Non-invasive phrenic nerve stimulation to avoid ventilator-induced diaphragm dysfunction in critical care

Abstract

Background: Diaphragm muscle atrophy during mechanical ventilation begins within 24 h and progresses rapidly with significant clinical consequences. Electrical stimulation of the phrenic nerves using invasive electrodes has shown promise in maintaining diaphragm condition by inducing intermittent diaphragm muscle contraction. However, the widespread application of these methods may be limited by their risks as well as the technical and environmental requirements of placement and care. Non-invasive stimulation would offer a valuable alternative method to maintain diaphragm health while overcoming these limitations.

Methods: We applied non-invasive electrical stimulation to the phrenic nerve in the neck in healthy volunteers. Respiratory pressure and flow, diaphragm electromyography and mechanomyography, and ultrasound visualization were used to assess the diaphragmatic response to stimulation. The electrode positions and stimulation parameters were systematically varied in order to investigate the influence of these parameters on the ability to induce diaphragm contraction with non-invasive stimulation.

Results: We demonstrate that non-invasive capture of the phrenic nerve is feasible using surface electrodes without the application of pressure, and characterize the stimulation parameters required to achieve therapeutic diaphragm contractions in healthy volunteers. We show that an optimal electrode position for phrenic nerve capture can be identified and that this position does not vary as head orientation is changed. The stimulation parameters required to produce a diaphragm response at this site are characterized and we show that burst stimulation above the activation threshold reliably produces diaphragm contractions sufficient to drive an inspired volume of over 600 ml, indicating the ability to produce significant diaphragmatic work using non-invasive stimulation.

Conclusion: This opens the possibility of non-invasive systems, requiring minimal specialist skills to set up, for maintaining diaphragm function in the intensive care setting.

Keywords: critical care; electrical stimulation; phrenic nerve; ventilator-induced diaphragm dysfunction.

Conflict of interest statement

The authors declare no conflict of interest.

© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.

Figures

FIGURE 1

Electrode design. (A) Schematic and photograph of concentric electrode for initial testing. A 20 mm diameter cathode is surrounded by a ring‐shaped anode with an inner diameter of 30 mm and an outer diameter of 40 mm. (B) Schematic and photograph of linear array used for parameter optimization. Six 1 cm × 1 cm cathodes, separated by 2 mm intervals, are surrounded by an anode

FIGURE 2

System set up. (A) Schematic stimulation and monitoring equipment. Stimulation electrodes were placed on the neck bilaterally. Respiratory pressure and flow were measured in line with the mechanical ventilator. EMG recordings were taken from bipolar electrodes in the sixth and eighth intercostal spaces bilaterally. MMG was recorded using sensors placed just medial to the EMG electrodes. Stimulation and recording were controlled from a common interface. (B) Flowchart of parameter optimization protocol. Electrode position, amplitude, pulse width, and stimulation frequency were set and delivered via electrodes overlying the phrenic nerve. The response to stimulation was measured and the required parameters were updated according to the response elicited. (C) Flowchart of overall parameter optimization. All electrode positions were assessed. The best position was used for testing the amplitude required to elicit a response at a range of pulse widths. The strength‐duration curve was used to determine pulse train parameters. Pulse trains with varying frequencies were then applied and the work done by the diaphragm measured

FIGURE 3

Response to phrenic nerve stimulation. (A) Bilateral EMG, respiratory flow and pressure, and bilateral MMG were recorded during stimulation. An example 15 s window during delivery of 20 mA, 200 μs pulses at 13 Hz with a pulse train duration of 1.1 s and an inter‐pulse interval of 2.2 s, synchronized to the ventilator, is shown. There is a clear response to phrenic nerve stimulation in all modalities measured. (B) Example diaphragmatic response to phrenic nerve stimulation assessed by ultrasound. Stimulation with 14 mA, 200 μs pulses at 15 Hz with a pulse duration of 1.1 s produced a diaphragm thickening fraction of 45.1%, demonstrating a robust diaphragm contraction in response to non‐invasive phrenic nerve stimulation

FIGURE 4

Effect of electrode position. (A) Example of differential pressure generated by single stimulation pulses at each electrode over a range of amplitudes. The response is sensitive to electrode positioning, with a rapid drop‐off in response between the optimal electrode and its neighbor. In this example, electrode 4 shows the strongest response with little response outside of this electrode. (B) Heatmap of optimal electrode position across participants; color indicates the number of participants for which that electrode was optimal. The number of participants is also shown within the heatmap. Electrode 1 is most medial with electrode 6 lateral. All participants responded to one of electrodes 4–6; the optimal electrode did not change with head position

FIGURE 5

Strength‐duration curve showing the minimum stimulation current required to produce a diaphragm response for a range of pulse widths. The individual participants' strength‐duration curves are shown as gray dashed lines. The mean strength‐duration curve for all participants (n = 14) is shown as a black dashed line. The standard deviation is indicated by the shaded region. The amplitude required to induce diaphragm contraction decreases as pulse width increases. A hyperbola fit to the strength‐duration curves for all participants is shown as a solid line (R2 = 0.94)

FIGURE 6

Effect of stimulation frequency on diaphragmatic work. (A) Example of diaphragm activity (W) following pulse train at a range of frequencies up to 100 Hz. (B) Diaphragmatic work done (J) following stimulation for a range of frequencies. Mean work done is shown. The standard deviation is shown as the shaded region. Increasing stimulation frequency induces greater diaphragmatic work