The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: A randomized trial
- Department of Neurosurgery, Washington University School of Medicine, United States
- Department of Biomedical Engineering, Washington University in St. Louis, United States
- Department of Neuroscience, Washington University in St. Louis, United States
- Department of Neurology, Washington University in St. Louis, United States
Figures
Figure 1
Study rationale and clinical trial design.
(A) Immunomodulation neural pathways associated with vagus nerve stimulation include cholinergic anti-inflammatory pathway, sympathetic nervous system, and hypothalamic–pituitary–adrenal (HPA) axis. …
Figure 2 with 2 supplements
The effects of transcutaneous auricular vagus nerve stimulation (taVNS) on cardiac function.
(A) Signals encoding treatment period and electrocardiogram (ECG) signals in a representative patient. (B) 3-lead ECG configuration in the intensive care unit. (C) P wave, T wave, and QRS complex …
Figure 2—figure supplement 1
The effect of repetitive and acute transcutaneous auricular vagus nerve stimulation (taVNS) on uncorrected QT interval.
(A) QT interval changes from the first hospitalized day in the two treatment groups. (B) Normalized QT interval aligned at the treatment onset over time for the two treatment groups. The QT interval …
Figure 2—figure supplement 2
The distribution of Hunt & Hess classification and modified Rankin Scale for transcutaneous auricular vagus nerve stimulation (taVNS) and Sham groups.
(A) Hunt & Hess classification for both groups. (B–C) mRS at admission (B) and discharge (C) for patients in both groups. In each panel, the height of each histogram bar indicates the count (left …
Figure 3 with 4 supplements
The effects of transcutaneous auricular vagus nerve stimulation (taVNS) on overall heart rate variability and parasympathetic activity.
(A, B) Changes in standard deviation of NN interval (SDNN) changes and root mean squares of successive differences over time for the two treatment groups. The color represents the treatment group. …
Figure 3—figure supplement 1
Heart rate variability in transcutaneous auricular vagus nerve stimulation (taVNS) and Sham treatment groups.
(A) In the linear regression model (RMSSD change ~ Day * Treatment), the coefficient for interaction effect is 2.01 (p = 0.21), the coefficient for Day is −2.61 (p = 0.02), and the coefficient for …
Figure 3—figure supplement 2
Time- and frequency-domain cardiac measures in transcutaneous auricular vagus nerve stimulation (taVNS) and Sham treatment groups.
(A-E) show the changes of heart rate variability metrics following SAH. These standard heart rate variability metrics were used to perform factor analysis.
Figure 3—figure supplement 3
The normalized high-frequency power may not fully represent parasympathetic activity when the respiration rate exceeds 25 bpm.
(A) The relationship between frequency-domain HRV measures and respiration rate. (B) Increase in RR in the transcutaneous auricular vagus nerve stimulation (taVNS) treatment group was associated …
Figure 3—figure supplement 4
The impact of clinical outcome on heart rate variability.
(A) The change in modified Rankin Score (mRS) was similar between the transcutaneous auricular vagus nerve stimulation (taVNS) and Sham treatment groups. (B) Change in heart rate during treatment …
Figure 4 with 1 supplement
Effects of repetitive transcutaneous auricular vagus nerve stimulation (taVNS) on vascular function.
(A) Representative vital signs and their physiology. Arterial line blood pressure (see Figure 4—figure supplement 1), intracranial pressure (ICP), and mean blood pressure measured regularly by …
Figure 4—figure supplement 1
The effect of transcutaneous auricular vagus nerve stimulation (taVNS) on arterial line blood pressure monitoring and noninvasive blood pressure monitoring.
(A-C) Changes in systolic blood pressure (A), diastolic blood pressure (B), and arterial line blood pressure (C) from the first hospitalized day for the two treatment groups. (D) The relationship …
Figure 5 with 3 supplements
The acute effects of transcutaneous auricular vagus nerve stimulation (taVNS) on cardiac function.
(A) Daily fluctuation of heart rate of a subject receiving VNS treatment. The treatment period, a 20-min period before and after treatment, is highlighted. Note that a small proportion of …
Figure 5—figure supplement 1
Cardiac effects of acute transcutaneous auricular vagus nerve stimulation (taVNS).
(A, C) Temporal dynamics of normalized SDNN (high-frequency power). Normalized SDNN (high-frequency power) for the two treatment groups at the treatment onset was set to 0. The data is presented as …
Figure 5—figure supplement 2
Vascular effects of acute transcutaneous auricular vagus nerve stimulation (taVNS).
(A, C, E, G) (left) Temporal dynamics of normalized blood pressure (BP), intracranial blood pressure (ICP), peripheral perfusion index (PPI), and respiration rate (RR) in both treatment groups, …
Figure 5—figure supplement 3
The effect of acute transcutaneous auricular vagus nerve stimulation (taVNS) on peak frequencies within the high-frequency (HF) and the low-frequency (LF) bands.
To investigate the potential effects of acute taVNS treatment on the autonomic system, we analyzed the peak frequency of the HF and LF bands. (A). representative RR intervals over 6 min were linear …
Author response image 1
Tables
Table 1
Patient demography.
HH: Hunt & Hess classification. mRS: modified Rankin Scale. Y: yes. N: no.
| Patient | Decade of life | Gender | Race | HH | mRS(admission) | mRS(discharge) | Vasospasm treated by blood pressure goal augmentation | Indwelling arterial lines | ICP monitoring |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 70s | M | White | 3 | 5 | 5 | Y | Y | Y |
| 2 | 50s | M | Black/African American | 3 | 4 | 3 | N | Y | Y |
| 3 | 50s | F | White | 2 | 2 | 3 | N | N | N |
| 4 | 60s | M | White | 2 | 3 | 4 | Y | N | N |
| 5 | 60s | F | White | 2 | 2 | 3 | Y | N | N |
| 6 | 70s | F | White | 2 | 3 | 2 | N | Y | N |
| 7 | 60s | M | White | 4 | 5 | 4 | N | Y | Y |
| 8 | 60s | F | White | 4 | 5 | 2 | N | Y | Y |
| 9 | 70s | F | White | 2 | 3 | 0 | Y | N | N |
| 10 | 70s | F | White | 2 | 3 | 3 | Y | Y | N |
| 11 | 40s | M | Black/African American | 4 | 5 | 4 | Y | Y | Y |
| 12 | 40s | F | White | 2 | 4 | 3 | N | N | N |
| 13 | 50s | F | Black/African American | 2 | 2 | 1 | Y | N | N |
| 14 | 80s | F | White | 1 | 3 | 3 | Y | N | N |
| 15 | 70s | F | Black/African American | 4 | 5 | 3 | N | N | Y |
| 16 | 40s | F | Black/African American | 2 | 2 | 3 | N | N | N |
| 17 | 60s | F | White | 2 | 1 | 0 | N | N | N |
| 18 | 30s | F | White | 3 | 4 | 2 | N | N | Y |
| 19 | 60s | F | White | 3 | 4 | 2 | N | N | Y |
| 20 | 80s | F | White | 2 | 2 | 3 | N | Y | Y |
| 21 | 50s | F | White | 3 | 4 | 4 | N | Y | Y |
| 22 | 70s | F | White | 1 | 2 | 4 | N | N | N |
| 23 | 40s | F | Black/African American | 2 | 2 | 4 | N | Y | N |
| 24 | 60s | M | White | 4 | 5 | 5 | Y | Y | Y |
Table 2
Relationship between HR changes following acute transcutaneous auricular vagus nerve stimulation (taVNS) and clinical outcomes.
| Model | |||
|---|---|---|---|
| Coefficient | p-value | 95% confidence interval | |
| 0.73 | 0.211 | −0.41 to 1.87 | |
| −0.29 | 0.737 | −1.95 to 1.38 | |
| 1.47 | 0.006 | 0.43 to 2.51 | |
| −1.85 | 0.005 | −3.12 to 0.57 | |
-
Bold values denote statistical significance at the p < 0.05 level.
Table 3
Summary of effects of acute and repetitive transcutaneous auricular vagus nerve stimulation (taVNS) on cardiovascular function in subarachnoid hemorrhage (SAH) patients.
Metrics for cardiovascular function include heart rate variability, heart rate, QT interval, blood pressure, intracranial pressure, peripheral perfusion index, and respiration rate.
| Positive findings | Null findings | Implications | ||
|---|---|---|---|---|
| Repetitive | Cardiac function | Increased HRV | QT interval Heart rate | Increased parasympathetic activity |
| Vascular function | Reduced peripheral perfusion index Increased respiration rate | Blood pressure Intracranial pressure | Compensatory mechanisms to maintain autonomic balance | |
| Acute | Cardiac function | Heart rate Heart rate variability QT interval | No to small acute effect | |
| Vascular function | Increased peripheral perfusion index | Intracranial pressure Respiration rate |
Appendix 2—table 1
Summary of statistical tests.
Bolded values were used to make inferences in this paper.
| Test name | Variable | Distribution A | Distribution B | N(A) | N(B) | p | Statistics | Effect size |
|---|---|---|---|---|---|---|---|---|
| T | RMSSD change | taVNS | Sham | 94 | 95 | 0.004 | t = 2.91 | 0.42 |
| T | SDNN change | taVNS | Sham | 94 | 95 | 0.48 | t = 0.71 | 0.10 |
| Mann–Whitney U | HR change | taVNS | Sham | 94 | 95 | 0.69 | U(A) = 4317 | –0.01 |
| Equivalence test (two one-sided t-tests) | HR change | taVNS | Sham | 94 | 95 | 0.006 (lower), 0.004 (upper) | 2.53 (lower) –2.72 (upper) | –0.01 |
| Mann–Whitney U | QTc change | taVNS | Sham | 94 | 95 | <0.01 | U(A) = 3539 | –0.57 |
| Equivalence test (two one-sided t-tests) | QTc change margin: 30 ms | taVNS | Sham | 94 | 95 | 0.50 (lower), 1.45*10−13 (upper) |
| –0.57 |
| Mann–Whitney U | Percentage of prolonged QT | taVNS | Sham | 94 | 95 | <0.01 | U(A) = 2885 | –0.72 |
| Mann–Whitney U | Overall HRV change | taVNS | Sham | 94 | 95 | 0.04 | U(A) = 5237 | 0.37 |
| Mann–Whitney U | Parasympathetic activity change | taVNS | Sham | 94 | 95 | 0.04 | U(A) = 5238 | 0.29 |
| Mann–Whitney U | ICP change | taVNS | Sham | 66 | 52 | 0.61 | U(A) = 1972 | 0.25 |
| Equivalence test (two one-sided t-tests) | ICP change margin: 2 mmHg | taVNS | Sham | 66 | 52 | 3.66*10−13 (lower), 3.33*10−10 (upper) | 8.07 (lower) –6.73 (upper) | 0.12 |
| Mann–Whitney U | BP change | taVNS | Sham | 66 | 81 | 0.73 | U(A) = 2842 | –0.11 |
| Equivalence test (two one-sided t-tests) | BP change margin: 2 mmHg | taVNS | Sham | 66 | 81 | 0.07 (lower), 0.002 (upper) | 1.51 (lower) –3.00 (upper) | –0.12 |
| Mann–Whitney U | SBP change | taVNS | Sham | 66 | 81 | 0.90 | U(A) = 2719 | –0.07 |
| Mann–Whitney U | DBP change | taVNS | Sham | 66 | 81 | 0.73 | U(A) = 2846 | –0.17 |
| Mann–Whitney U | ABP change | taVNS | Sham | 28 | 24 | 0.46 | U(A) = 295 | –0.48 |
| Mann–Whitney U | PPI change | taVNS | Sham | 83 | 95 | 0.002 | U(A) = 2877 | –0.49 |
| Mann–Whitney U | RR change | taVNS | Sham | 94 | 95 | 0.004 | U(A) = 5530 | 0.37 |
| Mann–Whitney U | HR difference (post–pre) | taVNS | Sham | 188 | 199 | 0.28 | U(A) = 17,527 | 0.10 |
| Wilcoxon signed rank | HR difference (post–pre) | taVNS | 188 | 0.02 | 7525 | 0.11 | ||
| Mann–Whitney U | QTc difference (post–pre) | taVNS | Sham | 188 | 198 | 0.86 | U(A) = 18,412 | 0.02 |
| Mann–Whitney U | RMSSD difference (post–pre) | taVNS | Sham | 188 | 199 | 0.31 | U(A) = 17,581 | 0.14 |
| Mann–Whitney U | SDNN difference (post–pre) | taVNS | Sham | 188 | 199 | 0.48 | U(A) = 17,923 | 0.03 |
| Mann–Whitney U | HR difference (post–pre) | mRS change <−1 | mRS change ≥−1 | 53 | 122 | 0.01 | U(A) = 4019 | 0.38 |
| Mann–Whitney U | BP difference (post–pre) | taVNS | Sham | 159 | 180 | 0.03 | U(B) = 12,400 | 0.21 |
| Mann–Whitney U | ICP difference (post–pre) | taVNS | Sham | 146 | 114 | 0.82 | U(B) = 12,400 | 0.09 |
| Mann–Whitney U | PPI difference (post–pre) | taVNS | Sham | 186 | 227 | 0.002 | U(B) = 17,386 | 0.19 |
| Mann–Whitney U | RR difference (post–pre) | taVNS | Sham | 214 | 224 | 0.10 | U(B) = 21,806 | 0.11 |
Appendix 3—table 1
Clinical characteristics and cardiovascular metrics of the two arms.
Values in this table represent the median.
| taVNS | Sham | |
|---|---|---|
| Age | 67 | 53 |
| % of female | 63.6% | 84.6% |
| % with known hypertension | 90.9% | 46.2% |
| % with known diabetes mellitus | 18.2% | 7.7% |
| % with arrhythmia PTA | 9.1% | 7.7% |
| % with coronary artery disease PTA | 0% | 15.4% |
| % on beta blockers PTA | 27.3% | 38.5% |
| % on calcium channel blockers PTA | 27.3% | 7.7% |
| % on angiotensin-converting enzyme inhibitors PTA | 27.3% | 15.4 |
| Heart rate (bpm) | 86.0 | 78.8 |
| Change from pre- to post-treatment | 1.1 | 0.3 |
| Change from pre- to during-treatment | 0.4 | –0.2 |
| QTc (ms) | 509.9 | 483.6 |
| Change from pre- to post-treatment | –0.4 | –0.2 |
| Change from pre- to during-treatment | 1.3 | 1.0 |
| SDNN (ms) | 72.7 | 77.1 |
| Change from pre- to post-treatment | –0.4 | –1.7 |
| Change from pre- to during-treatment | –1.0 | –1.4 |
| RMSSD (ms) | 24.8 | 24.5 |
| Change from pre- to post-treatment | –0.1 | –0.4 |
| Change from pre- to during-treatment | –0.3 | –0.8 |
| Relative power of high-frequency band (%) | 30.4 | 30.7 |
| Change from pre- to post-treatment | –0.4 | –0.7 |
| Change from pre- to during-treatment | –0.5 | –0.3 |
| Blood pressure (mmHg) | 92.4 | 95.3 |
| Change from pre- to post-treatment | 1.8 | 0.0 |
| Change from pre- to during-treatment | 0.0 | 0.0 |
| PPI (a.u.) | 1.6 | 2.3 |
| Change from pre- to post-treatment | 0.0 | –0.1 |
| Change from pre- to during-treatment | 0.0 | –0.1 |
| ICP (mmHg) | 6 | 6.3 |
| Change from pre- to post-treatment | 0.0 | 0.0 |
| Change from pre- to during-treatment | 0.0 | 0.0 |
| Respiration rate (bpm) | 20.1 | 18.3 |
| Change from pre- to post-treatment | 0.1 | 0.1 |
| Change from pre- to during-treatment | 0.0 | 0.0 |
-
QTc: corrected QT interval; PPI: peripheral perfusion index; ICP: intracranial pressure; PTA: prior to admission.
Appendix 4—table 1
Effect of taVNS on cardiac metrics adjusted for age.
The regression formula is: cardiac metric ~ Treatment + Age.
| Coefficient | p-value | 95% CI | |
|---|---|---|---|
| Heart rate change from Day 1 (F = 9.49, p < 0.01 for the overall model) | |||
| taVNS treatment | 1.87 | 0.21 | [–1.05, 4.80] |
| Age | –0.26 | <0.01 | [–0.37, –0.14] |
| QTc change from Day 1 (F = 14.23, p < 0.01 for the overall model) | |||
| taVNS treatment | –30.79 | <0.01 | [–42.16, –19.43] |
| Age | 0.19 | 0.40 | [–0.26, 0.65] |
| SDNN change from Day 1 (F = 29.40, p < 0.01 for the overall model) | |||
| taVNS treatment | 15.43 | <0.01 | [5.14, 25.72] |
| Age | –1.56 | <0.01 | [–1.97, –1.15] |
| RMSSD change from Day 1 (F = 25.09, p < 0.01 for the overall model) | |||
| taVNS treatment | 16.90 | <0.01 | [10.02, 23.78] |
| Age | –0.83 | <0.01 | [–1.10, –0.56] |
