Wheat Grain Moxibustion as an Adjuvant Therapy for Chronic Fatigue in Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Summary

This protocol aims to detail wheat grain moxibustion for chronic fatigue in Pulmonary hypertension associated with chronic obstructive pulmonary disease, including methods, criteria, and assessment, to offer a new treatment option.

Abstract

Chronic Obstructive Pulmonary Disease (COPD) often coexists with Pulmonary Hypertension (PH). Chronic fatigue is prevalent among patients with COPD-related PH (PH-COPD), significantly impacting patients' quality of life. Existing treatment measures for PH-COPD have limited efficacy in alleviating chronic fatigue. As a promising alternative therapy in Traditional Chinese Medicine (TCM), wheat grain moxibustion (a form of moxibustion therapy) has demonstrated unique advantages in adjuvant treatment for chronic fatigue associated with various diseases in recent years. This study aims to elaborate on the specific methods of treating PH-COPD-related chronic fatigue using wheat grain moxibustion and establish a standardized protocol.

This protocol meticulously outlines patient selection criteria, applicable equipment, acupuncture point selection principles, treatment course settings, postoperative care, and emergency handling measures. During the treatment, specific acupuncture points are gently stimulated with five small moxa cones placed on each point, once daily, for a duration of 2 weeks. To objectively reflect changes before and after treatment, efficacy assessment employs indicators such as the Fatigue Scale-14 (FS-14), Fatigue Severity Scale (FSS), EMPHASIS-10 scores, Partial pressure of arterial oxygen (PaO₂), and the Six-Minute Walk Distance (6MWD). Preliminary clinical data suggest that wheat grain moxibustion can effectively alleviate chronic fatigue in PH-COPD patients, and enhance their exercise tolerance and quality of life, with minimal adverse effects. This method is simple, cost-effective, and holds broad application potential. By developing a detailed protocol, we hope to provide a new therapeutic option for more patients suffering from PH-COPD-related chronic fatigue, while also fostering further research and development in this field.

Introduction

Chronic Obstructive Pulmonary Disease (COPD)represents a progressive respiratory condition defined by airflow limitation and enduring respiratory symptoms¹. COPD now ranks as the third highest global cause of mortality, imposing a significant disease burden^1,2. Pulmonary Hypertension (PH) represents a severe comorbidity of COPD. It is marked by a sustained increase in pulmonary artery pressure, which may result in right ventricular failure and progressive exercise limitation^3,4. It is estimated that the prevalence of PH among COPD patients ranges from 30% to 70%^5,6.

Fatigue is a multi-dimensional symptom prevalent in chronic diseases⁷. The prevalence of fatigue in COPD spans between 17% and 95%, and in PH, it is over 90%^8,9. As a common and debilitating non-specific symptom in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD), this kind of fatigue is different from the ordinary tiredness after exertion. It often persists and cannot be alleviated by rest¹⁰. It significantly impacts patients' quality of life and social participation and is associated with reduced activity, disease exacerbation, increased utilization of healthcare services, and higher mortality rates^11,12.

The treatment of PH-COPD mainly focuses on controlling the underlying COPD. For instance, bronchodilators, corticosteroids, and oxygen therapy are used to improve lung function and alleviate hypoxemia^5,13. However, the management of chronic fatigue in PH-COPD patients remains unsatisfactory. Current approaches are mainly symptomatic treatments, including advocating for adequate rest, implementing physical rehabilitation programs, and using antidepressant medications when comorbid depression exists^14,15,16. There is no definitive and targeted treatment for this specific form of fatigue. Therefore, identifying a safe and efficacious adjuvant intervention is particularly crucial.

In recent years, traditional Chinese medicine (TCM), as a complementary and alternative therapy, has demonstrated unique merits in managing various chronic diseases, thus offering a new perspective for the treatment of chronic fatigue in PH-COPD^17,18. Wheat Grain Moxibustion, a type of acupuncture and moxibustion therapy in TCM, has drawn much attention due to its simple operation, definite curative effect, and high safety. This method involves igniting tiny moxa cones (shaped like wheat grains) on specific acupoints, harnessing the thermal stimulation to warm meridians and promote their dredging, regulate qi and blood, and strengthen the healthy qi to eliminate pathogenic factors. Over recent years, Wheat Grain Moxibustion has shown potential clinical value in managing multiple chronic diseases, such as pain management, regulation of immune function, adjuvant treatment of neurological diseases, and cardiovascular diseases^19,20,21.

However, the application of Wheat Grain Moxibustion in the context of PH-COPD has been limited, and there is a lack of standard protocols. Existing research indicates that moxibustion may alleviate chronic fatigue symptoms by exerting antioxidant effects, activating the vagus nerve, etc., and its efficacy is superior to that of acupuncture and medications^22,23,24,25. This research aims to assess the effectiveness and safety of Wheat Grain Moxibustion as an adjuvant intervention in ameliorating the symptoms of chronic fatigue among patients with PH-COPD. The intervention effect of Wheat Grain Moxibustion will be evaluated via objective assessment tools. Through this research, we hope to offer a new, safe, and effective non-pharmacological treatment option for PH-COPD patients.

Protocol

This protocol received approval from the Ethics Committee of Chengdu Xinjin District Hospital of Traditional Chinese Medicine (Approval No. 202411). Subjects were fully informed and signed the informed consent form.

1. Assess patients

1. Inclusion criteria
   1. Confirm patients have a clinical history of PH-COPD according to the 2025 report and 2022 ESC/ERS Guidelines^1,3.
   2. Check for chronic fatigue lasting or recurring for 6 months or more, with at least 4 out of 8 specified symptoms (no earlier than fatigue onset), also persisting or recurring for 6 months or more (Supplemental Table S1).
      NOTE: The 8 specified symptoms include a significant decline in short-term recall or inability to concentrate, throat soreness, swollen and tender lymph nodes in cervical or axillary regions, myalgia, multi-joint pain without redness or swelling, change in the type, pattern and severity of headache attacks, unrefreshing sleep, and malaise after exertion lasting more than 24 h.
   3. Ensure patients are aged between 18 and 85 years old.
2. Exclusion criteria
   1. Exclude patients with disorders of consciousness, aphasia, dementia, etc., who are unable to cooperate with clinical investigations.
   2. Exclude patients with other primary diseases that can cause chronic fatigue, such as hypothyroidism, malignant tumors, multiple sclerosis, or myasthenia gravis.
   3. Do not include patients participating in other clinical trials.
   4. Exclude patients with severe skin damage or skin diseases at acupoint selection sites.
   5. Do not include patients allergic to moxa wool and moxa smoke.
   6. Exclude pregnant or lactating women.
3. Withdrawal criteria
   1. Withdraw patients experiencing severe adverse reactions or other complications during treatment, unsuitable for continued treatment.
   2. Remove patients receiving other treatment methods during the treatment period.
   3. Allow patients to voluntarily exit the study.

2. Grouping and treatment methods

1. Grouping method
   1. Generate a randomization sequence
      1. Create a new spreadsheet.
      2. Add a column named "subjectID" and fill it with numbers from 1 to 14 by dragging the fill handle down.
      3. Add a column named "Random1" and enter the formula "=Rand()" in the first cell.
      4. Press Enter to generate a random number and then drag the fill handle down to generate 14 random numbers.
      5. Copy this column, and when pasting, select Paste Values to convert the formulas to actual numbers.
      6. Rename this column as "Random" and delete the original "Random1" column.
      7. Sort the "Random" column in ascending order.
      8. Allocate the first seven subjects to the experimental group and the last seven subjects to the control group.
      9. Sort the data by "subjectID" to generate the final randomized subject allocation.
   2. Implement allocation concealment.
      1. Place the random number sequences in sequentially numbered, opaque, and sealed envelopes.
      2. Designate a third-party researcher (not involved in recruitment/assessment) to maintain the allocation sequence.
   3. Assign groups.
      1. Have investigators not involved in recruitment or outcome evaluation allocate patients to two groups at a 1:1 ratio based on the random sequence.
         NOTE: The random sequence generation and group assignment should be carried out by separate researchersto segregate duties and minimize bias.
2. Treatment methods
   1. Provide the Control group with conventional treatments for PH-COPD according to the 2025 report and the 2022 ESC/ERS Guidelines^1,3. Refer to Supplemental Table S2 for specific medications and treatment measures.
   2. For the Experimental group, apply wheat grain moxibustion (see section 3) in addition to conventional treatments. Perform the treatment once a day in the morning. Complete two courses of treatment, with each course consisting of 7 consecutive days.
   3. Ensure consistent management for both groups, excluding wheat grain moxibustion, until the end of treatment.
      NOTE: All practitioners have a licensed Chinese medicine practitioner qualification certificate and 1 year of independent clinical treatment experience. Follow the national standard for treatment²⁶. Unless necessary, the operators will not be changed during the treatment process.

3. Operational procedures

1. Prepare materials before making wheat grain moxa cones (Figure 1).
   1. Select appropriate refined moxa wool. Check for mildew or dampness.
   2. Wear a medical hat and a mask.
   3. Use soap and water to wash hands and keep them dry and clean.
2. Prepare wheat grain sized moxa cones.
   1. Place a small amount of moxa wool in the palm of the non-dominant hand (Figure 2A).
   2. Use the thumb, index finger, and middle finger of the dominant hand to knead the moxa wool evenly, forming an appropriately sized moxa ball (Figure 2B).
   3. Hold the moxa ball between the right thumb and index finger of the dominant hand. Move the thumb forward and index finger backward, then reverse the motion, repeatedly and evenly rolling the moxa ball. Apply firm pressure to compact the moxa ball into a spindle-shaped form about the size of a wheat grain (Figure 2C).
   4. Grasp the moxa ball with the dominant hand, exposing its base. Use the thumb and index finger of the non-dominant hand to firmly pinch the exposed base of the moxa ball and tear it off (Figure 2D).
   5. Gently press the exposed bottom of the moxa ball with the index finger of the non-dominant hand to shape it into a conical moxa cone (Figure 2E).
      NOTE: Ensure the moxa cone is tightly packed and not too loose, as loose moxa cones will not stick to the skin well and may fall off, causing accidents.
3. Implement safety procedures before treatment
   1. Select a safe and clean treatment environment. Ensure there are no flammable items around the treatment area.
   2. Set the indoor temperature between 20 °C-25 °C. Make sure the treatment area has sufficient lighting.
   3. Ensure the room is equipped with ventilation or smoke-exhaust facilities.
4. Perform preparations before moxibustion
   1. Check items, including moxa cones the size of wheat grains, 75% medical alcohol, petrolatum, joss sticks (with smoldering fire, used to ignite moxa cones), and medical cotton swabs (Figure 1).
   2. Confirm the patient's identification details, including name, bed number, and ID. Brief patients and their families on the treatment protocols.
   3. Instruct the patient to void their bladder. Ensure that the skin at the moxibustion site is not damaged or ulcerated. Guide the patients to expose the acupoints and instruct them to report discomfort.
5. Select and locate acupoints
   1. Select Zusanli (ST36) (bilateral), Dazhui (GV14), Feishu (BL13) (bilateral), and Gaohuang (BL43) (bilateral) acupoints (Figure 3).
   2. Follow the principles of moxibustion: moxibustion on the upper part first, then the lower part; on the yang meridians first, then the yin meridians; on the head and body first, then the limbs. Specifically, for this protocol, follow this order for wheat grain moxibustion: Dazhui (GV14) first, followed by bilateral Feishu (BL13) and Gaohuang (BL43), and finally, bilateral Zusanli (ST36).
   3. Locate acupoints according to the national standard ²⁷.
      1. Zusanli (ST36):
         1. Find Dubi (ST35) in the depression on the lateral side of the patellar ligament.
         2. Find Jiexi (ST41) in the central depression anterior to the ankle joint, between the tendons of extensor hallucis longus and extensor digitorum longus.
         3. Locate Zusanli (ST36) 3 cun below Dubi (ST35) on the line connecting Dubi (ST35) and Jiexi (ST41), on the tibialis anterior muscle.
            NOTE: "Cun" is a traditional Chinese measurement in acupuncture and moxibustion. It is a proportional unit based on the patient's own body dimensions, typically corresponding to the width of the patient's thumb at the interphalangeal joint.
      2. Dazhui (GV14): Locate it in the depression below the spinous process of the 7th cervical vertebra, on the posterior mid-line.
      3. Feishu (BL13): Find it on the dorsum, inferior to the spinous process of the third thoracic vertebra, 1.5 cun laterally from the posterior midline.
      4. Gaohuang (BL43): Locate it on the dorsum, inferior to the spinous process of the fourth thoracic vertebra, 3 cun laterally from the posterior midline.
6. Perform wheat grain moxibustion.
   1. Carry out standardized hand hygiene disinfection.
   2. Use medical cotton swabs to dip into 75% medical alcohol to disinfect the skin of the patient's moxibustion site.
   3. Apply a small amount of petrolatum on the skin surface of the acupoint as an adhesive.
   4. Pick up a wheat grain-sized moxa cone (approximately 8 mm in height and 3 mm in base diameter) and place it vertically on the acupuncture point coated with petrolatum. Gently press to ensure it adheres closely to the skin.
   5. Pick up the joss stick and shake off any ash at the tip. Light the apex of the moxa cone with the joss stick and let it burn naturally.
   6. Monitor the burning process every 10 s to maintain a consistent temperature. Ensure patients feel a mild, diffused warmth (equivalent to 40-45 °C skin surface temperature, verified by a non-contact infrared thermometer if necessary) without pain or scorching. If the patient reports sharp pain or visible skin reddening beyond a pink hue, remove the moxa cone immediately.
   7. Perform moxibustion 5x on each acupoint each time by placing five moxa cones on each acupoint in sequence. Let each moxa cone burn for approximately 30 s and use tweezers to remove the residue when the residual ash reaches 1/3 of the original height (corresponding to 2/3 combustion), to prevent excessive heat accumulation (Figure 4).
   8. Repeat steps 3.6.4 to 3.6.7 for each acupuncture point.
7. Post treatment nursing
   1. Wipe off residual ash and petrolatum with a medical cotton swab after each acupoint treatment.
   2. Ask the patient about discomfort and check for blister formation after treatment.
      NOTE: After moxibustion, the skin usually shows a flushed and burning sensation, which requires no special treatment and will disappear on its own.

4. Adverse event prevention and countermeasures

1. Take precautions
   1. Communicate in detail with patients and their families before treatment. Ensure they understand the treatment purpose, procedure, and precautions, and obtain their active cooperation.
   2. Strictly follow the operating procedures during the experiment.
   3. Stop the experiment immediately if the patient's condition changes or deteriorates. Adjust the treatment plan according to relevant guidelines^1,3. After the condition improves, re-evaluate in consultation with the patient to decide whether to continue the experiment.
2. Response measures
   1. Manage skin burns
      1. For non-blistered skin scalds, apply burn ointment to the affected area²⁶.
      2. For blisters larger than 1 cm, disinfect the area with 75% medical alcohol. Use a disinfected needle to prick and drain the fluid. Apply anti-inflammatory ointment to prevent infection. Leave the sterile pus on the wound surface until it scabs²⁶.
         NOTE: If the burn is severe or shows signs of infection (such as redness, swelling, increased pain, or pus discharge), seek medical advice immediately.
   2. Manage allergic reactions
      1. If the patient shows allergic symptoms like rash or itching, stop the treatment immediately.
      2. Check if the patient is allergic to moxa wool or moxa smoke. If so, record the reaction details.
      3. Provide antihistamine drugs according to the doctor's advice. If the reaction is severe, consider using corticosteroids.
   3. Manage respiratory symptom exacerbation or infection events
      1. Immediately pause treatment if patients report increased shortness of breath, cough, sputum change, or fever.
      2. Assess vital signs and document symptom severity according to clinical guidelines.
      3. Record the onset time, duration, and any interventions in the adverse event log.
      4. Consult a pulmonologist for severe cases and decide whether to resume treatment based on clinical evaluation.

5. Observation Indicators

1. Record general Information
   1. Record sex, age, Body Mass Index (BMI), FEV1/FVC, Tricuspid regurgitation velocity, and pulmonary artery systolic pressure,
2. Record outcome Indicators
   1. Evaluate patients using Fatigue Scale-14 (FS-14)^28,29, Fatigue Severity Scale (FSS)³⁰, EMPHASIS-10^31,32, Six-Minute Walk Distance (6MWD)³³, and partial pressure of arterial oxygen (PaO₂) at the start and end of the treatment. Use the following total score interpretation and scoring criteria for FS-14 and FSS:
      1. For FS-14, have the overall score span between 0 and 14. Use a greater score to signify a more severe degree of fatigue. Positively score the first 11 items (1 = Yes, 0 = No), and reverse-score items 10, 13, and 14 (0 = Yes, 1 = No) (Supplemental Table S3).
      2. For FSS, have the aggregate score range between 9 and 63. Use a greater score to denote more severe fatigue. Rate each of the nine statements on a 7-point scale (1 = Strongly Disagree, 7 = Strongly Agree). Sum all nine item scores to get the overall score (Supplemental Table S4).
3. Safety evaluation
   1. Systematically record all potential adverse reactions, including but not limited to skin reactions, allergic responses, respiratory symptom exacerbation, and infection events. Record the occurrence time, duration, severity (mild/moderate/severe), and implemented interventions for each event.

6. Conduct statistical analysis

1. Adopt within-subject pre-post comparison and between-group comparison.
2. Employ the Shapiro-Wilk test to analyze data normality.
3. Analysis for baseline table
   1. Describe measurement data following a normal distribution as Mean ± SD. Use the two-independent-samples t-test for between-group comparison.
   2. Represent continuous data with a skewed distribution as M (Q₁, Q₃). Use the Mann-Whitney test for two independent samples.
   3. Present categorical data as n (%). Apply the chi-square test or Fisher's exact test.
4. Analysis for outcome measures
   1. Check the normality of the outcome measure data. For data with non-normal residuals, perform Box-Cox transformation to make the data approximately normal.
   2. Use Analysis of covariance (ANCOVA) with baseline adjustment for all outcome measures.
   3. Apply Bonferroni correction for multiple comparisons when analyzing multiple outcome measures.
5. Take p < 0.05 as statistically significant.

Results

This study enrolled 14 patients, with 7 in the experimental group and 7 in the control group. As shown in Table 1, the two groups exhibited no significant differences in baseline characteristics. The mean age of the total population was 74.36 ± 8.28 years, with 73.86 ± 10.25 years in the control group and 74.86 ± 6.54 years in the experimental group (t = -0.22, p = 0.831). FEV1/FVC also showed no significant difference, with values of 51.66 ± 7.04 in the total group, 51.74 ± 7.46 in the control group, an...

Discussion

This exploratory study aimed to conduct a preliminary evaluation of the therapeutic effects and feasibility of wheat grain moxibustion for managing chronic fatigue symptoms in patients with PH-COPD. The results show that after 2 consecutive weeks of Wheat Grain Moxibustion treatment, the fatigue scores of the patients decreased significantly, and their physical activity ability and quality of life were both improved. These results suggest that Wheat Grain Moxibustion can not only effectively relieve the fatigue symptoms ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
75% medical alcohol	Infection Control Guard (Shandong) Medical Technology Co., Ltd.	10123381277989
Joss sticks	Xiamen Sanye Bodhi Industry and Trade Co., Ltd.	100093487599
Medical cotton swabs	Hebei Kangji Medical Devices and Pharmaceuticals Co., Ltd.	10118283560368
Moxa wool	Nanyang Xingwantang Moxa Products Co., Ltd.	100054545934
Petrolatum	Shandong Lierkang Medical Technology Co., Ltd.	100107439417
R 4.3.0 software			Statistical analysis