Comparing the Effects of Distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix Pharmacopuncture With Heart Rate Variability (HRV): A Randomized, Sham-controlled and Double-blind Clinical Trial

Article Outline

• Abstract
• 1.. Introduction
• 2.. Materials and Methods
  • 2.1.. Study design and subject selection
  • 2.2.. Materials
  • 2.3.. Treatment methods
  • 2.4.. Measuring HRV
  • 2.5.. Statistical analysis
• 3.. Results
  • 3.1.. The comparison of mean HRV
  • 3.2.. The comparison of standard deviation of all normal R-R intervals
  • 3.3.. The comparison of complexity
  • 3.4.. The comparison of HRV index
  • 3.5.. The comparison of the proportion derived by dividing NN50 by the total number of NN intervals
  • 3.6.. The comparison of the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals
  • 3.7.. The comparison of the standard deviations difference between adjacent normal to normal intervals
  • 3.8.. The comparison of the log normalized transformation value of total power
  • 3.9.. The comparison of the log normalized transformation value of very low frequency oscillation power
  • 3.10.. The comparison of the log normalized transformation value of low frequency oscillation power
  • 3.11.. The comparison of the log normalized transformation value of high frequency oscillation power
  • 3.12.. The comparison of normalized low frequency
  • 3.13.. The comparison of normalized high frequency
• 4.. Discussion
• References
• Copyright

Abstract 

This study compared the effects of distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture on the autonomic nervous system and heart rate variability. The purpose of the trial was to observe the influence distilled Astragali Radix, Wild Ginseng and Rehmannia glutinosa pharmacopuncture have on the autonomic nervous system. 120 healthy male volunteers were divided into four groups, which consisted of three experimental groups and a control group. This study was a randomized, placebo-controlled, double-blind clinical trial. Volunteers in experimental groups were underwent pharmacopuncture at GB21 (Kyonjong), and volunteers in the control group were injected with normal saline at GB21 (Kyonjong). Heart rate variability was measured seven times: before and after injection, every 5 minutes for 30 minutes. The result was distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture in healthy adult males tended to activate the autonomic nervous system, particularly the sympathetic nervous system.

Key Words:  autonomic nervous system , Astragali Radix , HRV , pharmacopuncture , Rehmannia glutinous , Wild Ginseng

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1. Introduction 

Pharmacopuncture is herbal acupuncture. Herbal acupuncture is a unique treatment method in Korean traditional medicine which combines the benefits of herbs and acupuncture ^[1]. Various herbs are devel oped for injection on the meridian points and the most suitable herbal acupuncture points are selected depending on the patient's constitution and the state of disorder ^[2]. Rehmannia glutinosa (RG) is the herb used to strengthen the heart, liver and kidney ^[3] and to alleviate hypertension ^[4] and diabetes mellitus ^[5]. Wild Ginseng (WG) is believed to have an anti-cancer effect ^[6]. Astragali Radix (AR) is used to promote the immune system ^[7]. Recently distilled RG, WG and AR pharmacopuncture were reported to promote human autonomic nervous system function in oriental medical clinics ⁸, ⁹, ¹⁰. The kinds of RG, WG and AR are different, but have common effects on human autonomic nervous system ^[1].

In this study, we compared the effects of distilled RG, WG and AR pharmacopuncture on heart rate variability (HRV). The HRV test evaluates the functioning of the autonomic nerves by monitoring the change in heart rate. The HRV test is well known for reflecting the states of the sympathetic and parasympathetic nerves ^[11]. The acupoint was GB21 (Kyonjong), have the effect of descending fire of heart ¹², ¹³, ¹⁴. We recruited 120 healthy volunteers and divided into four groups, three experimental groups were given pharmacopuncture and one control group was injected with normal saline. We measured activity of the autonomic nervous system by measuring HRV over a period of 35 minutes. Significant results were obtained when the effect of each pharmacopuncture was compared.

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2. Materials and Methods 

2.1. Study design and subject selection 

One hundread and twenty healthy male volunteers who were students of Woosuk University in Korea were recruited. They had no central nervous system problems including stroke, mental illness, cardiovascular disease, endocrinological disease and were not on medications that affect the autonomic nerve system. Subjects were divided into four groups which consisted of three experimental groups, RG (n = 28), WG (n = 31) and AR (n = 31) pharmacopuncture, and a control group [injected with normal saline (NS); n = 30]. Twenty one volunteers were excluded from analysis because of error during measuring HRV. At the conclusion of the study, HRV analysis for 99 volunteers was completed. This study was a randomized, placebo-controlled, double-blind clinical trial and was approved by the Institutional Review Board of Woosuk University Affiliated Hospital.

2.2. Materials 

NS was purchased from Daihan Pharm (Korea). RG and AR used in this experiment were purchased by Woosuk University Affiliated Hospital (Korea). WG was estimated to be 20 to 30 years old and obtained from Mount Changbaishan in China. Each pharmacopuncture solution was made using the following process: RG, WG and AR were rinsed in running water and then decocted for 2 hours in distilled water. Remnants were then removed and the decoction was distilled before yielding the desired herbal acupuncture. The herbal acupuncture solution was then filtered three times using 0.45 μm, 0.2 μm, 0.1 μm filtering paper and kept in a container. Finally, the herbal acupuncture solution was sterilized before use.

2.3. Treatment methods 

Pharmacopunctures and normal saline were injected intramuscularly using a sterile hypodermic syringe (DM Medicrat 1.0 mL, 26 Gauge, Sindongbang Medical Company, Korea) at the point of GB₂₁ (Kyonjong) to effect the descending fire of heart ⁹, ¹⁰, ¹². Each 0.1 mL injection was performed on both sides of the GB21 point. The grade of pain experienced by the subjects was under 2 on the visual analogue scale.

2.4. Measuring HRV 

The HRV was measured with electrodes attached to both wrists and ankles for 35 minutes using QECG-3: LXC3203 (Laxtha Inc., Korea). Before the experiment began, volunteers relaxed for 20 minutes. HRV was measured seven times: 5 minutes before injection and every 5 minutes during a 30-minute period after injection. The outcome measure was converted to a variation ratio for minutes. Δ1 was from injecting to 5 minutes, Δ2 was from 5 minutes to 10 minutes, Δ3 was from 10 minutes to 15 minutes, Δ4 was from 15 minutes to 20 minutes, Δ5 was from 20 minutes to 25 minutes and Δ6 was from 25 minutes to 30 minutes. The variation ratio was calculated by “variation ratio = (outcome measure — measure for first 5 minutes)/measure for first 5 minutes”.

2.5. Statistical analysis 

To compare the HRV values (Δ0, being defined as the value 5 minutes before the injection, with Δ1-6) of the four groups, we performed paired t-tests and differences between groups were analyzed using one-way ANOVA. When a significant overall effect was observed, post hoc comparison between groups was performed using the Duncan's method. We used SPSS for Windows (version 13.0) for the statistics, and examined these data in the significance level of 5%.

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3. Results 

3.1. The comparison of mean HRV 

Mean HRV of RG and WG decreased at Δ1, and AR decreased at Δ1-4 and 6. Differences between groups were not significant (Table 1, Figure 1).

Table 1. Comparison of Mean-HRV

Values shown are mean ± SD (cycle/min),

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• Figure 1. 

  Comparison of Mean-HRV.

3.2. The comparison of standard deviation of all normal R-R intervals 

Standard deviation of all normal R-R intervals (SDNN) of the NS group increased at Δ4-6, WG and AR group increased at Δ2-6 and the RG group increased at Δ1-6. Differences between groups were significant at Δ5 and NS group differed from the WG group following a post hoc test (Table 2, Figure 2).

Table 2. Comparison of standard deviation of all normal R-R intervals (SDNN)

Values shown are mean ± SD (cycle/min),

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• Figure 2. 

  Comparison of SDNN.

3.3. The comparison of complexity 

Complexity of the WG group decreased at Δ4-6 and the AR group decreased at Δ4-5. Differences between groups were not significant (Table 3, Figure 3).

Table 3. Comparison of complexity

Values shown are mean ± SD (cycle/min),

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• Figure 3. 

  Comparison of complexity.

3.4. The comparison of HRV index 

HRV index of the NS group increased at Δ4-5, the RG group at Δ1, 3-6, the WG group at Δ3-6, and the AR group at Δ2-6. Differences between groups were not significant (Table 4, Figure 4).

Table 4. Comparison of HRV-index

Values shown are mean ± SD (cycle/min),

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• Figure 4. 

  Comparison of HRV-index.

3.5. The comparison of the proportion derived by dividing NN50 by the total number of NN intervals 

The Proportion Derived by Dividing NN50 by The Total Number of NN Intervals (pNN50) of the NS group decreased at Δ4, at Δ1-6 for the RG group, at Δ2-6 for the WG group and at Δ2, 4-6 for the AR group. Differences between groups were significant at Δ6 and the NS group differed from the RG, WG, and AR groups following a post hoc test (Table 5, Figure 5).

Table 5. Comparison of the proportion derived by dividing NN50 by the total number of NN intervals (pNN50)

Values shown are mean ± SD (cycle/min)

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• Figure 5. 

  Comparison of pNN50.

3.6. The comparison of the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals 

The square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals (RMSSD) of the RG group increased at Δ4 and at Δ2-4, and 6 for the AR group. Differences between groups were not significant (Table 6, Figure 6).

Table 6. Comparison of the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals (RMSSD)

Values shown are mean ± SD (cycle/min)

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• Figure 6. 

  Comparison of RMSSD.

3.7. The comparison of the standard deviations difference between adjacent normal to normal intervals 

The standard deviations difference between adjacent normal to normal intervals (SDSD) of the RG group increased at Δ1, 3-5, at Δ3-5 for the WG group, and at Δ2 for the AR group. Differences between groups were significant at Δ3 and the RG group differed from the AR and NS groups following a post hoc test (Table 7, Figure 7).

Table 7. Comparison of the standard deviations difference between adjacent normal to normal intervals (SDSD)

Values are mean±SD (cycle/min)

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• Figure 7. 

  Comparison of SDSD.

3.8. The comparison of the log normalized transformation value of total power 

The log normalized transformation value of total power (Ln(TP)) of the NS group increased at Δ4-5, at Δ1-6 for the RG group and at Δ2-6 for both the WG and AR groups. Differences between groups were significant at Δ5 and the NS group differed from the WG group following a post hoc test (Table 8, Figure 8).

Table 8. Comparison of the log normalized transformation value of total power (Ln(TP))

Values shown are mean ± SD (cycle/min)

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• Figure 8. 

  Comparison of Ln(TP).

3.9. The comparison of the log normalized transformation value of very low frequency oscillation power 

The log normalized transformation value of very low frequency oscillation power (Ln(VLF)) of NS group increased at Δ4, 6, RG group increased at Δ1-6, and WG and AR group increased at Δ2-6. Differences between groups were significant at Δ5 and NS group differed to RG and WG groups by post hoc test (Table 9, Figure 9).

Table 9. Comparison of the log normalized transformation value of very low frequency oscillation power (Ln(VLF))

Values shown are mean ± SD (cycle/min)

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• Figure 9. 

  Comparison of Ln(VLF).

3.10. The comparison of the log normalized transformation value of low frequency oscillation power 

The log normalized transformation value of low frequency oscillation power (Ln(LF)) of the NS group increased at Δ2-6, at Δ1-6 for the RG group, at Δ2-6 for the WG group, and at Δ2, 4-6 for the AR group. Differences between groups were not significant (Table 10, Figure 10).

Table 10. Comparison of the log normalized transformation value of low frequency oscillation power (Ln(LF))

Values shown are mean ± SD (cycle/min)

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• Figure 10. 

  Comparison of Ln(LF).

3.11. The comparison of the log normalized transformation value of high frequency oscillation power 

Differences between groups were not significant (Table 11, Figure 11).

Table 11. Comparison of the log normalized transformation value of high frequency oscillation power (Ln(HF))

Values shown are mean ± SD (cycle/min)

^*p<0.05 (by paired t-test).

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• Figure 11. 

  Comparison of Ln(HF).

3.12. The comparison of normalized low frequency 

Normalized low frequency (LF) of NS group increased at Δ2-6, at Δ2-4, 6 for the RG group, Δ2-6 for the WG group, and at Δ4-6 in the AR group. Differences between groups were not significant (Table 12, Figure 12).

Table 12. Comparison of normalized low frequency

Values shown are mean ± SD (cycle/min)

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• Figure 12. 

  Comparison of normalized low frequency.

3.13. The comparison of normalized high frequency 

Normalized high frequency (HF) from the NS group decreased at Δ2-6, at Δ3-4, 6 in the RG group, at Δ2, 4-6 in the WG group, at Δ5-6 in the AR group. Differences between groups were not significant (Table 13, Figure 13).

Table 13. Comparison of normalized high frequency

Values shown are mean ± SD (cycle/min)

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• Figure 13. 

  Comparison of normalized high frequency.

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4. Discussion 

Analyzed time data revealed that mean HRV reflected an activation of the autonomic nervous system. The RG and WG group was activated for first 5 minutes but the AR group was activated for a longer time. The WG and AR groups increased at Δ5 for the mean time, but this increase was not significant, because WG and AR have a “hot” character, while RG has a “cold” character. The SDNN result indicates an activation of the autonomic nervous system and an increase in stress resistance. The RG group was fastest than the other groups to activate. The WG and AR groups were faster to activate than the NS group. The WG group showed the largest increase among the groups at Δ5 highest, revealing a significant difference with the NS group. Complexity results show a decrease in the disillusion. The NS, RG and AR groups tended to increase at Δ6, meaning that disillusion recovered after 25 minutes in these groups. HRV index and the pNN50 demonstrate the activation of the autonomic nervous system and func tions of the heart. The pNN50 of the RG, WG and AR groups is significantly higher than that of the NS group at Δ6. The RMSSD and SDSD data reveal that the RG, WG and AR groups tend to activate function of the heart to be a stable state. However, the RMSSD and SDSD of the RG group are higher than those of the other groups at Δ3. This may indicate that the RG has more special effects on the activation of the heart.

Frequency data was also analyzed. Ln(TP), Ln(VLF), Ln(LF) and Ln(HF) analysis reveal that all groups activated the autonomic nervous system, particularly the sympathetic nervous system. Ln(TP) of the WG group was significantly higher than that of the NS group at Δ5 and Ln(VLF) of the RG and WG groups was significantly higher than that of the NS group at Δ5. Ln(TP), Ln(VLF), Ln(LF) of the RG group were higher and more quickly activated than other groups, but these changes were not significant. RG is able to activate the autonomic nervous system from the first 5 minutes and WG is able to powerfully activate the autonomic nervous system from 20 to 25 minutes as WG has a “hot” character that reveals itself from 20 to 25 minutes. Data from the analysis of normalized LF and HF, demonstrate that all groups were able to activate the sympathetic nervous system and restrain of parasym-pathetic nervous system. The AR group, however, tended to show a delayed restraint of parasym-pathetic nervous system than the other groups.

We have demonstrated that distilled RG, WG and AG pharmacopuncture in healthy adult males tends to activate the autonomic nervous system, and in particular the sympathetic nervous system. This study did not however obtain significant results as the number of subjects was small and the period of the experiment was short.

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