A Porcine Model of Acute Autologous Pulmonary Embolism

Summary

This study presents a porcine model of pulmonary embolism (PE) using large autologous emboli that replicate acute intermediate-risk PE. The model is well-suited for the evaluation of both pathophysiology and treatment responses.

Abstract

Acute pulmonary embolism (PE) is a potentially life-threatening condition that causes abrupt obstruction of the pulmonary arteries, leading to acute right heart failure. Novel diagnostic methods and catheter-directed therapies are being developed rapidly, and there is an obvious need for a realistic PE animal model that can be used for pathophysiological evaluation and preclinical testing.

This protocol introduces a porcine model employing large autologous pulmonary emboli. Instrumentations are performed with minimally invasive techniques, creating a close-chest model that enables the investigation of various treatment options with high reproducibility. Three hours after drawing blood to create autologous emboli ex vivo, the induction of PE caused an immediate increase in the mean pulmonary arterial pressure (17 ± 3 mmHg to 33 ± 6 mmHg, p < 0.0001) and heart rate (50 ± 9 beats·min^-1 to 63 ± 6 beats·min^-1, p < 0.0003) accompanied by a decreased cardiac output (5.0 ± 0.8 L/min to 4.5 ± 0.9 L/min, p < 0.037) compared to baseline. The CT pulmonary angiography revealed multiple emboli, and the pulmonary obstruction percentage was increased compared to baseline (0% [0-0] to 57.1% [38.8-63.3], p < 0.0001). In the acute phase, the phenotype is comparable to intermediate-risk PE.

The model represents a realistic and well-characterized phenotype of intermediate-risk PE and creates an opportunity to test novel diagnostic methods, interventional and pharmaceutical treatments, and hands-on training for healthcare workers in interventional procedures.

Introduction

Acute pulmonary embolism (PE) is the third most common cause of cardiovascular death and is a manifestation of venous thromboembolism (VTE)¹. The incidence of VTE ranges between 75 to 269 per 100,000 population per year and is increasing with age². Initial survivors face a 30-day risk of death ranging from 0.5 % for low-risk patients and up to 22 % for high-risk patients³. The cause of death is right ventricular (RV) failure, which predominantly happens within hours^4,5. Even if patients survive, there is still a risk of significant morbidi....

Protocol

This study was conducted with approval from the Danish Animal Inspectorate (license no. 2021-15-0201-00944) and in compliance with the Danish and university guidelines on laboratory animal welfare and ethics.

NOTE: This study followed the ARRIVE guidelines 2.0¹⁷. The principles of the 3Rs (Replacement, Reduction, and Refinement) were respected by evaluating each animal repeatedly to serve as its own control, thereby reducing the number of animals needed and to maximize the information gathered. The pigs used in this animal model were female Danish slaughter pigs of

Results

In a pooled analysis of pigs included in previous studies, we present the results characterizing the acute PE model described in this protocol^15,16. Two pigs died from acute right heart failure following PE. In total, we included 24 pigs.

Hemodynamics
The response after each embolus is evident in Figure 5. The induction of PE (5 ± 1) caused an immediate increase in mPAP (17.......

Discussion

This paper describes a porcine model of acute, intermediate-risk PE using autologous emboli that is minimally invasive and reproducible.

There are some critical steps in this protocol. First, the dilation of the access in the right external jugular vein is crucial for the model as it serves as the access point for the emboli. When advancing the large sheath, it is essential to adhere to the guidance of the stiff wire under continuous fluoroscopy to prevent rupture or dissection of major vessel.......

Materials

Name	Company	Catalog Number	Comments
12L-RS	GE Healthcare Japan	5141337	Ultrasound probe
50 mL BD Luer-Lock	BD Plastipak	300865
Adhesive Aperature Drape (OneMed)	evercare	1515-01	75 cm x 90 cm (hole: 6 cm x 8 cm)
Alaris GP Guardrails plus	CareFusion	9002TIG01-G	Infusion pump
Alaris Infusion set	BD Plastipak	60593
Alcohol swap	MEDIQ Danmark	3340012	82% ethanol, 0.5% chlorhexidin, skin disinfection
Amplatz Support Wire Guide Extra-Stiff	Cook Medical	THSF-25-260-AES	diameter: 0.025 inches, length: 260 cm
Aortic Perfusion Cannula	Edwards Lifesciences	AA024TFTA	Size: 24F. Length: 30 cm.
BD Connecta	BD	394601	Luer-Lock
BD Emerald	BD	307736	10 mL syringe
BD Platipak	BD	300613	20 mL syringe
BD Venflon Pro	Becton Dickinson Infusion Therapy	393204	20 G
BD Venflon Pro	Becton Dickinson Infusion Therapy	393208	17 G
Butomidor Vet	Richter Pharma AG	531943	10 mg/mL
Chlorhexidine 0.5%	Meda AB	N/A
Cios Connect S/N 20015	Siemens Healthineers	N/A	C-arm
CP Oxygenation System Adult With Fusion and Cardioplegia 1/B	Medtronic	M450311W	Custom cardiopulmonary oxygenation system including a cardioplegia line.
D-LCC12A-01	GE Healthcare Finland	N/A	Pressure measurement monitor
Durapore	3M	N/A	Adhesive tape
E-PRESTIN-00	GE Healthcare Finland	6152932	Respirator tubes
Euthanimal	Alfasan	136278	Pentobarbitalnatrium 400 mg/mL (0.5 mL/kg for euthanasia)
Favorita II	Aesculap	GT104
Fentanyl	B. Braun	71036	50 µg/mL
Glucose isotonic	SAD	419358	55 mg/mL Isotonic glucose (500 mL bag)
Gore DrySeal Flex Introducer Sheath	GORE	DSF2633	Size: 26 French. Working length: 33 cm.
Ketaminol Vet	MSD/Intervet International B.V.	511519	100 mg/mL
Lawton 85-0010 ZK1	Lawton	N/A	Laryngoscope
Lectospiral	VYGON	1159.90	400 cm (Luer-LOCK)
MBH qufora	MBH-International A/S	13853401	Urine bag
Natriumchlorid	Fresenius Kabi	7340022100528	9 mg/mL Isotonic saline
Noradrenalin	Macure Pharma	425318	1 mg/mL
PICO50 Aterial Blood Sampler	Radiometer	956-552	2 mL
Portex Tracheal Tube	Smiths Medical	100/150/075	Cuffed Clear Oral/Nasal Murphy Eye
Pressure Extension set	CODAN	7,14,020	Tube for anesthetics, 150 cm long, inner diameter 0.9 mm
Propolipid	Fresenius Kabi	21636	Propofol, 10 mg/mL
Radiofocus Introducer II	Radiofocus/Terumo	RS+B80N10MQ	7 + 8F sheaths
Rompun Vet	Beyer	86450917	Xylazin, 20 mg/mL
Rüsch Brilliant AquaFlate Glycerine	Teleflex	178000	Bladder catheter, size 14
S/5 Avance	Datex-Ohmeda	N/A	Mechanical ventilator
Safersonic Conti Plus & Safergel	SECMA medical innovation	SAF.612.18120.WG.SEC	18 cm x 120 cm (Safersonic Sterile Transducer Cover with Adhesive Area and Safergel)
Standard Dilator	Cook Medical	G01212	Size: 16 French. Length: 20 cm.
Swan-Ganz CCOmbo	Edwards Lifesciences	744F75	110 cm
TruWave Pressure Monitoring Set	Edwards Lifesciences	T434303A	210 cm
Vigilance VGS Patient Monitor	Edwards Lifesciences	N/A
Vivid iq	GE Medical Systems China	Vivid iq
Zoletil 50 Vet (tiletamin 125 mg and zolazepam 125 mg)	Virbac	83046805	Zoletil Mix for pigs: 1 vial of Zoletil 50 Vet (dry matter); add 6.25 mL Xylozin (20 mg/mL), 1.25 mL ketamin (100 mg/mL) and 2.5 mL Butorphanol (10 mg/mL). Dose for pre-anesthesia: 0.1 mL/kg as intramuscular injection