Name: invasive hemodynamic characterization of the portal-hypertensive syndrome in cirrhotic rats
Uploaded: 2018-08-01T13:00:00
Description: Watch this Scientific Journal Video about Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats at JoVE.com

We thank the veterinarians, nurses, and animal keepers at the Center of Biomedical Research for their continuous support during our research projects. The authors acknowledge the important input of all reviewers of this protocol. Some of the research was funded by the &#34;Young Science Award&#34; of the Austrian Society of Gastroenterology and Hepatology (&#214;GGH) to PS and the &#34;Skoda Award&#34; of the Austrian Society of Internal Medicine to TR.

All methods described here have been approved by the ethics committee of the Medical University of Vienna and the Austrian Ministry of Science, Research and Economy (BMWFW). Procedures must be performed in aseptic conditions in an operation room or similar clean working area since the hemodynamic measurements represent surgical interventions. Generally, working in sterile conditions is recommended. When using an inhalation anesthesia, consider adequate ventilation of the surgery room for work safety. A time period of 40&...

<ol>
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M., Van Steenkiste, C., Van Vlierberghe, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemodynamic+Changes+in+Splanchnic+Blood+Vessels+in+Portal+Hypertension.">Hemodynamic Changes in Splanchnic Blood Vessels in Portal Hypertension.</a> Advances in Integrative Anatomy and Evolutionary Biology. 291 (6), 699-713 (2008).</li><li>Laleman, W., Van Landeghem, L., Wilmer, A., Fevery, J., Nevens, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Portal+hypertension:+from+pathophysiology+to+clinical+practice.">Portal hypertension: from pathophysiology to clinical practice.</a> Liver International. 25 (6), 1079-1090 (2005).</li><li>Franchis, R. d. . <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Updating+Consensus+in+Portal+Hypertension:+Report+of+the+Baveno+III+Consensus+Workshop+on+definitions,+methodology+and+therapeutic+strategies+in+portal+hypertension.">Updating Consensus in Portal Hypertension: Report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension.</a> Journal of Hepatology. 33 (5), 846-852 (2000).</li><li>Zardi, E. 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PP is the main outcome parameter for evaluation of the portal hypertensive syndrome and reflects the severity of underlying cirrhosis. Both matrix deposition (i.e., fibrosis) and sinusoidal vasoconstriction (due to increased hepatic expression of vasoconstrictors and decreased responsiveness to vasodilators) cause increased IHVR. The importance of PP and its impact on chronic liver disease has been shown in multiple preclinical11,12,<sup class...

PHT is defined as pathologically increased blood pressure in the portal venous system that can cause severe complications in patients with cirrhosis such as variceal bleeding and ascites1. While pre-hepatic (e.g., portal vein thrombosis) and post-hepatic (e.g., Budd-Chiari Syndrome) PHT are rare, intrahepatic PHT due to liver cirrhosis represents the most common cause of PHT2.
In liver cirrhosis, PP is primarily increased as a consequence of elevated IHVR3. In advanced stages, PHT is aggravated by the increased PVBF due to increased cardiac output and decreased systemic and splanchnic vascular resistance &#8212; defining the portal hypertensive syndrome4. Ohm&#39;s law (&#916;P = Q * R) implies that the IHVR and blood flow are proportional to PP5. In patients, direct measurement of PP is risky and not routinely performed; instead, the hepatic venous pressure gradient (HVPG) is used as an indirect measure of PP6,7. The HVPG is calculated by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP), which are measured using a balloon catheter placed in a hepatic vein8. The physiological HVPG ranges between 1&#8211;5 mmHg, while an HVPG &#8805;10 mmHg defines clinically significant portal hypertension (CSPH) and indicates increased risk for PHT-related complications, such as variceal bleeding, ascites, and hepatic encephalopathy9. Although PP (i.e., HVPG) is the most relevant parameter for PHT severity, information about other components of PHT, including the severity of hyperdynamic circulation (HR, MAP), splanchnic/mesenteric arterial blood flow, and IHVR, are critical to obtain a comprehensive understanding of the distinct underlying mechanism of PHT.
Thus, in contrast to indirect measurements of PP in humans, the introduced methodology for rats offers the advantage of a direct measurement of PP and allows the recording of additional hemodynamic parameters characterizing the portal hypertensive syndrome. In addition, the direct measurement of PP is an excellent integrative readout of the amount of liver fibrosis (a major determinant of IHVR) and overcomes certain limitations of fibrosis quantification related to liver tissue sampling errors.
The most commonly used rodent models of cirrhotic PHT include surgical bile duct ligation (BDL), toxin-induced liver injury (i.e., by carbon tetrachloride, thioacetamide, or dimethylnitrosamine administration), and diet-induced metabolic liver disease models. Prehepatic (non-cirrhotic) PHT can be induced by partial portal vein ligation (PPVL)10.
Small rodents are well suited for the presented method, including mice, hamsters, rats, or rabbits, and are associated with relatively low maintenance costs. Despite that all the hemodynamic assessments are feasible to perform in mice, better accuracy and reproducibility of results are seen with rats or larger rodents due to the obvious advantage of animal size. In addition, specific micro-instruments and devices are needed to obtain similar hemodynamic parameters in mice. Finally, rats are more robust with lower associated morbidity and mortality and thus, the drop-out rates are likely lower in rats than in mice.
The presented methodology is well-suited for evaluating specific treatments of liver disease (i.e., anti-fibrotic or anti-inflammatory drugs) or novel pharmacological approaches that influence vascular tone and/or endothelial biology; and thus, likely effect hemodynamic parameters in PHT.

<table>
	<tbody>
		<tr>
			<td>Instruments</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>LabChart 7 Pro software</td>
			<td>ADInstruments, Colorado Springs, CO, USA</td>
			<td>&#160;-</td>
			<td>Software</td>
		</tr>
		<tr>
			<td>ML870 PowerLab 8/30</td>
			<td>ADInstruments, Colorado Springs, CO, USA</td>
			<td>&#160;-</td>
			<td>Electronic multichannel recorder</td>
		</tr>
		<tr>
			<td>MLT0380/D</td>
			<td>ADInstruments, Colorado Springs, CO, USA</td>
			<td>&#160;-</td>
			<td>Pressure transducer (x2: for Portal Pressure and Arterial Pressure)</td>
		</tr>
		<tr>
			<td>ML112 Quad Bridge Amplifier</td>
			<td>ADInstruments, Colorado Springs, CO, USA</td>
			<td>&#160;-</td>
			<td>Bridge amplifier</td>
		</tr>
		<tr>
			<td>TS420</td>
			<td>Transonic Systems Inc., Ithaca, NY, USA</td>
			<td>&#160;-</td>
			<td>Flowmeter module</td>
		</tr>
		<tr>
			<td>Biological Research Apparatus 7025</td>
			<td>UGO BASILE S.R.L., Comerio, Italy</td>
			<td>&#160;-</td>
			<td>Ventilator</td>
		</tr>
		<tr>
			<td>Vapor 2000</td>
			<td>Dr&#228;ger Medical AG &#38; Co. KG, L&#252;beck, Germany</td>
			<td>&#160;-</td>
			<td>Isofluran Vaporizer</td>
		</tr>
		<tr>
			<td>Perivascular probes (rat) for Transonic systems (Superior Mesenteric Artery)</td>
			<td>Transonic Systems Inc., Ithaca, NY, USA</td>
			<td>#MA1PRB</td>
			<td>Ultrasonic flow probe (1mm)</td>
		</tr>
		<tr>
			<td>Perivascular probes (rat) for Transonic systems (Portal Vein)</td>
			<td>Transonic Systems Inc., Ithaca, NY, USA</td>
			<td>#MA2PSB</td>
			<td>Ultrasonic flow probe (2mm)</td>
		</tr>
		<tr>
			<td>1st for intubation &#38; 2nd for clean skin incisions</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Mayo scissor [x2]</td>
		</tr>
		<tr>
			<td>Metzenbaum scissor</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Cuticle scissor</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>e.g. Adson Brown tissue forceps</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Tissue Forceps</td>
		</tr>
		<tr>
			<td>High precision 45&#176; angle broad point forceps [x2]</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Hemostat [x4]</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>e.g. Mikulicz peritoneal clamp</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Curved clamp</td>
		</tr>
		<tr>
			<td>e.g. Dieffenbach clamp</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Micro clamp</td>
		</tr>
		<tr>
			<td>e.g. micro spatula with flat ends, width 4 mm,</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Micro metal spatula</td>
		</tr>
		<tr>
			<td>for transbuccal suture at intubation</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Needle holder</td>
		</tr>
		<tr>
			<td>Scalpel grip</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>selfmade</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Intubation desk</td>
		</tr>
		<tr>
			<td>blut, flexible and with a suitable diameter for arterial cannula and venflow</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>Blunt steel wire</td>
		</tr>
		<tr>
			<td>modified arterial line 20G with Flowstich</td>
			<td>Becton Dickinson, Farady Road, Swindon, UK</td>
			<td>#682245</td>
			<td>Arterial line</td>
		</tr>
		<tr>
			<td>Heating pad</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Rectal temerature probe</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Saline heater</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Laryngoscope (specific for animal size, e.g. rat)</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Inductionbox for inhalation anesthesia</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Scale (able to measure mg)</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Hair clipper</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
			<td>&#160;-</td>
		</tr>
		<tr>
			<td>Name </td>
			<td>Company </td>
			<td>Catalog Number</td>
			<td>Comments</td>
		</tr>
		<tr>
			<td>Consumables </td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>e.g. modified BD Venflon Pro Safety 14GA</td>
			<td>Becton Dickinson Infusion Therapy, AB, SE251 06 Helsingborg, Sweden</td>
			<td>#393230</td>
			<td>Peripheral venous catheter (14G)</td>
		</tr>
		<tr>
			<td>Fine-Bore Polyethylene Tubing, ID 0.58mm, OD 0.96mm, Portex,</td>
			<td>Smiths Medical International Ltd., Kent, UK</td>
			<td>#800/100/200</td>
			<td>Catheter tube (PE-50)</td>
		</tr>
		<tr>
			<td>e.g. Omnifix-F Solo</td>
			<td>B. Braun Melsungen AG, Melsungen, Germany</td>
			<td>#9161406V</td>
			<td>Syringe 1mL</td>
		</tr>
		<tr>
			<td>e.g. Injekt Solo</td>
			<td>B. Braun Melsungen AG, Melsungen, Germany</td>
			<td>#4606051V</td>
			<td>Syringe 5mL</td>
		</tr>
		<tr>
			<td>e.g. Injekt Solo</td>
			<td>B. Braun Melsungen AG, Melsungen, Germany</td>
			<td>#4606205V</td>
			<td>Syringe 20mL</td>
		</tr>
		<tr>
			<td>e.g. BD Microlance 3, 18G - 1 1/2&#34;</td>
			<td>Becton Dickinson S.A., Fraga, Spain</td>
			<td>#304622</td>
			<td>Cannula (18G)</td>
		</tr>
		<tr>
			<td>e.g. BD Microlance 3, 23G - 1&#34;</td>
			<td>Becton Dickinson S.A., Fraga, Spain</td>
			<td>#300800</td>
			<td>Cannula (23G)</td>
		</tr>
		<tr>
			<td>e.g. BD Microlance 3, 30G - 1/2&#34;</td>
			<td>Becton Dickinson S.A., Fraga, Spain</td>
			<td>#304000</td>
			<td>Cannula (30G) </td>
		</tr>
		<tr>
			<td>e.g. Leukoplast S</td>
			<td>BSN medical GmbH, Hamburg,&#160; Germany</td>
			<td>#47619-00</td>
			<td>Adhesive tape</td>
		</tr>
		<tr>
			<td>e.g. Gazin RK Mullkompressen (18x8cm)</td>
			<td>Lohmann &#38; Rauscher, Vienna, Austria</td>
			<td>#10972</td>
			<td>Gauze compress (small)</td>
		</tr>
		<tr>
			<td>e.g. Gazin RK Mullkompressen (5x5cm)</td>
			<td>Lohmann &#38; Rauscher, Vienna, Austria</td>
			<td>#10961</td>
			<td>Gauze compress (big)</td>
		</tr>
		<tr>
			<td>Silk Braided black, USP 4/0, EP 1.5</td>
			<td>SMI AG, St. Vith, Belgium</td>
			<td>#2021-04</td>
			<td>Suture (Silk 4/0, EP 1.5)</td>
		</tr>
		<tr>
			<td>e.g. Mersilk, 2-0 (3 Ph. Eur.), PS-1 Prime</td>
			<td>Johnson &#38; Johnson Medical GmbH - Ethicon Deutschland, Germany</td>
			<td>#EH7552</td>
			<td>Transbuccal suture</td>
		</tr>
		<tr>
			<td>e.g. Cottonbuds (2.2mm, 15cm)</td>
			<td>Paul Hartmann AG, Heidenheim, Germany</td>
			<td>#967936</td>
			<td>Cotton buds</td>
		</tr>
		<tr>
			<td>e.g. Vue Ultrasoundgel</td>
			<td>Optimum Medical Limited, UK</td>
			<td>#1157</td>
			<td>Ultrasound gel</td>
		</tr>
		<tr>
			<td>e.g. Glubran 2</td>
			<td>Gem srl, Viareggio, Italy</td>
			<td>#G-NB2-50</td>
			<td>Tissue glue</td>
		</tr>
		<tr>
			<td>e.g. Surgical scalpell knife Nr. 10 - carbon steel</td>
			<td>Swann-Morton, England, B.S.</td>
			<td>#202</td>
			<td>Scalpel Knife</td>
		</tr>
		<tr>
			<td>Heparin, 5000 i.E./mL (Natriumheparin)</td>
			<td>Medicamentum Pharma GmbH, Allerheiligen im M&#252;rztal, Austria</td>
			<td>&#160;-</td>
			<td>Heparin</td>
		</tr>
		<tr>
			<td>Florane</td>
			<td>Aesica Queenborough Ltd., Queenborough, UK</td>
			<td>&#160;-</td>
			<td>Isoflurane</td>
		</tr>
		<tr>
			<td>OeloVital (5g)</td>
			<td>Fresenius Kabi Austira Gmbh, Graz, Austria</td>
			<td>&#160;-</td>
			<td>Eye gel</td>
		</tr>
		<tr>
			<td>Ketasol</td>
			<td>aniMedica GmbH, Senden-B&#246;sensell, Germany</td>
			<td>&#160;-</td>
			<td>Ketamine</td>
		</tr>
		<tr>
			<td>Rompun</td>
			<td>Bayer Austria Ges.m.b.H., Vienna, Austria</td>
			<td>&#160;-</td>
			<td>Xylazine</td>
		</tr>
		<tr>
			<td>Xylocain 10% Pumpspray</td>
			<td>AstraZeneca &#214;sterreich GmbH, Vienna, Austria</td>
			<td>&#160;-</td>
			<td>Lidocaine pump spray</td>
		</tr>
		<tr>
			<td>Dipidolor</td>
			<td>Jansen-Cilag Pharma GmbH, Vienna, Austria</td>
			<td>&#160;-</td>
			<td>Piritramide</td>
		</tr>
		<tr>
			<td>NaCl 0.9% Fresenius, 1L</td>
			<td>Fresenius Kabi Austira GmbH, Graz, Austria</td>
			<td>#13LIP132</td>
			<td>Physiological saline solution</td>
		</tr>
	</tbody>
</table>

invasive hemodynamic characterization of the portal-hypertensive syndrome in cirrhotic rats

This is a detailed protocol describing invasive hemodynamic measurements in cirrhotic rats for the characterization of portal hypertensive syndrome. Portal hypertension (PHT) due to cirrhosis is responsible for the most severe complications in patients with liver disease. The full picture of the portal hypertensive syndrome is characterized by increased portal pressure (PP) due to the increased intrahepatic vascular resistance (IHVR), hyperdynamic circulation, and increased splanchnic blood flow. Progressive splanchnic arterial vasodilation and increased cardiac output with elevated heart rate (HR) but low arterial pressure characterizes the portal hypertensive syndrome.
Novel therapies are currently being developed that aim to decrease PP by either targeting IHVR or increased splanchnic blood flow &#8212; but side effects on systemic hemodynamics may occur. Thus, a detailed characterization of portal venous, splanchnic, and systemic hemodynamic parameters, including measurement of PP, portal venous blood flow (PVBF), mesenteric arterial blood flow, mean arterial pressure (MAP), and HR is needed for preclinical evaluation of the efficacy of novel treatments for PHT. Our video article provides the reader with a structured protocol for performing invasive hemodynamic measurements in cirrhotic rats. In particular, we describe the catheterization of the femoral artery and the portal vein via an ileocolic vein and the measurement of portal venous and splanchnic blood flow via perivascular Doppler-ultrasound flow probes. Representative results of different rat models of PHT are shown.

Depending on the animal model and the severity of liver disease, the degree of PHT and severity of the portal hypertensive syndrome is different (Figure 7).
The BDL model causes biliary cirrhosis due to cholestasis. Accordingly, PP increases over time and a hyperdynamic circulation develops, as seen by an increase of HR and decrease of MAP. In cirrhotic animals, SMABF, PVBF and IHVR also increase co...

Watch this Scientific Journal Video about Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats at JoVE.com

Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats

Here we describe a detailed protocol for invasive measurements of hemodynamic parameters including portal pressure, splanchnic blood flow, and systemic hemodynamics in order to characterize the portal hypertensive syndrome in rats.

This is a detailed protocol describing invasive hemodynamic measurements in cirrhotic rats for the characterization of portal hypertensive syndrome. ...

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