Assessing Pulmonary Function in ALS using Electrical Impedance Tomography

Abstract

Objective:

We sought to determine whether thoracic electrical impedance tomography (EIT) could characterize pulmonary function in ALS patients, including those with facial weakness. Thoracic EIT is a non-invasive, technology in which a multi-electrode belt is placed across the chest, producing real-time impedance imaging of the chest during breathing.

Methods:

We enrolled 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) without underlying lung disease. All participants had EIT measurements performed simultaneously with standard pulmonary function tests (PFTs), including slow and forced vital capacity (SVC and FVC) in upright and supine positions and maximal inspiratory and expiratory pressures (MIPs and MEPs, respectively). Intraclass correlation coefficients (ICCs) were calculated to assess the immediate reproducibility of EIT measurements and Pearson correlations were used to explore the relationships between EIT and PFT values.

Results:

Data from 30 ALS patients and 27 HCs were analyzed. Immediate upright SVC reproducibility was very high (ICC 0.98). Correlations were generally strongest between EIT and spirometry measures, with R values ranging from 0.64–0.82 (p<0.001) in the ALS cohort. There were less robust correlations between EIT and both MIP and MEP measurements in the ALS patients, with R values ranging from 0.33–0.44. There was no significant difference for patients with and without facial weakness. There were no reported adverse events.

Conclusions:

EIT-based pulmonary measures hold the promise of providing an alternative approach for lung function assessment in ALS patients. Based on these early results, further development and study of this technology is warranted.

INTRODUCTION

Pulmonary function tests (PFTs) remain the major means of assessing respiratory function in amyotrophic lateral sclerosis (ALS) (1). These tests provide important markers of clinical status, assist with initiation of positive pressure pulmonary support, inform timing of gastrostomy tube insertion for nutrition supplementation, and guide end-of-life care (2–5). In addition, PFTs are included as standard measures in clinical therapeutic trials. Slow vital capacity (SVC) is now increasingly favored over forced vital capacity (FVC) since it is more easily performed and thought to be less affected by facial weakness (6).

Nevertheless, both FVC and SVC have limitations. First, both are dependent on the ability to create a good lip seal around the mouthpiece (7). Moreover, PFTs can be fatiguing and require dedicated trained staff to effectively encourage the patients to perform well (8,9). A technique that accurately measures pulmonary function without the need for a standard mouth spirometer could find wide application in ALS patients. Accordingly, thoracic electrical impedance tomography (EIT), an established imaging technology for which commercial, FDA-cleared systems are already available (10), could serve as an alternative approach for characterizing pulmonary function in ALS patients. To date, EIT has been mainly used for lung assessment of surgical patients undergoing anesthesia and post-anesthesia complications and for intensive care unit patients to assess lung health (11,12). EIT provides real-time imaging, with a low-resolution image of the lungs filling with air (increasing electrical resistance) and emptying of air (decreasing resistance) with each breath. The technique is performed by placing a series of electrodes across the entire chest held by a single belt. A low-amplitude, high-frequency electrical current is applied across different pairs of electrodes and the resulting voltages are measured from other pairs of electrodes in rapid succession. Dynamic images are derived from the change in electrical properties with breathing. Previous work specifically assessing EIT as a PFT substitute has been limited to only a few publications (13,14), including a small preliminary study from our group in ALS (15).

We sought to extend our initial study (15) to explore the use of EIT as a surrogate marker of pulmonary function in ALS patients. Here, we assessed EIT in a larger group of ALS patients and in healthy, age- and sex-matched controls. This report details the relationship between EIT values and a variety of PFT parameters in the upright and supine positions.

MATERIALS AND METHODS

Participants.

Patients were recruited through the ALS Clinics at Beth Israel Deaconess Medical Center (BIDMC), Boston, MA and Dartmouth-Hitchcock Medical Center (DHMC), Lebanon, NH. Procedures were approved by the central Institutional Review Board of Dartmouth-Hitchcock Medical Center, and all participants provided written informed consent. Inclusion criteria: 1. Age ≥ 18 years; 2. Capable of giving informed consent 3. A clinical diagnosis of ALS; 4. Ability to perform standard PFTs; Exclusion Criteria: 1. Presence of implanted thoracic electrical device or wires; 2. Underlying pulmonary disease; 3. Skin lesions at site of belt placement 4. Pregnancy Healthy Participants. Healthy controls were recruited through advertisement or through primary care offices and through word of mouth matched to age and sex of the recruited ALS patients, aiming to be within ±5 years of each specific ALS patient. Inclusion criteria: 1. Age ≥ 18 years, 2. Capable of giving informed consent; Exclusion criteria: Same as above.

Devices and Data Recorded. EIT technique.

EIT was performed using the 32-channel SenTec EIT Pioneer System (SenTec AG, Landquart, Switzerland) with an injection current of 3mA, signal frequency of 195kHz, 4-skip injection pattern, and 48Hz imaging rate. A custom elastic electrode belt was instrumented with 32 adhesive electrodes (either OTC Patient’s Choice^® Silver 0.8′′ Round Tan Tricot electrodes or Red Dot ECG electrodes, depending on supplier availability) affixed circumferentially around the thorax at approximately the T5 level, just above or below the nipple line (and under pendulous breasts of women). A small amount of conductive gel (Parker Laboratories, Tensive Conductive Adhesive Gel at BIDMC and Spectra 360 Electrode Gel at DHMC) was applied to each electrode to ensure good contact. Pulmonary Function Testing. PFTs were performed using the nSpire Classic Pulmonary Test Laboratory system (nSpire Health, Longmont, CO) at BIDMC and Pneumotrac 6800 system (Vitalograph, Buckingham, UK) at DHMC. Both SVC and FVC were measured using standard procedures (6). Maximal inspiratory and expiratory pressures (MIP and MEP) were recorded using a MicroRPM respiratory pressure meter (Micro Direct, Inc, Lewiston, ME). ALSFRS-R data collection. The standard ALS functional rating scale-revised (ALSFRS-R)(16) was completed with the assistance of formally trained staff.

Measurement Protocol.

The circumference of the patient’s chest was measured to determine the correct electrode belt size (small, medium, or large). Once the belt was positioned, the seated participants were asked to breathe at a calm, comfortable rate (tidal breathing) for 30 seconds, without the spirometer tube in the mouth during which EIT data only were recorded. Next, the spirometer tube was placed in the mouth, and participants were asked to complete three upright FVC measurements followed by three SVC measurements (into the spirometry tube) as the EIT and PFT data were simultaneously recorded. To test immediate repeatability the electrode belt was removed, electrodes re-gelled, and then the belt placed back in position before a 4^th upright SVC test was completed. Following this, participants were placed in the supine position and FVC and SVC measurements repeated along with EIT while the spirometer tube was in place. The patient was then asked to sit upright, and MIP and MEP were measured without EIT being recorded simultaneously. The exam concluded with a final 30 second tidal breathing (without breathing tube) recording in the upright position. The maximum value for any given repetition (FVC and SVC in both positions and MIP/MEP) were used in all subsequent analyses.

EIT-Data Processing.

For each subject and for each PFT, several timepoints were defined for data analysis: (1) the period of normal, artifact-free, tidal breathing during baseline recordings (final-initial time of tidal breathing recording) t_tbf - t_tbi, (2) the time at maximal inspiration, $t_{MX}$, and (3) the time at maximal expiration, $t_{MN}$ (see Fig. 1). Each complete EIT chest image, or frame, was recorded at 48Hz and consisted of 928 individual impedance values, Z_IIVV, corresponding to a set of “IIVV patterns” using a standard 4-skip injection paradigm to capture a full set of measurements across the chest (17). The term IIVV refers to the two electrodes used for current injection (II) and the two electrodes used for differential voltage measurement (VV). For each frame of data, the contact impedance of every electrode was checked. If the contact impedance was greater than 700 Ω or if any IIVV patterns had a standard deviation (across time) greater than 0.5 Ω, the corresponding electrode was considered bad or poorly contacting, and data disregarded; if 10 or more electrodes were considered bad (i.e., >30% of the 32 total electrodes), the entire data set was excluded from analysis. For each patient a common set of IIVV patterns was used for that measurement session to ensure there were no inconsistencies in the data. Impedance metrics are based on the time series of the average of all good Z_IIVV or subsets of good Z_IIVV values at each time. A noise-reducing moving average filter (window size = 5 frames) was used to smooth out each Z_IIVV time series.

Figure 1.

The derivation of the zSVC and zFVC values, which utilizes the average impedance obtained during baseline relaxed tidal breathing (blue line) and maximum and minimum impedance points recorded during the FVC and SVC tests. Corresponding EIT images are also included.

Impedance Metrics.

Since Z is the symbol used to designate impedance, we termed the impedance metrics obtained from this study as the zSVC and zFVC. These were measured by obtaining the impedance change from peak inspiration to peak expiration and dividing by the baseline average impedance obtained during resting tidal breathing while sitting upright. These values are shown in Figure 1, and the impedance metric is described by the equation:

$$\mathit{\text{zSVC}}\left(or\mathit{\text{zFVC}}\right)=100\times \frac{\mathit{\text{Zmax}}-\mathit{\text{Zmin}}}{\mathit{\text{Zbaseline}}}$$

This is the same metric used in our earlier work (15). The time-points were semi-automatically identified, wherein a user confirmed the automatically generated times or adjusted the times if needed for each PFT effort of each subject.

Data Analysis.

We assessed immediate reproducibility via intraclass correlation coefficient calculation including all subjects. For identifying the relationship between zFVC and zSVC and standard PFT parameters, we performed Pearson correlations separately in the ALS patients and healthy subjects. These calculations were completed once with all participants and then again excluding patients with clinical facial weakness. Given that no normative database is available for PFT-based impedance metrics our main focus here was to assess the relationship between raw impedance-based data and absolute PFT data. Statistical analyses were completed with R Statistical Software (v4.3.2; R Core Team 2023)) and Graphpad Prism 10.1.2 (Graphpad Software, Boston, MA)

Results:

Demographics and Data inclusion.

Sixty-four subjects, including 32 patients living with ALS (21 males, 11 females) and 32 healthy sex and age (+/−5 years) matched controls, were enrolled. One ALS subject was ultimately unable to perform the PFTs, and seven subjects were removed (1 ALS, 5 healthy subjects) because all impedance data were too noisy to confidently identify timepoints for impedance-based metrics. A single additional zSVC measurement was also removed due to its being an extreme outlier, likely related to technical issues. Of the 57 subjects included for data analysis, the average number of nonfunctioning electrodes was 6.4±4.9. The demographic data for ALS patients and matched healthy control subjects used in the subsequent analyses are provided in Table 1 (note: ALSFRS-R subscores were inadvertently not recorded in 8 of the 32 participants).

Table 1.

Participant Demographics of All Enrolled

	ALS Patients	Healthy subjects
Sex (females, males)	(11,21)	(11,21)
Age (mean, range, SD)	63.6±11.9	64.2±11.3
Height (cm)	170.2±9.2	169.1±9.0
Weight (kg)	83.5±17.1	75.9±16.3
Baseline total ALSFRS-R score	36.0±7.9	NA
ALSFRS-R Bulbar sub-score	10.5±2.3	NA
ALSFRS-R Respiratory sub-score	10.3±2.2	NA

Safety and Tolerability.

No observed adverse events occurred throughout data recordings, beyond some participants finding the repeated measurements fatiguing.

Intrasession repeatability.

Repeatability of the impedance metric was assessed during the upright SVC maneuver on a subset of the participants. Specifically, for this subset of healthy and ALS subjects (N=19), the belt was removed, gel was reapplied, and an additional SVC test was performed. Of note, only a subset of patients had this additional data acquisition due to repeatability testing not being initially incorporated into the protocol. In addition, the repeatability maneuvers were not performed if there were insufficient support staff or the PFT lab was running behind schedule. The intraclass correlation coefficient for zSVC was 0.98 as shown in Figure 2.

Figure 2.

Immediate reproducibility of upright zSVC data after removing and replacing the electrode bet. AU, arbitrary units.

Relationships between raw PFT values and impedance (z) metrics for ALS patients and healthy controls.

Table 2 summarizes the correlations (R values) between Z metrics and absolute PFT data. In this table, we provide the cumulative data for the entire cohort (all ALS and healthy controls) and individual subgroups. Figures 3, 4, 5, and 6 highlight a selection of the results provided in Table 2. Figures 3 and 4 separate those ALS patients with facial weakness from those without. Of note, in two patients, the FVC and SVC values are considerably lower than the corresponding zFVC and zSVC values, potentially due to air escaping around the spirometer from an incomplete seal in the setting of facial weakness.

Table 2.

Summary of correlations between EIT (z-metrics) and standard PFT parameters

All Participants	Upright FVC	Supine FVC	Upright SVC	Supine SVC	Upright MIP	Upright MEP
zFVC (upright/supine)	0.70*** (n=43)	0.69*** (n=41)			0.46** (n=42)	0.61*** (n=42)
zSVC (upright/supine)			0.73*** (n=44)	0.69*** (n=38)	0.53*** (n=43)	0.66*** (n=43)
All ALS patients
zFVC (upright/supine)	0.65*** (n=24)	0.77*** (n=19)			0.41* (n=23)	0.40 (n=23)
zSVC (upright/supine)			0.68*** (n=24)	0.79*** (n=16)	0.43* (n=23)	0.44* (n=23)
ALS patients without facial weakness
zFVC (upright/supine)	0.64** (n=20)	0.77*** (n=15)			0.39 (n=19)	0.33 (n=19)
zSVC (upright/supine)			0.69*** (n=20)	0.82*** (n=13)	0.41 (n=19)	0.36 (n=19)
Healthy controls
zFVC (upright/supine)	0.59** (n=19)	0.41 (n=22)			0.31 (n=19)	0.62** (n=19)
zSVC (upright/supine)			0.59** (n=20)	0.29 (n=22)	0.41 (n=20)	0.67*** (n=20)

^*,p < 0.05,

^**,p < 0.01,

^***p< 0.001

Figure 3.

Correlations between vital capacity (FVC and SVC) and z-metrics in both upright and supine positions for all participants. AU, arbitrary units

Figure 4.

Correlations between vital capacity (FVC and SVC) and z-metrics for ALS patients. Note that two of the patients with clinical facial weakness (red points) had relatively low standard FVC and SVC compared to their corresponding impedance metrics, which could be expected in the setting of an incomplete lip seal around the spirometer. AU, arbitrary units

Figure 5.

Correlations between vital capacity and z-metrics for healthy participants. AU, arbitrary units

Figure 6.

Correlations between MIP and MEP and z-metrics for all participants. AU, arbitrary units

DISCUSSION

These results confirm that there is a moderate-to-strong association between thoracic EIT values and non-normalized PFT values, including SVC, FVC, MIP, and MEP in this cohort of ALS patients and healthy participants. A major motivation for performing this work was to determine if this technology could circumvent the potential limitation of lip closure weakness which could reduce the accuracy of standard pulmonary function values. Unfortunately, the current analysis could not fully explore issue since only four patients with lip closure weakness could be included in the correlation analyses. Nevertheless, the results here extend our previously published work by including a larger number of participants and a broader range of PFT maneuvers in both the upright and supine positions (18). Overall, the results support the earlier work although the correlations were somewhat weaker. Consistent with that work, we again obtained very high immediate reproducibility, with an ICC value of 0.98 here.

Another important point to consider in this work is that the impedance values were all obtained simultaneously with standard PFTs. If EIT were measured alone, there would be no need to have a mouthpiece. The patient would simply be requested to take as deep a breath as possible and exhale completely to obtain an zFVC or zSVC. How the absence of a mouthpiece being present will impact the data is uncertain.

The explanation as to why the supine values showed somewhat stronger correlations than did the upright values is unclear. One potential reason is that while lying supine, the posterior EIT electrodes made better contact with the skin since they were being pressed against the thorax. Alternatively, this could reflect a different selection of people since many were unable to complete a supine SVC. Similarly, it is unapparent why the MIP and MEP had weaker correlations, though conceptually it makes more sense that FVC and SVC are more closely tied to EIT values. Although two ALS patients with facial weakness had considerably lower FVC and SVC values than their corresponding zFVC and zSVC, as would be expected if standard spirometry measures were falsely low due to incomplete lip seal around the spirometer, this did not impact the overall analysis. This is likely due to the few patients with facial weakness in this cohort and limits any analysis specific related to this factor.

There were several limitations impacting our analysis as well as the broader question of using EIT to track ventilatory function in ALS patients. The first major limitation revolves around challenges with the belt and electrode contact. While we recruited and studied a total of 32 ALS patients and 32 healthy subjects, we were only able to analyze 24 ALS patients and 22 healthy controls due to excess noise during EIT data acquisition. The fact that nearly one-third of participants had unusable data speaks to a fundamental challenge with the current technology and its application in this population that needs to be addressed. While reasonable correlations may have been obtained with additional subjects with fewer functioning electrodes, we intentionally chose to take a more conservative approach in this analysis. A second limitation involves our focus on only correlating to “raw” absolute FVC, SVC, MIP, and MEP values. While this basic concept helps confirm the legitimacy of the technique, it does not address a primary concern of its applicability to clinical care. Indeed, caregivers generally focus on % predicted normal values, namely those that normalize for age, birth sex, and height. Such values are not available for the impedance measures. Despite this, change in absolute lung function (measured traditionally or via EIT) in an individual may be equally or more clinically useful versus their relationship to normative values in ALS clinical care. Third, study PFTs were performed with a standard mouthpiece and not a mask despite some patients having facial weakness. Though not ideal, this is standard in many facilities, including our two sites. Fourth, we performed immediate reproducibility measurements only on a subset of the participants. Fifth, we did not attempt to compare EIT to other lung function technologies, such as phrenic nerve motor responses or diaphragm ultrasound. Finally, despite our best efforts of standardizing EIT belt placement, there was some inconsistency with the belt being placed above the nipple line in some and below in others. Clearly, it would be important to ensure that whichever position is chosen, it remains consistent across all participants and over time.

EIT has been mainly studied in individuals in the intensive care unit, given its ease of application for continuous monitoring of lung condition. Yet its ability to measure lung function without the placement of a mouthpiece could have broader value. Beyond our earlier study, three studies have evaluated its use as a PFT substitute, including 2 in children (14,19). A more recent study in healthy adults assessed a variety of approaches for using EIT values to offer standard PFT-type data and showed a similarly strong concordance (Pearson coefficients >0.7; p<0.001) (20).

While the focus here was ALS, the technology could be used in other neuromuscular disorders. Indeed, many conditions require close monitoring of pulmonary function and many neuromuscular patients have facial weakness (21,22). These include patients with Guillain-Barre Syndrome and generalized myasthenia gravis. EIT electrodes could be applied at the time of hospital admission and left in place and followed serially over time with ease.

In conclusion, we have shown that thoracic EIT could serve as potential assessment of pulmonary function in ALS. While analogous to the proposed use of sustained phonation (23) or single breath counting (24) for assessing pulmonary function, thoracic EIT provides a very direct measure of changes in lung volume that should be unaffected by bulbar or facial weakness. Additional results of this work will be reported separately, including longitudinal assessments, analyses of tidal breathing values, and multiple regression analyses to evaluate the relationship between EIT values and normalized FVC and SVC values. It may be possible to simplify the technique, either by using an adhesive electrode patch or an array with an embedded impedance monitor that does not encompass the entire chest. For example, it may be possible to use an electrode distribution positioned hemi-thoracically or only anteriorly (25). We hope this work offers a strong starting point from which to further extend and develop the technology for wider use in patients with ALS and other neuromuscular disorders.