A Theoretical Argument for Extended Interpulse Delays in Therapeutic High-Frequency Irreversible Electroporation Treatments

High-frequency irreversible electroporation (H-FIRE) is a tissue ablation modality employing bursts of electrical pulses in a positive phase–interphase delay (d
₁
)–negative phase–interpulse delay (d
₂
) pattern. Despite accumulating evidence suggesting the significance of these delays, their effects on therapeutic outcomes from clinically-relevant H-FIRE waveforms have not been studied extensively.
Objective:
We sought to determine whether modifications to the delays within H-FIRE bursts could yield a more desirable clinical outcome in terms of ablation volume versus extent of tissue excitation.
Methods:
We used a modified spatially extended nonlinear node (SENN) nerve fiber model to evaluate excitation thresholds for H-FIRE bursts with varying delays. We then calculated non-thermal tissue ablation, thermal damage, and excitation in a clinically relevant numerical model.
Results:
Excitation thresholds were maximized by shortening d
₁
, and extension of d
₂
up to 1,000 μs increased excitation thresholds by at least 60% versus symmetric bursts. In the ablation model, long interpulse delays lowered the effective frequency of burst waveforms, modulating field redistribution and reducing heat production. Finally, we demonstrate mathematically that variable delays allow for increased voltages and larger ablations with similar extents of excitation as symmetric waveforms.
Conclusion:
Interphase and interpulse delays play a significant role in outcomes resulting from H-FIRE treatment.
Significance:
Waveforms with short interphase delays (d
₁
) and extended interpulse delays (d
₂
) may improve therapeutic efficacy of H-FIRE as it emerges as a clinical tissue ablation modality.