Title of the project
Pre-Clinical Assessment of TEE Probe
NTS Identifier
NTS-NO-192110 v.1, 10-05-2024
NTS National Identifier
Field will not be published.
EU Submission
Field will not be published.
Yes
Project duration expressed in months.
49
Purpose(s) of the project
Translational and applied research: Human Cardiovascular Disorders
Describe the objectives of the project (for example, addressing certain scientific unknowns, or scientific or clinical needs).
An important application in echocardiographic imaging is transesophageal echocardiography (TEE). The current study is being conducted to investigate a new TEE probe which will be intended for use in adult and pediatric patients over the minimal patient size. The new probe has initially been tested with ultrasound imaging of phantoms. Phantoms are specially designed objects for the purpose of evaluate, analyze, and tune the performance of image devices. However, TEE ultrasound imaging depends on the ability for the physician to control the device and physiological conditions in addition to simulated acoustical imaging with phantoms. In order to optimize live or moving images, simulation data and phantom images are not adequate. No known phantom objects can reproduce all these at the same time. Hence imaging and optimization of device in phantoms or organ experiments are sub-optimal to patient imaging. Therefore, integration and resulting image quality optimization with ultrasound imaging systems are best accomplished through studies in whole organisms comparable with humans (in vivo).
Additionally, because TEE requires invasive procedures, it is unethical to conduct such early optimization studies in humans due to potential risks associated with extension or complication of invasive ultrasound techniques.
Porcine (pig) and canine (dog) models have similar anatomical structures to humans, making porcine and canine pre-clinical models optimal for optimization of TEE prior to clinical testing. Porcine and canine animal subjects will undergo ultrasound imaging of the heart with the 8VT-D probe and the Vivid E95/next- generation Vivid E-series scanners. A comparator probe may also be used for reference. Images and user feedback will be collected by GE HealthCare.
What are the potential benefits likely to derive from this project? Explain how science could be advanced, or humans, animals or environment may ultimately benefit from the project. Where applicable, differentiate between short-term benefits (within the duration of the project) and long-term benefits (which may accrue after the project is finished).
The objective of this study is to collect user feedback and images from the new probe as well as reference probes used in TEE examinations. User feedback will include elements such as usability, image quality, design, features, validation input, and open-ended feedback.
The goals of this study is to:
- Investigate a new TEE probe to potentially validate and/or improve usability, image quality, design and features through direct experience with or without the use of a comparator probe.
- Define the optimized parameters and settings which will be implemented on future platform of relevant ultrasound scanners.
- Collect in-vivo data to optimize ultrasound imaging for cardiac imaging and other organs may also be studied.
- Demonstrate feasibility and optimize transesophageal echo imaging on the ultrasound scanners Vivid E95/
next-generation Vivid E-series scanners.
All the above mentioned goals aim to improve and/or facilitate TEE ultrasound examination in both adult and children patients.
In what procedures will the animals typically be used (for example, injections, surgical procedures)? Indicate the number and duration of these procedures.
- Performance of sedation, analgesia and anaesthesia according to previously described in the previous chapter "Sedation, analgesia and anaesthesia" for each animal species.
Shortly this includes:
1. premedication through percutaneus injection,
2. vascular access (veinous) through positioning of PVC,
3. induction anaesthesia through PVC,
4. securing of the airways through endotracheal tube,
5. maintains of balanced general anaesthesia through anesthesia machine and intravenous infusions
6. vascular access (CVC and arterial line) performed surgically for medication administration, hemodynamic monitoring as well as intravascular access for devices
7. urinary output catheterisation.
- Each study participant and expert trained in echocardiography, one at the time, will perform examination using the new and reference transesophageal echo (TEE) probes.
The following evaluation will be repeated for each expert:
1. Each TEE probe is used one at the time. The TEE probe will be inserted through the mouth and placed in the esophagus using Xylocaine 2% gel applied on the probe head and reapplied hourly for each probe used. Ultrasound imaging will be performed on the heart, including different cardiac structures e.g., valves, leaflets and atria/ventricles. Electronic device data (images) will be stored during the procedure.
2. Through arterial and/or venous intravascular access, devices (guidewire, PiCCO catheter and/or ICE catheter) will be introduced in fluoroscopy control (with ionizing radiation from X-ray video fluoroscopy.) in the proximity of the heart to produce artefacts similar to ones seen during interventional surgical procedures in the heart.
3. Ultrasound images mare acquired and will be performed on the heart, including different cardiac structures e.g., valves, leaflets and atria/ventricles as well as surrounding structures.
4. The image quality analysis includes spatial resolution, penetration and sensitivity. The penetration will be analyzed with scanner's built-in measurement tool. Sensitivity will be evaluated by visualization.
5. Switching and reinsertion and of TEE probes maybe required.
6. Expert user feedback is collected, while the new cycle of evaluation begins with the next expert or the experiment is to be concluded after up to 11 hours from the start of balanced general anaesthesia.
- For the experiment a maximum of twenty (20) TEE probe insertions is allowed.
- Euthanasia induction.
What are the expected impacts/adverse effects on the animals, for example pain, weight loss, inactivity/reduced mobility, stress, abnormal behaviour, and the duration of those effects?
After establishment of balanced general anesthesia the research animals remain in in surgical state throughout the experiment until euthanization without wakening from the anesthesia. The animals have not been used for research prior to the experiments. Risk of complications such as oesophageal rupture/bleeding related to the use of TEE probes is low as these are regularly used on human patients in clinical practice.
What species and numbers of animals are expected to be used? What are the expected severities and the numbers of animals in each severity category (per species)?
Species
Total number
Estimated numbers per severity
Non recovery
Mild
Moderate
Severe
Dogs (Canis familiaris)
3
Pigs (Sus scrofa domesticus)
5
What will happen to the animals kept alive at the end of the procedure?
Species
Estimated numbers of animals to be reused, to be returned to habitat/husbandry system or to be rehomed
Reused
Returned
Rehomed
Please provide reasons for the planned fate of the animals after the procedure.
The animals will be anesthesized with balanced general anesthesia during the whole experiment, and will not experience pain or discomfort during any time.
This is an acute experiment with extensive surgical preparation of the animal. Survival is highly compromised based on postoperative complications such as infections and pain. For this reason animals are euthanised as per protocol.
1. Replacement
State which non-animal alternatives are available in this field and why they cannot be used for the purposes of the project.
An important application in echocardiographic imaging is transesophageal echo (TEE).The transducer is placed in the esophagus, close to the heart. This semi-invasive imaging application is typically optimized through simulations and phantom imaging. Furthermore, intra cardiac imaging is used during certain interventions where a catheter with a transducer head is inserted through the femoral vein and placed within the cavity of the heart.
Some preliminary optimization of image quality for TEE can be done through simulations and phantom imaging; however, prior to releasing new probes for clinical use it is crucial to optimize in a representative living model mimicking the human heart. To avoid unethical optimization and risk exposure from application of new TEE in human patients, and subsequent rejection due to sub-optimal instrument, optimization in animal models is needed. The study will simulate human imaging, especially with respect to physiological and acoustical properties. Different types of animals could be used from a physiological point of view, but ultrasound imaging is very dependent on the acoustical properties of the object. Ultrasound probes are designed to image at certain depths and within certain frequency ranges. Outside these ranges the probe does not work properly and therefore optimization would be inappropriate. These features limit the experimental subject to those animals with comparable dimensions to humans, such as pigs, dogs, sheep and goats.
2. Reduction
Explain how the numbers of animals for this project were determined. Describe steps that have been taken to reduce the number of animals to be used, and principles used to design studies. Where applicable, describe practices that will be used throughout the project to minimise the number of animals used consistent with scientific objectives. Those practices may include e.g. pilot studies, computer modelling, sharing of tissue and reuse.
As much as possible experiments will be done through simulations and phantom imaging, but some of the experimental development work must be done in animals. Imaging, clinical utility and various aspects of image quality are parameters which cannot be fully optimized in a simulatedsetup. Previous experience with similar animal preparations suggests that several animals will be needed to reach a stable setup for the intended testing and optimization of the complex equipment and experimental model. A maximum of 4 animals has been estimated (2 canine and 2-4 porcine dependent on availability of canine). The fewest number of animals will be used to accomplish the study objectives, as determined by the Sponsor. The Sponsor attests that the activities specified in this protocol do not unnecessarily duplicate a previous experiment.
3. Refinement
Give examples of the specific measures (e.g., increased monitoring, post-operative care, pain management, training of animals) to be taken, in relation to the procedures, to minimise welfare costs (harms) to the animals. Describe the mechanisms to take up emerging refinement techniques during the lifetime of the project.
The site personnel consists of appropriately qualified researchers with considerable experience managing experiments on animals, including procedures related to transportation, housing, anesthesia, pain, treatment, surgery and ultrasound. The team has had very few complications in previous studies, and work continuously to improve the quality of animal handling. Standard operating procedures of the site prioritize safety and ensure quality of animal handling. The research animals will be anesthetized with general anesthesia during the experiments. The animal will not experience pain or sensory impressions from the moment they are anesthetized.
Explain the choice of species and the related life stages.
The objective of this pilot pre-clinical assessment is to validate new ultrasound probes. In order to obtain this goal repeated experiments are needed after technical improvements or adjustments of ultrasound probes. A large Porcine and Canine models are chosen because of the size of the vascular bed and the heart mimicking the human anatomy. The animal model is selected because it is generally accepted as a model to mimic human vascular and heart anatomy and physiology. The models are chosen also because it will enable the demonstration of sufficient safety and ergonomics of transesophageal echocardiogram.
The experience from previous use of animal models for echocardiographic imaging is that the canine model provides ergonomic conditions that are more similar to human conditions. The images also appear closer to human anatomy than the porcine model. The porcine model will provide good conditions, but canine models will give an improved and closer to clinical reality experience and therefore improved evaluation.
The use of the porcine model is more readily accepted, and less costly. It would therefore be reasonable to use as few individuals as possible of both species from ethical and economic considerations.