An Innovative Assessment of Respiratory Function in Safety Pharmacology

Challenge

Reduce Animal Use While Assessing Continuous Respiratory Function in Safety Pharmacology

In the ever-evolving drug development landscape, speed, costs, and responsible animal use are often critical components of every drug program. With respiratory data needed for safety pharmacology studies, our experts worked to find out how can respiratory function be evaluated while simultaneously saving time, preserving budget, and actively fostering the 3Rs.

Hypothesis

Jacketed External Telemetry (JET) Systems can Assess Respiratory Function Simultaneously with ECG Leads

Our respiratory safety pharmacology experts believed that jacketed external telemetry (JET) systems, typically used in the collection of electrocardiographic (ECG) signals, could be used in place of traditional systems to assess respiratory function through the collection of impedance signals.

Impedance is the resistivity of a current flow from one source to another. Electrical currents prefer to flow through dense or fluid-filled mediums but encounter resistivity to flow through gaseous mediums within respiratory tissue. When respiratory tissue inflates with air, it causes a resistance of that current to flow from one side to another.

Our experts believed that with the right lead configuration (specifically lead I, spanning from right to left through the atria) they could determine what was responsible for the impedance signal, assessing respiratory function without compromising ECG signals and allowing them to be collected simultaneously.

Solution

Jacketed External Telemetry (JET) Systems Can Assess Respiratory with ECG Within the V10 Configuration

To determine if JET systems can simultaneously assess respiratory function and collect ECG leads, our respiratory safety pharmacology experts conducted their study in two phases. In phase one, they tested comparing the impedance signal against a standard known as respiratory inductance plethysmography (RIP) bands. The study design involved collecting the respiratory and ECG data in the presence of Doxapram, a powerful stimulant. In phase two of the study, they aimed to optimize the respiratory signal while minimizing impact on the ECG signal quality.

Phase One: Lead I Configuration

Phase one of the study showed that compared to the RIP signal, the lead I configuration had a strong correlation for respiratory signal quality itself from the ECG leads. Results showed there was a pharmacodynamic response following Doxapram administration, with an increase in minute volume. Impedance also showed good alignment with the RIP bands, but there was slightly more variability.

There was a great correlation for signal quality between the impedance and RIP signals.

Following Doxapram administration there was an increase in the subject's minute volume for the RIP and impedance signals.
The dotted lines shows the variability within the signal.

Phase Two: Lead I, II, and Low Lead I Configurations

Following initial excitement from the results of phase one, experts believed the signal could be further optimized to minimize cardiac artifact with the use of alternate lead configurations. Phase two was an anesthetized phase, allowing for the manipulation of the subjects in different postures to determine how it influences both the respiratory and ECG signal. Lead placement was moved to optimize the respiratory signal without compromising ECG signal. Data was collected in the right lateral, left lateral, dorsal, and ventral recumbency.

Consult an Expert

Respiratory safety pharmacology experts began the phase assessing the lead I configuration since it was used for the original phase of the study. Since plenty of data was already collected in phase one, the subject was only looked at in the right lateral recumbency. Lead I produced a good ECG as expected and there was a strong impedance correlation, however, this posture produced significant cardiac artifact within the respiratory signal. Therefore alternate configurations were explored.

Top = impedance signal, Middle = pneumotach, Bottom = ECG signal. Since each heartbeat in the ECG signal lines up with the impedance signal, this data confirms that the cardiovascular artifacts are responsible for the variability in phase one.

Following the assessment of lead I our experts shifted their focus to lead II, the most commonly employed configuration for quantitative analysis. From the subject's initial posture this configuration looked very promising as there was significantly reduced cardiac artifact in the impedance signal compared to lead I. After reviewing initial data, experts reviewed the respiratory data of the subject while in different postures. Data showed a variance in the tidal volume of two of the postures in comparison to the other two. Since the subject was under constant ventilation for volume and rate during the study, it was incorrect to assume that the change in posture altered the tidal volume. It was determined that the subject's posture changed its tissue distribution, resulting in a compromised impedance signal.

Each set of data above represents a different posture. The impedance data for the middle two postures shows a different tidal volume than the first and last.

After lead II's compromised signal, experts moved to a different configuration. They decided to change to a low lead I position, believing it should amplify the ECG signal since it passes through a dense area of respiratory tissue, they believed would provide a very solid deflection of the impedance. Placed at the lowest point of the intercostals. With the ECG (vector) being below the ventricles, the lead position provided a strong respiratory impedance signal with almost no cardiovascular artifact as expected. However, it compromised the ECG signal, making it unsuitable for future use.

Phase II Low lead I showed a great impedance signal with no cardiac artifact, but it came at the consequence of the ECG signal.

V10 Configuration

After three unsuccessful lead positionings, our experts were able to find out the best positioning possible for assessing respiratory activity and ECG signals. Called the V10 configuration, this placement featured solid landmarks and minimized interference from other body signals. It involves placing the negative electrode between the scapula and the positive electrode on the lowest point of the sternum (xiphoid process). The position resulted in a clean ECG with almost no cardiac artifact in the impedance signal. With initial positive results, our experts decided to examine the configuration in different postures.

The right lateral recumbency, dorsal, and left lateral were all found to have great deflection of the impedance signal. After calibrating these signals, it was found that regardless of the position, its measured tidal volume remained consistent throughout. To counter criticism that anesthetized and intubated subjects would be expected to produce quality signals, the subjects were allowed to recover from the anesthesia. As they recovered and started breathing on their own, a shift was seen in the tidal volumes along with a very strong breathing rate.

The V10 posture showed a very clean ECG with minimal cardiac artifact in the impedance signal. The tidal volume for the impedance signal also remained at a similar level amongst the different postures.

Results

External Impedance was Found to be Acquired in Freely Moving Subjects Concurrently with ECG Collection

The study showed that external impedance can be acquired in freely moving subjects concurrently with ECG collection. With collecting both sets of data in a single study, this replaces a program's need for standalone respiratory studies. As a result, this reduces animal use and test article needs. It also shortens program timelines, providing companies with additional assurance in meeting their milestones. Lastly, it reduces overall study costs, helping companies balance their tight budgets.

Meet with our respiratory safety pharmacology experts to learn how this approach to evaluating respiratory function can be applied to your program.

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