonosite Micromaxx Ultrasoundsystem</td>
			<td >Sonosite Bothell, WA, USA</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Stainless Macintosh Size 4</td>
			<td >Teleflex Medical Sdn. Bhd, Malaysia</td>
			<td >670000</td>
			<td ></td>
		</tr>
		<tr >
			<td >Sterofundin</td>
			<td >B.Braun Melsungen AG, Germany</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Stresnil 40mg/ml</td>
			<td >Lilly Germany GmbH, Abteilung Elanco Animal Health</td>
			<td ></td>
			<td ></td>
		</tr>
		<tr >
			<td >Syringe 10 mL</td>
			<td >Becton Dickinson S.A. Carretera Mequinenza Fraga, Spain</td>
			<td>309110</td>
			<td ></td>
		</tr>
		<tr >
			<td >Syringe 2 mL</td>
			<td >Becton Dickinson S.A. Carretera Mequinenza Fraga, Spain</td>
			<td>300928</td>
			<td ></td>
		</tr>
		<tr >
			<td >Syringe 20 mL</td>
			<td >Becton Dickinson S.A. Carretera Mequinenza Fraga, Spain</td>
			<td >300296</td>
			<td ></td>
		</tr>
		<tr >
			<td >Syringe 5 mL</td>
			<td >Becton Dickinson S.A. Carretera Mequinenza Fraga, Spain</td>
			<td>309050</td>
			<td ></td>
		</tr>
		<tr >
			<td >venous catheter 22G</td>
			<td >B.Braun Melsungen AG, Germany</td>
			<td>4269110S-01</td>
			<td ></td>
		</tr>
	</tbody>
</table>

oleic acid-injection in pigs as a model for acute respiratory distress syndrome

The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit patients. Despite treatment advances over the last decades, ARDS patients still suffer mortality rates between 35 and 40%. There is still a need for further research to improve the outcome of patients suffering from ARDS. One problem is that no single animal model can mimic the complex pathomechanism of the acute respiratory distress syndrome, but several models exist to study different parts of it. Oleic acid injection (OAI)-induced lung injury is a well-established model for studying ventilation strategies, lung mechanics and ventilation/perfusion distribution in animals. OAI leads to severely impaired gas exchange, deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The disadvantage of this model is the controversial mechanistic relevance of this model and the necessity for central venous access, which is challenging especially in smaller animal models. In summary, OAI-induced lung injury leads to reproducible results in small and large animals and hence represents a well-suited model for studying ARDS. Nevertheless, further research is necessary to find a model that mimics all parts of ARDS and lacks the problems associated with the different models existing today.

PaO2/FiO2-ratio decreases after fractionated application of oleic acid (Figure 1). In the presented study, 0.185 &#177; 0.01 ml kg-1 oleic acid was necessary for the induction of lung injury. All animals showed an impaired oxygenation after the induction of lung injury, with varieties in the further time course. In animal 1 and 3, it remained at one level with little fluctuations; in animal 2, we observe an initial increase, f...

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Oleic Acid-Injection in Pigs As a Model for Acute Respiratory Distress Syndrome

In this article, we present a protocol to induce acute lung injury in pigs by central-venous injection of oleic acid. This is an established animal model for studying the acute respiratory distress syndrome (ARDS).

The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit ...

This method can help answer key questions about the pathophysiologic changes that occur during ARDS for the development and evaluation of new treatment options for this disease. The main advantage of this technique is that it reproduces the basic pathologic changes observed in human ARDS. For ultrasound guided instrumentation, place an ultrasound probe on the right inguinal ligament of the experimental pig and scan for femoral vessels.Turn the probe 90 degrees to fully visualize the femoral artery in the long axis and use a Seldinger's needle to cannulate the right femoral artery under in-line ultrasound visualization. When pulsating bright blood flows out, introduce the guidance wire and retract the needle. Check to make sure that the positioning of the Seldinger's wire is correct by visualizing it with ultrasound.Visualize the femoral vein and cannulate the vein under in-line ultrasonography in continuous aspiration with the needle. When venous blood is able to be aspirated, insert Seldinger's wire and retract the needle. Use Seldinger's technique to insert a 5-French arterial introducer sheath and essential venous catheter and turn the corresponding three-way stopcocks back.Before inserting the pulmonary artery catheter, check that it is working properly and insert it through the left venous introducer sheath. When the pulmonary artery catheter has passed through the introducer sheath, inflate the balloon with one milliliter of air and advance the pulmonary artery catheter while monitoring the typical waveforms. Then deflate the balloon and check if blood can be aspirated through all of the ports of the pulmonary artery catheter.Then insert the probe for ultrafast measurement of the partial oxygen pressure through the right arterial introducer sheath. To induce lung injury, load one 20 milliliter syringe with 0.1 milliliters per kilogram of oleic acid and a second 20 milliliter syringe with two milliliters of freshly drawn blood. Add saline to the syringe with blood, to a total volume of 20 milliliters in both syringes and connect both syringes to a three-way stopcock.Connect a norepinephrine syringe pump to one port of the central venous catheter and begin an ultrafast partial oxygen pressure measurement. Record the baseline values of all of the relevant parameters and set the fraction of inspired oxygen to 1.0. Conduct a lung recruitment maneuver and connect the three-way stopcock to the proximal port of the pulmonary artery catheter.Then inject the oleic and blood saline mixtures, repeatedly from one syringe into the other, via the three-way stopcock, to thoroughly mix the solutions. When a homogeneous emulsion has been achieved, inject two milliliters of the emulsion into the central venous catheter and continue mixing. Closely monitor the hemodynamics after the injection, giving norepinephrine as 10 to 100 microgram bolus injection as necessary to keep the mean arterial pressure above 60 millimeters of mercury.Repeat the two milliliters oleic acid solution injection every three minutes, until the arterial partial pressure of oxygen fraction of inspired ratio is below 200 millimeters of mercury. Wait 30 minutes and reevaluate the partial pressure of oxygen fraction of inspired ratio. If the ratio is still over 200 millimeters of mercury, repeat the injections until the partial pressure of oxygen fraction of inspired ratio falls below 200 millimeters of mercury.Then set the ventilation according to the suggestions from the Acute Respiratory Distress Syndrome network. The partial oxygen pressure fraction of inspired oxygen ratio decreased after the fractionated application of oleic acid. Despite a typical impairment of oxygenation after the induction of lung injury, frequent variations in oxygen impairment are observed between animals across the impairment timecourse.Necessitating a close monitoring of the partial oxygen pressure fraction of inspired oxygen ratio while delivering the oleic acid. The decrease in partial oxygen pressure fraction of inspired oxygen ratio is paralleled by an increase in pulmonary arterial pressure which typically remains elevated for the rest of the experiment, with some fluctuation also observed between animals. Lung injury is visually detectable in lungs harvested six hours after lung injury induction, and histological analysis reveals alveolar edema and hemorrhage.After watching this video, you should have a good understanding of how to induce an acute lung injury in pigs by essential venous injection of oleic acid. Don't forget that working with oleic acid can be extremely hazardous and take precautions such as wearing gloves, and safety classes should always be taken while performing this procedure.

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