Effect of electro-thumbtack needles on symptoms during high-altitude exposure: a pilot, single-blind, randomized, controlled study

Abstract

OBJECTIVE:

To investigate the efficacy and safety of electro-thumbtack needles (ETN) compared with sham acupuncture (SA) on symptoms during high-altitude exposure.

METHODS:

In this pilot, single-blind, randomized, controlled study, we assessed the impact of ETN acupuncture on symptoms associated with high-altitude exposure. Participants were randomized into two groups: an ETN group and a SA group. The intervention involved routine skin disinfection and stimulation of seven acupuncture points: bilateral Neiguan (PC6), bilateral Hegu (LI4), bilateral Taiyang (EX-HN5), and Zhongwan (CV12), with pressure for approximately 1 min on each point. The primary outcome was the Lake Louise Score after intervention. Secondary outcome measures were heart rate, blood pressure, blood oxygen saturation, headache visual analogue scale score, clinical function score, and sleep scale scores after the intervention.

RESULTS:

We enrolled 125 patients with high-altitude exposure; 59 in the ETN group and 66 in the SA group. AMS was present in 37.90% of the 125 patients. The Lake Louise Score in the ETN group was significantly lower than that in the SA group 6 h postintervention [P =0.05; adjusted mean difference: 0.56; 95% confidence interval (CI) (0.01, 1.11)]. The changes in blood pressure, blood oxygen saturation, and Groningen Sleep Quality Survey, Stanford Sleepiness Scale, visual analog scale, and clinical functioning scores 48 h postintervention showed no significant differences between the groups. Decreases in cerebral oxygen saturation postintervention differed significantly between the ETN and SA groups [P< 0.05; t = −1.39; 95% CI (3.50, 0.59)].

CONCLUSIONS:

This study assessed the feasibility of ETN to address AMS and was a preliminary evaluation of its efficacy. This study provides a basis for the development of intervention programs and scale implementation. ETN is a possible intervention in AMS for special populations, such as those with drug contraindications or pregnant women. This study may guide future research by presenting novel insights, strategic directions, and foundational evidence.

1. INTRODUCTION

Physiological and pathological changes in the human body caused by hypobaric and hypoxic exposures have recently attracted much attention.¹ Previous studies have focused on high-altitude exposure and aerospace.^2-4 High-altitude exposure affects various body systems, and with prolonged exposure, the physiological changes gradually transform to pathological damage.⁵ Acute mountain sickness (AMS) is a major representative disease of acute high-altitude exposure.⁶ AMS consists of a group of nonspecific symptoms⁷, and its onset depends mainly on the altitude and climbing rate.^8-10 Sex, environmental factors, and underlying diseases also affect its incidence.^11-12At the onset of severe symptoms, descending in altitude is often the treatment of choice but this is usually not achieved sufficiently quickly. The 2024 update of the Wilderness Medical Society medical guidelines strongly recommended the use of acetazolamide as a prophylactic medication.¹³ However, there is limited evidence regarding the dosage and efficacy of acetazolamide for varying rates of ascent.¹⁴ Additionally, few studies have determined how to choose appropriate interventions for people with drug contraindications. Therefore, there is still a great need for research into the development of new interventions.

Previous studies have shown that acupuncture can prevent AMS and alleviate conditions such as hypoxia-induced headache and insomnia.^15,16 However, the application of acupuncture is often limited by participants’ fear and resistance.^17,18 A new type of spontaneous electro-thumbtack needle (ETN) (sometimes referred to as press needle) was used in this study, as a convenient alternative to acupuncture. This type of electricity is mainly bioelectricity; however, if conductive adhesive tape is used to fix the thumbtack needles to the skin, ETN can substantially increase the spontaneous electrochemical current in the covered area. At the same time, users can enhance the intervention stimulus by applying pressure at prescribed timepoints over several days. Thus, ETN increases the efficacy of conventional thumbtack needles. ETN permits easier participant movement compared with conventional electric thumbtack needles, which must be connected to an electrical lead. The simplicity and portability of ETN therefore benefit both physicians and participants.¹⁹ Compared with conventional acupuncture or electro-acupuncture, ETN provides gentler stimulation and longer treatment time (the duration of a single treatment is 24-72 h), with minimal interference with daily activities.²⁰ Previous studies have shown no significant difference in long-term efficacy between thumbtack needling and traditional acupuncture, and patients who receive thumbtack needling have higher compliance.²¹ This study evaluated the methodology and effect of ETN to modulate symptoms in people exposed to high altitudes. The study design was a randomized controlled trial to provide the basis for a future formal trial.

2. METHODS

2.1. Study design and participants

This study was performed from August 31st to September 7th, 2023 at a university located at an altitude of 3650 m. All participants were current students. The inclusion criteria were (a) the altitude at which the participant was located during the test period was ≥ 3000 m; (b) each participant’s time at the high-altitude plateau prior to the study was not more than 1 week; (c) age ≥ 18 years and < 45 years; (d) no time living or working at the high-altitude plateau within 2 months of the study; (e) no participation in other clinical trials within 3 months; and (f) voluntary participation in this study and signed informed consent. The exclusion criteria were (a) chronic headache, dizziness, severe cardiovascular and cerebrovascular diseases, respiratory diseases, or digestive diseases before arriving at the high altitude area (i.e., the university); (b) concurrent other serious diseases, such as malignant tumors and psychiatric diseases that could affect participant evaluation during this study; (c) contraindication for electroacupuncture, such as cardiac pacemakers; (d) oral ulcers or bleeding, and other oral lesions or poor oral hygiene; and (e) taking oral contraceptives. Discontinuation criteria were the occurrence of high-altitude cerebral edema or high-altitude pulmonary edema.

2.2. Randomization and blinding

Randomization was performed through a centralized randomization system at the clinical evaluation center of the participating institute. The statistical team generated a random sequence using a specific randomization method and imported the random sequence table into the system. The system then assigned random numbers to the participants through the corresponding random algorithm, and the participants were divided into an EN group and a sham acupuncture (SA) group in a 1∶1 ratio. In the SA group, blunt-tipped needles were used that were indistinguishable in appearance from the ETN. However, the sham needles could not puncture the skin and were a control that simulated the puncture of an ETN. The sham needles did not produce a physiologic response, ensuring participant blinding. The acupuncturists were unblinded regarding the interventions because of the specific maneuvers that are required.

2.3. Ethics and consent

This study was approved by the Institutional Research Ethics Board of the Institute of Basic Research in Clinical Medicine of the China Academy of Chinese Medical Sciences (approval No. P23002/PJ02). In accordance with the Declaration of Helsinki, each participant provided written informed consent and was fully informed of the process and purpose of the study. Participants consented to the publication of all images, clinical data, and other data included in the manuscript, and all participants received a fee. The preliminary protocol has been published.²² Trial registration: Chinese Clinical Trials Registry ChiCTR2300073882; registered on July 24th, 2023.

2.4. Intervention procedures

The interventions were performed by acupuncturists with clinical and research experience in acupuncture. Prior to the study, all acupuncturists underwent uniform and standardized training to ensure consistent mastery of the uniform protocols and standards for both ETN and SA. The ETN intervention involved seven acupuncture points, as per the guidelines specified in the “WHO standard acupuncture point locations in the Western Pacific region”.²³ The acupuncture points were as follows: Zhongwan (CV12), bilateral Neiguan (PC6), bilateral Hegu (LI4), and bilateral Taiyang (EX-HN5).

The intervention involved routine skin disinfection prior to needle placement in both groups. Next, the acupuncturists applied the ETN to stimulate the target acupuncture points, aiming for the patient to experience a sensation of tingling, swelling, numbness, or aching in the respective areas. Each acupuncture point was stimulated for approximately 1 min. The patients were advised to apply pressure to the ETN three times a day for 1 min each time.

To ensure safety and sterility, a single-use sterile ETN measuring 0.22 mm × 2 mm (registration No. 20172200965) was used for each acupuncture point. Regarding the frequency, duration, and timing of the intervention, the ETN was left in place for 48 h before removal. The SA group was treated with the same protocol as that in the ETN group. The needle was blunt-tipped and did not pierce the skin. The ETN and SA methods each involved uniform operation procedures and standards, and were consistently and precisely mastered by the acupuncturists. Throughout the study, operation steps, time, and techniques were standardized to minimize differences caused by human factors. Additionally, an independent supervision team was established to regularly observe and evaluate the operators’ performance. Through these standard operating procedures, bias was controlled to the lowest level. The operators and evaluators were different researchers, with evaluations performed by researchers blinded to the group assignments.

During follow-up, personnel and participants were paired to establish a WeChat group for management, and the participants were urged to improve their self-treatment compliance. Daily check-ins were performed after the participant completed the self-treatment. If intolerable physical discomfort developed during acute high-altitude exposure, participants remained at the current altitude and were treated symptomatically (e.g., nonopioid analgesics for headache, antiemetic medication for nausea and vomiting). If symptoms did not improve or worsened after 1-2 d of appropriate intervention, participants were hospitalized and withdrawn from the study.

2.5. Endpoint

Both the ETN and the SA groups were evaluated before and 6, 24, 48, 72, 120, and 168 h after the interventions. The primary outcome was improvement in the 2018 Lake Louise Score (LLS) after the interventions. Secondary outcomes were the visual analogue scale (VAS) score for headache, clinical functioning score, Groningen Sleep Quality Survey (GSQS) score, Stanford Sleepiness Scale (SSS) score, blood pressure (BP), peripheral blood oxygen saturation (SpO₂), cerebral oxygen saturation (ScO₂), heart rate (HR), salivary cortisol concentration, and adverse events (supplementary Figure 1).

2.6. Laboratory measurements

The day before and immediately after the interventions, at 10 pm, 5 mL of saliva was collected. No food was allowed 1 h before saliva collection. Each participant rinsed their mouth with water, and a sterile tube was used to collect the saliva. The sample was then centrifuged at 2-8 ℃ and 3000 rpm (1500 × g) for approximately 15 min. The supernatant was carefully collected. If precipitate formed during preservation, the sample was recentrifuged. The supernatant was carefully aspirated with a pipette and dispensed into a clean tube, labeled, and frozen at −80 ℃ until cortisol measurement.

2.7. Sample size

Based on a previous study, at least 70 participants were required to estimate the standard deviations with sufficient precision for future sample size calculation.²⁴ Because of the participants’ specific characteristics and the disease incidence pattern in this study, there were only two recruitment opportunities per year, and each recruitment window was approximately 2 d. Therefore, on the basis of the minimum sample size, we recruited participants to the fullest extent possible to assess the efficiency of the maximum sample size that could be recruited in a single cycle.

2.8. Statistics analysis

Participants in the full analysis set were analyzed in the intention-to-treat population with two-sided hypothesis tests for superiority. Data processing and analysis were performed using R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria), with the Storm Statistical Platform (Zhengweijun's team, Hangzhou, China) and SPSS (version 27.0; IBM Corp., Armonk, NY, USA). We used descriptive analysis to analyze the participants’ demographic and clinical characteristics. Quantitative data were described as mean and standard deviation or median with interquartile range, and group comparisons were performed using the t-test or Wilcoxon rank sum test for nonnormally distributed data. Qualitative data were described as frequency and percentage, and the χ ² test or Fisher’s exact test was used to compare groups of categorical data. Within-group comparisons were made using paired t-tests. P < 0.05 was considered statistically significant.

A mean fill-in method was used for missing values in the baseline data, and the last-observation-carried-forward method was used for the follow-up data. Repeated-measures analyses were performed using generalized estimating equation models to compare differences between the groups in the LLS from baseline to day 7 of follow-up. We added an interaction term (group × time) to each model to investigate the interactive effects of intervention and time. Wald’s test was used to assess the significance level of the parameters.

To assess whether the intervention effect was statistically different between subgroups, we performed several subgroup analyses in advance, namely for sex, AMS, body mass index (BMI), BP, time of arrival at the plateau, SpO₂, ScO₂, mode of transportation to the high-altitude plateau from low altitude, and presence or absence of prophylactic therapeutic drug use before travel. We included an interaction term (group × subgroup) in the generalized estimating equation models to assess differences between subgroups. The sensitivity analysis was conducted using the per-protocol set.

3. RESULTS

3.1. Participants

From August 31, 2023 to September 2, 2023, 159 participants were recruited, of which 13 did not meet the inclusion criteria and 3 did not agree to provide written informed consent. The remaining 143 participants with acute high-altitude exposure were randomized into the ENT or SA groups (Figure 1). Participants with no observational data after randomization, who did not receive treatment, or who violated important inclusion and exclusion criteria were excluded in accordance with the intention-to-treat principle. After randomization, 18 participants were excluded (13 from the ETN group and 5 from the SA group) for the following reasons: withdrawal without receiving treatment (n = 14) and withdrawal because of high-altitude pulmonary/cerebral edema (n = 4). The final number of participants in the analysis was 125, indicating a dropout rate of 12.6% (18/143). The included 125 participants were randomly assigned to the ETN group (59 participants) or SA group (66 participants) and included 47 (37.6%) cases of AMS.

Figure 1. Flowchart of patient enrollment.

ETN: electro-thumbtack needle; SA: sham acupuncture; HAPE: high altitude pulmonary edema.

In the full analysis set, the median age was 20 years (range: 18-43 years), and 94 (75.20%) participants were men. The SpO₂ was 88.8% ± 4.9%, and the ScO₂ was 64.3% ± 4.2%; 71 (59.20%) traveled to the plateau by train or car and 51 (40.80%) by plane. Baseline data between the two groups were not statistically significantly different except for BMI and ScO₂ (P > 0.05) (Table 1).

Table 1.

Baseline participants’ characteristics in the full analysis set

Variable	Total (n = 125)	ETN (n = 59)	SA(n = 66)	P value
Age (years, $\overline{x}$ ± s)	20.6±3.1	20.6±3.7	20.6±2.4	0.93
Sex [n (%)]				0.57
Female	31 (24.80)	16 (27.12)	15 (22.73)
Male	94 (75.20)	43 (72.88)	51 (77.27)
Hight (cm,$\overline{x}$ ± s)	172.0±7.7	172.2±7.8	171.79±7.8	0.77
Weight (kg,$\overline{x}$ ± s)	66.9±12.0	65.1±12.0	68.48±11.9	0.12
BMI (kg/m2,$\overline{x}$ ± s)	22.6±3.6	21.9±3.5	23.19±3.6	0.05a
SBP (mm Hg,$\overline{x}$ ± s)	120.3±14.2	118.5±12.5	121.92±15.4	0.77
DBP (mm Hg,$\overline{x}$ ± s)	84.8±9.6	83.5±9.3	86.0±9.8	0.15
HR (bpm,$\overline{x}$ ± s)	103.7±15.2	104.0±13.5	103.6±16.7	0.90
SpO2 (%,$\overline{x}$ ± s)	88.8±4.9	89.9±3.4	88.5±5.9	0.50
ScO2 (%,$\overline{x}$ ± s)	64.3±4.2	63.1±4.8	65.4±3.2	0.00a
Transportation [n (%)]				0.64
Plane	51 (40.80)	22 (37.29)	29 (43.94)
Train/ Car	74 (59.20)	39 (62.71)	37 (56.06)
LLS (points,$\overline{x}$ ± s)	2.2±1.8	2.3±2.0	2.1±1.7	0.57
AMS [n (%)]	47 (37.60)	25 (42.37)	22 (33.33)	0.30
AMS >5 [n (%)]	5 (4.0)	4 (6.7)	1 (1.5)	0.43
Prevention medication history [n (%)]				0.27
Yes	57 (45.60)	30 (50.85)	27 (40.91)
No	68 (54.40)	29 (49.15)	39 (59.09)
GSQS [Me (Q1, Q3)]	5.0 (2.0, 9.0)	5.0 (2.0, 9.0)	5.0 (2.0, 9.0)	0.26
SSS [Me (Q1, Q3)]	2.0 (2.0, 3.0)	2.0 (2.0, 3.0)	2.0 (2.0, 3.0)	0.84
	1.0 (0.0, 1.0)	1.0 (0.0, 1.0)	1.0 (0.0, 1.0)	0.53
CFS [Me (Q1, Q3)]	1.0 (0.0, 1.0)	1.0 (0.0, 1.0)	1.0 (0.0, 1.0)	0.79
Cortisol (pg/mL,$\overline{x}$ ± s)	1218.8±432.9	1286.9±362.4	1178.5±471.7	0.43

Notes: total: all participants; ETN: treated with electro-thumbtack needle. SA: treated with sham acupuncture. This table is the baseline data. FAS: full analysis set; SD: standard deviation; y: years; ETN: electro-thumbtack needle; SA: sham acupuncture; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; SpO₂: blood oxygen saturation; ScO₂: cerebral oxygen saturation; LLS: lake louise score; AMS: acute mountain sickness; Me: median; Q1: first quartile; Q3: third quartile; GSQS: groningen sleep quality survey; SSS: stanford sleepiness cale; VAS: visual analog scale; CFS: clinical functioning score. ^aP < 0.05, ETN vs SA. Calculated using the t-test.

Further analysis of the baseline data revealed that among the male participants, those with BMI ≥ 24 kg/m² without AMS had significantly higher BP and greater prevalence of BP ≥ 130/80 mm Hg than those with BMI < 24 kg/m² and AMS (P < 0.05). SpO₂ was significantly lower in male than female participants and in those who reached the high-altitude area in < 48 h vs > 48 h (P < 0.05). Higher VAS scores for headache and higher GSQS and SSS scores were found in participants with AMS and participants who travelled to the high-altitude plateau in < 48 h than in those without AMS and in those who travelled to the high-altitude plateau in > 48 h (P < 0.05) (supplementary Table 1).

3.2. Variations in symptoms over time

After adjusting for baseline variables, there were group × time effects for both the ETN (Wilks’ lambda F = 51.7; P < 0.001) and SA groups (Wilks’ lambda F = 77.3; P < 0.001). However, there was no statistically significant difference between the groups (P = 0.188). There was no interaction between the effect of time and intervention (P = 0.706).

There was a statistical difference in LLS 6 h after the ETN intervention compared with SA [P = 0.05; adjusted mean difference: 0.56; 95% CI (0.01, 1.11)] (Table 2). There was also a statistically significant difference between the groups when comparing the difference in LLS (Figure 2A). No significant differences were seen between the groups in the scores for VAS for headache and CFS, and the prevalence of AMS (Figures 2B-2D). The rate of asymptomatic patients (LLS = 0) in the ETN group was higher than that in the SA group, but without statistical significance (Figure 2E). ETN showed an intervention advantage for short-term efficacy, as evidenced by LLS scores, and showed great potential to delay or even reverse short-term symptom exacerbations, as evidenced by the VAS score for headache and the incidence of AMS.

Table 2.

LLS at different timepoints postintervention (points)

Group	Baseline	6 hd	24 h		48 h	72h	120 h	168 h	Wald	P value
ETN (n = 59)	2.31 (1.95)	1.64 (1.67)		1.46 (1.58)	1.20 (1.39)	1.05 (1.38)	0.73 (1.19)	0.54 (1.01)	51.7	<0.001k
SA (n = 66)	2.12 (1.70)	2.18 (1.81)		1.56 (1.69)	1.33 (1.47)	1.12 (1.39)	0.74 (1.21)	0.42 (0.82)	77.3	<0.001l
Adjusted Me D or Me D, 95% CI	0.56a (－0.46,0.83)	0.56 (0.01,1.11)		0.13 (－0.36,0.61)	0.15 (－0.28,0.59)	0.09 (－0.35,0.54)	0.05 (－0.35,0.46)	－0.10 (－0.44,0.25)
Wald	0.56b	4.01		0.26	0.47	0.17	0.07	0.30
P value	0.57c	0.05e		0.61f	0.49g	0.69h	0.80i	0.582j

Notes: ETN: treated with electro-thumbtack needle; SA: treated with sham acupuncture. LLS: Lake Louise Score; h: hours; Wald: Wald’s test; ETN: electro-thumbtack needle; SA: sham acupuncture; Me D: median deviation; CI: confidence interval. ^{a. b. c} Calculated using the t-test. ^{e. f. g. h. I, j} Calculated using a generalized estimating equation. ^d Time after intervention. The statistical values all represent the results of the ETN group compared to the SA group. ^k.l P < 0.001. Calculated using a generalized estimating equation.

Figure 2. Evaluated outcomes after the ETN and SA interventions.

A: D-LLS over time; B: VAS scores for headache over time; C: CFS over time; D: incidence of AMS over time; E: rate of asymptomatic participants (LLS = 0) over time. ETN: treated with electro-thumbtack needle; SA: treated with sham acupuncture. D-LLS: decline from baseline in Lake Louise Score. VAS: visual analog scale. CFS: clinical functioning scores. AMS: acute mountain sickness. LLS: Lake Louise Score. A-C: baseline data calculated using the t test, others calculated using a generalized estimating equation. Data were described as mean and standard deviation; D, F: calculated using the χ ² test. Qualitative data were described as percentage. ^aP < 0.05, ETN (n = 59) compared with SA (n = 66).

3.3. Effect of ETN therapy on BP and HR

The t-test analysis of systolic BP, diastolic BP, and HR values, which declined in both groups after the interventions, were not significantly different between the groups (P > 0.05) (Table 3).

Table 3.

Secondary outcomes in the participants 48 h postintervention

Outcome	ETN (n = 59)	SA (n = 66)	t/Z value	P value	95% CI
d-SBP (mm Hg,$\overline{x}$ ± s)	－0.7±9.3	0.3±11.5	－0.51	0.61	－4.63, 2.71
d-DBP (mm Hg,$\overline{x}$ ± s)	2.7±8.6	3.5±7.9	－0.55	0.59	－3.73, 2.12
d-HR (bpm,$\overline{x}$ ± s)	5.9±11.8	3.1±15.9	1.11	0.27	－2.22, 7.77
d-SpO2 (%,$\overline{x}$ ± s)	0.0±5.3	1.5±6.3	－1.39	0.17	－3.50, 0.59
d-ScO2 (%,$\overline{x}$ ± s)	0.9±5.4	－1.0±5.0	2.10	0.04a	0.10, 3.78
d-GSQS [points, Me (Q1, Q3)]	1.00 (0.00, 5.00)	2.00 (0.00, 6.00)	－0.83	0.41	0.39, 0.41
d-SSS [points, Me (Q1, Q3)]	0.00(0.00, 1.00)	0.00 (0.00, 1.00)	－0.31	0.76	0.75, 0.77
d-VAS [points, Me (Q1, Q3)]	0.00 (0.00, 1.00)	0.00 (0.00, 1.00)	－1.06	0.30	0.29, 0.31
d-CFS [points, Me (Q1, Q3)]	0.00 (0.00, 0.00)	0.00 (0.00, 0.00)	－0.16	0.88	0.87, 0.89
Cortisol (pg/mL, $\overline{x}$± s)	985.3±361.5	1193.1±465.3	－1.53	0.13	－482.00, 66.22

Notes: total: all participants; ETN: treated with electro-thumbtack needle; SA: treated with sham acupuncture; Treatment for 48 h. d: difference between pre- and postintervention; ETN: electro-thumbtack needle; SA: sham acupuncture; CI: confidence interval; SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; SpO₂: blood oxygen saturation; ScO₂: cerebral oxygen saturation; GSQS: groningen sleep quality survey; SSS: stanford sleepiness cale; VAS: visual analog scale; CFS: clinical functioning score. ^aP < 0.05, ETN vs SA. Calculated using the t-test.

3.4. Effect of ETN therapy on oxygen saturation

Participants had significantly higher ScO₂ values after 48 h of ETN compared with SA [P < 0.05; t = −1.39; 95% CI (−3.50, 0.59)]; no significant difference was seen between the groups for SpO₂ (P < 0.05) (Table 3).

3.5. Effect of ETN therapy on GSQS and SSS scores

Two scales were used to assess the participants’ sleep quality. The GSQS evaluated the quality of the participant’s sleep the previous night, and the SSS reflected the participant’s sleepiness at a specific moment in time. There was no significant difference between the groups for either score in the degree of decline in the postintervention scores (P > 0.05) (Table 3).

3.6. Subgroup analyses

We performed subgroup analyses to determine whether the intervention effect noted in the entire cohort was homogeneous across the subgroups. Subgroup data were analyzed for sex, BMI, BP, time of arrival at the plateau, presence or absence (asymptomatic) of AMS, SpO₂, ScO₂, method of transportation to the plateau, and whether prophylactic therapeutic drugs were used before travelling to the plateau. The subgroup analysis was corrected using the Bonferroni method, and the significance threshold was set at 0.0056.

We converted LLS into a dichotomous variable for further subgroup analysis on the basis of the ratio of asymptomatic participants (LLS = 0). ScO₂, BMI, prophylactic therapeutic drug use prior to travel, and travel time to the plateau were adjusted as a covariate to control for the effect of potential confounders on the results.

In the exploratory analyses, with the exception of SpO₂, the proportional effect of ETN on the participants was consistent across the remaining five prespecified subgroups. (supplementary Figures 2-7). After 48 h of intervention, at SpO₂ < 90%, the ETN group showed higher rates of asymptomatic parti-cipants vs the SA group (46.9% vs 23.3%, res-pectively; odds ratio: 0.13, 95% CI: 0.03-0.53; P = 0.005; Cohen’s h = 0.48) (supplementary Figure 4).

No significant dif-ferences in cortisol levels were seen bet-ween the groups after 48 h of intervention (Table 3); however, significant differences in the ETN group were seen in the within-group comparisons [1286.85 vs 985.25 pg/mL; P = 0.04; 95% CI (20.99, 582.22)].

3.7. Adverse events

No deaths or skin infections were reported in this study. The most common adverse event was a tingling sen-sation. Six participants reported intolerable pain at the puncture site. The incidence of severe skin irritation (including intolerable pain) was 10.17% in the ETN group and 0.00% in the SA group (P < 0.05).

3.8. Sensitivity analysis

3.8.1. Analysis of the asymptomatic subgroup

We excluded 15 participants who were asymptomatic (LLS = 0) throughout the study period. LLS scores 6 h postintervention were significantly better in the ETN group than in the SA group [P = 0.05; adjusted mean dif-ference: 0.67; 95% CI (0.08, 1.27)] (supplementary Table 2). Cortisol levels were significantly lower in the ETN group than in the SA group after the intervention [(904.44 ± 305.94) vs (1184.15 ± 461.16) pg/mL; t = −2.03; P = 0.05] (supplementary Table 3). The blood pressure, oxygen saturation, heart rate, symptom rating scale, and sleep rating scale showed no significant differences between the ETN and SA groups.

After further adjustments for weight, travel time to the plateau, use of prophylactic therapeutic drugs prior to travel, and ScO₂, the subgroup analyses of LLS after 48 h of intervention showed that the intervention, sex, and SpO₂ had an interaction effect, but the subgroup stratified test was not significant (supplementary Figure 8).

3.8.2. Analysis of the per-protocol set

The per-protocol set comprised 94 participants, namely 43 in the ETN group and 51 in the SA group. LLS scores 6 h postintervention were significantly lower in the ETN group than in the SA group [P = 0.01; adjusted median difference: −0.78; 95% CI (−1.39, −0.16)] (supplementary Table 4). There was a significant difference in ScO₂ values between the ETN and SA groups (score of −2.03 ± 5.86 vs 1.77 ± 4.53, respectively; P < 0.001) (supplementary Table 5). There was an interaction between the intervention and SpO₂, but the subgroup-stratified test result was not significant (supplementary Figure 9).

4. DISCUSSION

This pilot study demonstrated the feasibility of ETN therapy in high-altitude settings and provides preliminary evidence for its efficacy in alleviating AMS symptoms. Compared with traditional electro-acupuncture, ETN has a longer single intervention time and better portability. Our findings position ETN as a promising nonpharmacological alternative with marked potential to broaden intervention choices for populations contraindicated for conventional pharmacotherapy for AMS (e.g., sulfonamide-allergic individuals or pregnant women).

As in low-altitude areas, compared with women and those with BMI < 24 kg/m², men and those with BMI ≥ 24 kg/m² in our study had higher BP values at baseline.^25-27 Furthermore, we observed that participants who developed AMS had a BMI ≥ 24 kg/m² and had low SpO₂ or poor sleep quality. Notably, significant interactions have been identified between these factors, in previous studies.^28-31

LLS values decreased significantly 6 h after ETN (P = 0.05). This finding is similar to the results of previous studies, showing the rapid effect of acupuncture intervention (3-6 h)³². The incidence of AMS and the LLS, VAS, and CFS scores demonstrated that ETN could slow or even reverse symptom progression in participants exposed to high-altitude environments within 6 h, suggesting that ETN is suitable for symptom management in acute diseases.

Acupuncture is highly effective in treating symptoms such as headache, dizziness, nausea, and vomiting; however, there is limited direct clinical evidence for acupuncture in high-altitude settings.^28,33-36 Acute high-altitude exposure induces a pathophysiological cascade characterized by hypoxia-mediated cerebral vasodilation, trigeminovascular system activation, mitochondrial damage, oxidative stress, and blood-brain barrier compromise, culminating in AMS and possibly high-altitude cerebral edema.³⁷ Central to headache symptomatology is hypoxia-driven microglial activation, which potentiates neuroinflammation via proinflammatory cytokine release (e.g., interleukin-1β, tumor necrosis factor-alpha), leading to central sensitization that manifests as cutaneous allodynia and headache.^38-40 ETN counteracts this cascade by suppressing microglial hyperactivation.⁴¹ Concurrently, ETN preserves blood-brain barrier integrity through structural reinforcement via induction of tight junction proteins and functional stabilization by rebalancing autophagy-apoptosis kinetics in cerebrovascular endothelium.⁴¹ Acupuncture enhances cerebral perfusion through vascular endothelial growth factor/fibroblast growth factor 2-mediated angiogenesis, while increasing hypoxia-inducible factor 1 alpha/Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 signaling-mediated autophagy and decreasing oxidative stress.^42-44 Systemically, acupuncture engages integrated neuroimmune circuits to dynamically modulate inflammation in an acupoint via intensity-dependent mechanisms, including in the cholinergic anti-inflammatory pathway and vagus-adrenal axis.^45,46 This orchestrated multi-target action, which includes the nervous, vascular, and immune systems, underpins acupuncture’s capacity to interrupt AMS progression and offers a mechanistic foundation for the observed clinical benefits.⁴⁷

In the current study, acupoints were selected in accordance with expert consensus. Acupoint Neiguan (PC6) stimulation, especially with acupuncture, can counteract the effects of acute normobaric hypoxia on end-diastolic velocity in the middle cerebral artery and significantly reduce systolic and diastolic BP. Hegu (LI4) relieves anxiety, pain during labor, and nausea and vomiting.^18,48-50 Taiyang (EX-HN5) has excellent effects in migraine¹⁶ and significantly reduces systolic and diastolic BP, and Zhongwan (CV12) can mitigate gastrointestinal symptoms via vagal activation.⁵¹ The intervention plan was closely designed on the symptoms of AMS.

A key approach in this study was the implementation of participant blinding to the acupuncture method. To avoid interfering with the participants’ daily activities, we selected thumbtack needle therapy as the target intervention, for convenience. However, the blinding methodology for thumbtack needle therapy has not yet reached the level of traditional acupuncture sham devices (such as Streitberger’s retractable sham acupuncture device). Therefore, in the SA group, we used blunt-tipped needles, which do not pierce the skin and do not produce electrical stimulation. In the original research design, we did not incorporate the assessment of participants’ guessing accuracy regarding group assignment, with the use of questionnaires, to evaluate blinding effectiveness. This decision was primarily because we considered that questionnaire assessment might interfere with participants’ subjective perception of treatment efficacy and indirectly compromise the authenticity of the study results. For example, preoccupation with guessing the group assignment could lead to biased self-perception of the changes in a participant’s symptoms. Future similar studies need to balance the feasibility and scientific rigor in blinded design.

Another key approach in this study was the selection of the outcome indicators, which were selected from common and recognized indicators for AMS. Additionally, performing evaluations at multiple timepoints optimized the choice of the best timepoint to assess the findings. Because AMS is altitude-dependent, onset occurs shortly after the start of acute high-altitude exposure. Previous studies have shown that outcome indicators for AMS are predominantly observed between 1 and 5 d after the start of exposure.^52,53 Epidemiological surveys indicate that AMS symptoms appear most often within 48 h of exposure, while longer-term exposure is associated with the gradual onset of chronic mountain sickness symptoms.^54,55 Our previous observational study showed that the peak incidence of AMS in the target population occurred 24 h after reaching high altitude, and that 72 h after arrival at high altitude, there is a protective effect, with a significantly lower incidence risk during this stage. Therefore, we set the intervention duration at 48 h to cover the peak incidence period and performed follow-ups 3, 5, and 7 d after the intervention to evaluate the therapeutic effects.

This study has several limitations. Pre-enrollment variability in the geographical locations of university students precluded implementation of preventive interventions. Moreover, because of the standardized arrival schedule for the participants and the timing of AMS symptom onset, the window for recruitment was very limited. Exogenous confounders may have introduced bias, including the summer season, the higher proportion of young men than women among the participants, and the high activity level associated with mandatory college physical education classes, which increased perspiration and friction and sometimes caused device detachment or skin irritation. Furthermore, the cohort exhibited substantial symptom homogeneity, with predominantly mild clinical symptoms, which may have limited the statistical power to detect different treatment effects across the AMS severity strata. Collectively, these limitations underscore the necessity for future investigations to incorporate optimized intervention timing, expanded sampling frameworks encompassing diverse symptom severity gradients, and multidimensional monitoring protocols to enhance methodological robustness.

In conclusion, this study provides a rationale for ETN to help alleviate symptoms after acute high-altitude exposure 6 h postintervention. This study evaluated the feasibility of ETN in AMS in clinical practice and was a preliminary efficacy evaluation to explore the technical, social, and environmental feasibility of ETN to provide direction and evidence for further research.

5. ACKNOWLEDGMENTS

We are grateful to all participants in this study. We thank the colleagues who assisted in sample and clinical data collection, namely Dawaciren, Bailang, Renzenglamu, Jiumiduoji, Duojiciren, Riqiong, Deyang, Biandan, Jiduonansen, Danzengqunpei, Rurongdawa, Baimayangzong, Yangji, Basangdunzhu, GUOFujing, Suolangjianshen, Danzengnima, Biancang, Danzhenmuduoji, Cirenduoqing, Gesangduoji, Gemachilie, Cibai, Danzenglamu, CHEN Tianhui, WANG Shuai, LI Xuanzi, ZHANG Chenshi, Baimacuomu, Nancuozhuoma, WANG Xiaoting, WANG Shenying, SHANG Xueni, Baimazhuoga, Caidanyang-zong, and QU Jiancai of department of preventive medicine, school of medicine, xizang university. We thank Jane Charbonneau, DVM, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

6. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://www.journaltcm.com.

Funding Statement

Supported by the Science and Technology Innovation Project of the China Academy of Chinese Medical Sciences: Registration and Enrollment Study on the Evaluation of the Efficacy of Traditional Chinese Medicine in the Real World (No. CI2021A05408); Standard Project of Chinese Acupuncture Society: Expert Consensus on Acupuncture and Moxibustion Treatment for High Altitude Sickness (No. Z0674, surplus funds); Project of China Academy of Chinese Medical Sciences: Research on the Key Technology of the Real-World Case Registry (No. 2022031); Project of the National Key Research and Development Program: Development of International Clinical Research Service Standard for Acupuncture and Moxibustion (No. 2019YFC1712205)