Abstract

Introduction

Obstructive sleep apnoea (OSA) is a highly prevalent condition that affects about one billion people worldwide (Benjafield et al., 2019). In patients with OSA, intermittent and repeated upper airway collapse during sleep results in irregular breathing at night. Nocturnal apnoeas and hypopnoeas lead to an altered drive to breathe, high work of breathing, oxygen desaturations, and arousals from sleep (Hilton et al., 2001). These effects can cause daytime symptoms, such as sleepiness, and are associated with increased sympathetic tone activation and elevated blood pressure (Remmers et al., 1978). OSA is associated with co-morbidities, including hypertension (Marin et al., 2005; Parati et al., 2014), ischaemic heart disease (Martinez et al., 2012), stroke (Palomäki et al., 1989), congestive heart failure (Bradley et al., 1985), obesity and metabolic syndrome (Levy et al., 2009), and diabetes (Punjabi et al., 2002).

Treatment of OSA includes continuous positive airway pressure (CPAP), and mandibular advancement devices (MAD) (National Institute for Care Excellence, 2021). Primary airway therapies aim to maintain upper airway patency during sleep and lead to a normalisation of the work of breathing and prevention of apnoeas, hypopnoeas, and arousals from sleep that could cause the sympathetic response. Long-term therapy of OSA improves daytime symptoms and, potentially, long-term cardiovascular risks (Somers et al., 2008).

CPAP therapy remains the most common treatment for moderate-to-severe OSA, while for milder cases of OSA, MADs can also be effective (NICE (National Institute for Health and Care Excellence), 2008). However, long-term adherence to CPAP therapy is limited, with only 70% adherence at 3-month (Benjafield et al., 2019b) and further reductions at later follow up (Benjafield et al., 2021). Non-CPAP therapies provide alternatives for patients who have difficulties with long-term compliance to CPAP (Randerath et al., 2021) and may be preferred over conventional treatment (Campbell et al., 2015).

Recently, electrical stimulation invasively applied using hypoglossal nerve stimulation (HNS) (Strollo et al., 2014) or transcutaneous electrical stimulation (TESLA) in the submental area to target the upper airway dilator muscles, particularly the genioglossus muscle, has been developed to treat OSA (Pengo et al., 2016). The randomised controlled trial using HNS (STAR-trial) reported modest improvements in the diastolic blood pressure with no significant changes in systolic blood pressure or heart rate over a 1-year period (Strollo et al., 2014). However, data on the acute cardiorespiratory responses to transcutaneous electrical stimulation of the upper airway dilator muscles, in both health and disease remain sparse (Pengo and Steier, 2015). This is a study to consider the physiological response to the use of electrical stimulation in direct proximity to the carotides, as hypoglossal nerve stimulation (HNS) and transcutaneous electrical stimulation is nowadays being used to treat obstructive sleep apnoea; the purpose of this study was to test the effects of the current has on the cardiorespiratory system in a cohort of normal subject (Strollo et al., 2014).

We hypothesize that acute application of transcutaneous electrical stimulation of the submental area will influence cardiovascular control in healthy, awake subjects. In the current study, we sought to describe the effect of transcutaneous electrical stimulation of the submental area on the cardiorespiratory control, for this particular purpose, we recorded beat-by-beat blood pressure with other cardiopulmonary variables when exposed to room air, hypoxic and hypercapnic gas mixtures (chemosensitivity) while in seated and supine postures, as well as with 50° HDT (baroreceptor response) while using electrical stimulation of the submental area (TES).

Methods and subjects

The study was approved by the local research ethics committee (King’s College London; RESCM-20/21-8487) and performed in accordance with the Declaration of Helsinki. All participants received an information sheet and provided informed and written consent prior to participation.

Primary and secondary outcomes

The primary outcome of the study was the change in the diastolic blood pressure (BP) with electrical stimulation, affecting baro- and chemoreceptor response. Secondary outcomes were changes in other cardiovascular (systolic/mean BP, heart rate) and respiratory variables (respiratory rate, tidal volume, minute ventilation, modified Borg scale) during electrical stimulation.

Equipment

Following the baseline visit without electrical stimulation the participants were continuously stimulated using electrical current in the submental area (4 × 4 cm dermal patches; Med-Fit Plus Ltd., Stockport, United Kingdom), at a frequency of 30 Hz and a pulse width of 250 microseconds during the second visit. Intensity of the electrical current was titrated according to individual comfort using a TENS machine (Premier Combo Plus, the TENS + Company Lets, Stockport, United Kingdom, placed in the submental area midway between angle of mandible and the chin (Figure 1) as previously described elsewhere (Steier et al., 2011). Continuous, beat-by-beat arterial blood pressure was measured continuously using digital artery photoplethysmography (Finapres, Ohmeda 2,300, BOC Healthcare, Englewood CO, United States of America). Heart rate was measured from the electrocardiogram (ECG) with electrodes positioned in the lead II configuration (ML132 bioamplifier, ADInstruments, Oxford, United Kingdom).

Open in a separate window

FIGURE 1

Placed in the submental area midway between angle of mandible and the chin as described previously (Steier et al., 2011).

Respiratory flow was measured via a mouthpiece, with the subject wearing a noseclip using a pneumotachograph (4,800 series, Hans Rudolph Inc., Shawnee Kansas, United States of America) and associated differential pressure transducer (Spirometer, ADInstruments, Oxford, United Kingdom). The distal end of the pneumotachograph was attached to a two way non-rebreathing valve (2,700 series, Hans Rudolph Inc., Shawnee, Kansas, United States of America, deadspace 77 ml) with inspired and expired gases measured continuously using a gas analyser (ML, 206, ADInstruments, Oxford, United Kingdom), connected to a side port on the pneumotachograph via a fine-bore catheter. Blood oxygen saturation (SpO2) was measured using a pulse oximeter (Sat 805 pulse oximeter, Charter Kontron, United Kingdom) attached to the subject’s finger. All data were acquired (PowerLab 16, ADInstruments, Oxford, United Kingdom) with 1 Khz sampling and displayed (LabChart ver 8, ADInstruments, Oxford, United Kingdom). Tidal volume was obtained by digital integration of flow by the acquisition software.

An open circuit (Figure 2) was used to deliver a continuous supply of medical air (wall outlet) to the inspiratory port of the two-way non-rebreathing valve via a low volume (2.5 L) reservoir bag. The inspired gas could be enriched with 100% nitrogen or 100% carbon dioxide from cylinders (BOC, Guildford, United Kingdom) to provide the appropriate inspired gas concentration. Three inspired gas mixtures were used; medical air (21% O², balance N₂), poikilokapnic hypoxia (12% O2, balance N₂) and normoxic hypercapnia (5% CO₂, balance N₂). Symptoms of breathlessness were scored using the modified Borg scale in each posture (seated, supine, and 50°HDT).

Open in a separate window

FIGURE 2

Experimental setup; and the inspiratory gas mixture could be enriched titrated (0%–100%) with 100% nitrogen or 100% carbon dioxide from cylinders (BOC, Guildford, United Kingdom).

An electrically operated tilt table (Plinth2000 Ltd., Stowmarket, United Kingdom) which could be adjusted from 0° (flat) to 50°HDT was used to change posture.

Short protocol

The following parameters were recorded at baseline: Demographic data (date of birth, height, weight, body mass index, ethnicity, and gender), clinical history, and medications. The neck, hips, and waist were measured along with vital signs (heart rate and blood pressure).

Measurements were first recorded in the seated position with the subject exposed to 5 min of each gas mixture, randomly assigned, before moving to the tilt table with measurements commencing in the supine position. Subjects were secured to the tilt table using a foam mattress and a foot strap across the ankles. Participants were familiarized with the 50°HDT procedure prior to the experiment commencing. After an initial period of stabilisation (at least 5 min) in the supine position, a period of 5 min resting breathing was recorded. The table was then tilted to the 50°HDT for 10 min. At the end of the 50°HDT, the subject was returned to the supine position for a further 5 min. Spontaneous ventilation and end-tidal gases (EtO₂, EtCO₂), and oxygen saturations were recorded throughout. The tilt table procedure was repeated three times with the subject breathing in random order (Figure 3). Participants were blinded to the identity of the gas being administered. For safety, the stop criterion for the hypoxic gas mixture was achieved if the arterial oxygen saturation (SpO₂) dropped below 80%. To account for equilibration for change in posture and different gas mixtures, the final 2 min of recording for each posture and each gas mixture were analysed and an average reported for each variable.

Open in a separate window

FIGURE 3

Schematic representation of study procedures. HDT: Head down Tilt. CO2: hypercapnic gas mixture (5% CO2). O2: hypoxic gas mixture (12% O2). Subjects were breathing room air, hypoxic, or hypercapnic gas mixtures in random order in seated, supine, and HDT (50) position. (off): electrical current off. (on): electrical current on (transcutaneous electrical nerve stimulation). Subjects were studied using each gas mixture for 5 min seated and supine, and for 10 min in HDT.

Data processing

All data were recorded in real-time using LabChart software (Chart V8, ADInstruments, Dunedin, New Zealand) with an analog-to-digital conversion at a sampling of 1 kHz. Data were exported and assigned key time periods for further analysis. Each variable was averaged over the last 2 min in seated, supine, and HDT positions. Respiratory variables (tidal volume (Vt) and respiratory rate (RR)) were extracted and multiplied to calculate minute ventilation (VE). Systolic (SBP), diastolic (DBP), and pulse blood pressure (pBP) was computed as pBP = SBP-DBP, and mean arterial pressure (MAP) was calculated as MAP = 1/3 SBP + 2/3 DBP. Heart Rate was derived from the 3-lead ECG, and SpO₂ from the pulse oximeter.

Results

We studied 13 healthy subjects (age 29 (12) years, six female, BMI 23 (1.6) kg/m², waist: hip (W: H) ratio 0.87 (0.05)) (Supplementary Table S1 ). Two more volunteers were unable to participate in the second visit and had incomplete datasets recorded for the primary outcome, these were not included in the analysis. Subjects used an electrical current of 8 (2) mA, which had been titrated to a comfortable and tolerable level of skin sensation. There were no adverse events, and no participant required electrical stimulation to be stopped.

Cardiovascular variables

Heart rate

The heart rate did not significantly change with electrical stimulation, and this observation was independent of posture or gas mixture. (Table 5).

Respiratory variables

There was no change in the respiratory rate with electrical stimulation in any of the three postures studied. (Table 6).

Tidal volume and minute ventilation

There was a trend towards increased tidal volume in the supine posture under hypercapnic conditions with electrical stimulation, although this did not reach significance. (Table 7) Additionally, there was increased minute ventilation with electrical stimulation (p=0.0443; Table 8;Figure 4; details is provided in Supplementary Table S3).

TABLE 7

Tidal volume with and without electrical stimulation in seated, supine and HDT postures. Data are presented as mean (SD). HDT, head down tilt. TENS-, electrical current off. TENS + electrical current turned on. CI, 95% confidence interval.

Posture	Gas mixtures	Tidal volume (ml)
		Visit 1 (TENS-)	Visit 2 (TENS+)	Delta Δ	95% CI
Seated	Room Air	590.47 (198.82)	684.74 (272.43)	94.27 (198.72)	- 90.86 to 279.4
	Hypercapnoea	1,217.12 (389.39)	1,239.29 (379.90)	21.39 (253.26)	- 214.5 to 257.3
	Hypoxia	653.90 (191.62)	774.35 (231.62)	120.45 (217.75)	- 82.40 to 323.3
Supine	Room Air	543.40 (251.31)	523.86 (170.34)	-19.54 (177.51)	- 184.9 to 145.8
	Hypercapnoea	903.30 (380.17)	1,107.63 (313.08)	204.33 (259.80)	- 37.69 to 446.4
	Hypoxia	587.55 (167.05)	597.86 (174.17)	10.31 (164.75)	- 143.2 to 163.8
HDT 50°	Room Air	540.18 (201.51)	468.71 (143.02)	-71.47 (190.91)	- 249.3 to 106.4
	Hypercapnoea	1,100.43 (378.97)	1,245.24 (464.19)	144.81 (381.93)	- 211.0 to 500.6
	Hypoxia	606.62 (160.60)	610.96 (151.57)	4.34 (193.44)	- 175.9 to 184.5

Open in a separate window

TABLE 8

Minute ventilation with and without electrical stimulation in seated, supine and HDT postures. Data are presented as mean (SD), HDT: head down tilt. TENS-, electrical current off. TENS + electrical current turned on. CI, 95% confidence interval.

Posture	Gas mixtures	Minute ventilation (L x min-1)
		Visit 1 (TENS-)	Visit 2 (TENS+)	Delta Δ	95% CI
Seated	Room Air	9.54 (2.40)	11.17 (3.40)	1.63 (2.81)	- 0.9907 to 4.242
	Hypercapnoea	21.69 (4.55)	22.98 (3.48)	1.29 (5.36)	- 3.709 to 6.284
	Hypoxia	11.49 (3.52)	12.65 (2.59)	1.17 (4.63)	-3.149 to 5.481
Supine	Room Air	8.70 (2.54)	8.69 (2.27)	- 0.01 (2.17)	-2.028 to 2.009
	Hypercapnoea	16.86 (5.34)	20.18 (3.58)	3.33 (5.24)	-1.552 to 8.203
	Hypoxia	10.28 (3.17)	8.80 (2.74)	- 1.48 (3.62)	-4.852 to 1.897
HDT 50°	Room Air	9.55 (2.42)	9.01 (2.21)	- 0.54 (2.02)	-2.415 to 1.345
	Hypercapnoea	22.43 (5.59)	23.61 (6.16)	1.18 (4.85)	-3.340 to 5.698
	Hypoxia	10.62 (3.40)	11.15 (3.69)	0.33 (4.10)	- 3.294 to 4.351

Open in a separate window

Open in a separate window

FIGURE 4

Results of 3-way ANOVA of minute ventilation derived from variation of three different factors, (A) TES (electrical stimulation on/off), (B) posture (seated, supine, HDT), and (C) inspired gas (room air, hypoxic and hypercapnic conditions). For further details of group assignments please refer to Supplementary Table S4. There was a significant interaction between factor b and c on minute ventilation. Data shown as median ±25 and 75% percentiles, behind individual data points.

Discussion

The cardiorespiratory response to submental transcutaneous electrical stimulation, a novel therapeutic approach in OSA, applied during enhanced chemoreceptor (gas conditions) activation and baroreceptor (posture) loading demonstrates marked effects on cardiovascular control, with a modest effect on the respiratory control. Electrical stimulation appears to sensitise the arterial baroreceptor response resulting in decreased diastolic blood pressure, by 19%–25%, under hypoxic conditions (chemoreceptor) supine and with HDT (baroreceptor). The effect of electrical current on the systolic blood pressure was slightly less consistent, albeit a reduction of 16% was observed in HDT position under hypoxic conditions. There were no significant differences in the heart rate or the pulse pressure with electrical current; this was independent of posture or gas mixture used. Respiratory variables did not change significantly with electrical stimulation, except for the minute ventilation.

Conclusion

Electrical stimulation of the submental area affects the chemo- and the baroreceptor response in normal healthy volunteers resulting in substantially lower levels of blood pressure. Similarly, inspired gas and posture impact on blood pressure regulation. Furthermore, electrical stimulation might modulate the cardiovascular risk in patients with hypertension and sleep-disordered breathing, a hypothesis that warrants further investigation in the respective clinical cohorts.

Acknowledgments

References