Real-Time Monitoring and Modulation of Blood Pressure in a Rabbit Model of Ischemic Stroke

Summary

Continuous arterial blood pressure recording allows the investigation of impacts of various hemodynamic parameters. This report demonstrates the application of continuous arterial blood pressure monitoring in a large animal model of ischemic stroke for determination of stroke pathophysiology, impact of different hemodynamic factors, and the assessment of novel treatment approaches.

Abstract

Control of blood pressure, in terms of both absolute values and its variability, affects outcomes in ischemic stroke patients. However, it remains challenging to identify the mechanisms that lead to poor outcomes or evaluate measures by which these effects can be mitigated because of the prohibitive limitations inherent to human data. In such cases, animal models can be utilized to conduct rigorous and reproducible evaluations of diseases. Here we report refinement of a previously described model of ischemic stroke in rabbits that is augmented with continuous blood pressure recording to assess the impacts of modulation on blood pressure. Under general anesthesia, femoral arteries are exposed through surgical cutdowns to place arterial sheaths bilaterally. Under fluoroscopic visualization and roadmap guidance, a microcatheter is advanced into an artery of the posterior circulation of the brain. An angiogram is performed by injecting the contralateral vertebral artery to confirm occlusion of the target artery. With the occlusive catheter remaining in position for a fixed duration, blood pressure is continuously recorded to allow for tight titration of blood pressure manipulations, whether through mechanical or pharmacological means. At the completion of the occlusion interval, the microcatheter is removed, and the animal is maintained under general anesthesia for a prescribed length of reperfusion. For acute studies, the animal is then euthanized and decapitated. The brain is harvested and processed to measure the infarct volume under light microscopy and further assessed with various histopathological stains or spatial transcriptomic analysis. This protocol provides a reproducible model that can be utilized for more thorough preclinical studies on the effects of blood pressure parameters during ischemic stroke. It also facilitates effective preclinical evaluation of novel neuroprotective interventions that might improve care for ischemic stroke patients.

Introduction

Ischemic stroke (IS) is a leading cause of death and long-term disability worldwide, and its prevalence is projected to increase as society ages¹. While substantial advances have been made in acute interventions and secondary prevention strategies, adjunctive neuroprotective treatments have not followed apace^2,3,4,5,6,7. Further research is needed into stroke pathobiology because mechanisms by which therapies may or may not prove effective are poorl....

Protocol

This protocol is approved by the Institutional Animal Care and Use Committee (University of Utah IACUC Protocol Number 21-09021). Mature New Zealand White rabbits are obtained from commercial vendors.

1. Animal acquisition

1. Acclimate the animals for the required duration after arrival according to institutional protocol, housing animals socially in a vivarium with standard chow diets. The acclimation period at our institution is 2 weeks.

2. Anesthesia and monitoring

1. Induce general endotracheal anesthesia with intramuscular injection of buprenorphine ....

Results

In the initial experiments with this model, our group successfully achieved the desired outcome of a posterior cerebral or superior cerebellar artery occlusion in 12 out of 14 animals (85.7%). For the experiment, seven males and seven females were studied. The mean animal weight was 3.6 kg (± 0.46 kg). In the two animals in which success was not achieved, profound catheter-induced vasospasm precluded safe access to the intracranial circulation. In one rabbit, intracranial access could not be obtained due to occlusive vas.......

Discussion

Substantial progress has been made in the management of IS, particularly considering advances in acute intervention and secondary prevention strategies. However, more work can be done to improve care for IS patients. Limited progress in other aspects of IS treatment, particularly in the realm of neuroprotection, likely results from the limitations in pathophysiological understanding of mechanistic processes at the tissue and molecular level. Impactful data from humans is unrealistic and likely impossible to acquire. In s.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
3-0 Silk Suture	Ethicon	A184H
Buprenorphine	Sigma-Aldrich	B9275
Catheter	Terumo	CG415	4F glide catheter
Endovascular Pressure Sensor	Millar	SPR-524
Euthasol	Virbac	PVS111
Guidewire	Terumo	GR1804
Iohexol	ThermoFisher	466651000	Iodinated Contrast
Ketamine	Biorbyt	orb61131
LabChart Software	ADInstruments
Lidocaine	Spectrum	LI102
Microcatheter	Medtronic	EV3 105-5056	Marathon Microcatheter
Microwire	Medtronic	EV3 103-0608	Mirage Microwire
PowerLab	ADInstruments
Rabbit Brain 2mm Coronal Cutting Matrix	Ted Pella	15026
Saline	FisherScientific	23-535435
Sheath	Merit Medical	PSI-5F-11
Xylazine	ThermoFisher	J61430.14