Autonomic Neuroscience: Basic and Clinical 155 (2010) 513

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Autonomic Neuroscience: Basic and Clinical

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

Review

Acupuncture and heart rate variability: A systematic review

Sanghoon Lee a, Myeong Soo Lee b,d,, Jun-Yong Choi c, Seung-Won Lee a, Sang-Yong Jeong b, Edzard Ernst d
a

Department of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea Division of Standard Research, Korea Institute of Oriental Medicine, Daejeon, South Korea c Department of Internal Medicine, School of Korean Medicine, Pusan National University, Yangsan, South Korea d Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, Exeter UK
b

a r t i c l e

i n f o

a b s t r a c t
Acupuncture has been reported to affect the autonomic system. Currently, there are no systematic reviews examining the effect of acupuncture on HRV available in the literature. Therefore, the aim of this systematic review was to summarize and critically assess the effects of acupuncture on heart rate variability. We searched the literature using 14 databases for articles published from the earliest available publications until October 2009 without language restrictions. We included randomized clinical trials (RCTs) comparing acupuncture and sham acupuncture. The risk of bias in each study was assessed using the Cochrane criteria. Twelve RCTs met all of the inclusion criteria. One RCT evaluated the effects of acupuncture in patients with minor depression or anxiety disorders and another RCT examined the effect of acupuncture on migraine patients. Another four RCTs tested the effects of acupuncture in healthy subjects who were exposed to several conditions, including mental stress, fatigue from driving, and caffeine intake. The remaining six RCTs assessed the effects of acupuncture on healthy subjects in a normal state without any stressors. Five RCTs found signicant differences in HRV between patients treated with acupuncture versus those treated with sham acupuncture (controls). However, the majority of the other RCTs showed inconsistent results or did not identify signicant differences in HRV spectral parameters among individuals treated with acupuncture as compared to those treated with sham acupuncture. In conclusion, sham-controlled RCTs showed variable results and no clear evidence that acupuncture has any specic effects on HRV. Therefore, more rigorous research appears to be warranted. 2010 Elsevier B.V. All rights reserved.

Article history: Received 17 July 2009 Received in revised form 13 January 2010 Accepted 17 February 2010 Keywords: Acupuncture Heart rate variability Placebo Systematic review

Contents Introduction . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . 2.1. Data sources . . . . . . . . . . . . . . . 2.2. Study selection . . . . . . . . . . . . . . 2.3. Data extraction and assessment of the risk of 2.4. Data synthesis . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . 3.1. Study description . . . . . . . . . . . . . 3.2. Risk of bias . . . . . . . . . . . . . . . . 3.3. Outcomes . . . . . . . . . . . . . . . . 3.3.1. Dysfunctional states . . . . . . . 3.3.2. Healthy subjects in stressed states . 3.3.3. Healthy subjects in normal states . 4. Discussion . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . 1. 2. . . . . . . . . . . . . bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6 6 6 6 8 8 8 9 9 9 9 11 11 12 12

Corresponding author. Division of Standard Research, Korea Institute of Oriental Medicine, Daejeon, 305-811, South Korea. Tel.: + 82 42 868 9266; fax: 82 42 863 9464. E-mail addresses: mslee@kiom.re.kr, drmslee@gmail.com (M.S. Lee). 1566-0702/$ see front matter 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.02.003

S. Lee et al. / Autonomic Neuroscience: Basic and Clinical 155 (2010) 513

1. Introduction Acupuncture is one of the most popular forms of complementary medicine available and it is used by many populations for a variety of conditions (Barnes et al., 2008). It can be dened as the insertion of needles into the skin and underlying tissues at particular sites of the body (known as acupuncture points) to treat patients' symptoms or diseases or as part of preventative medicine practices (Ernst, 2006 Wang, 2003). It is particularly widely used in East Asian countries, and is also becoming increasingly popular in Western countries. Its practitioners claim that it is effective at treating a wide range of conditions, including pain, musculoskeletal disorders, and several neurologic disorders (Ernst, 2006). However, the physiological mechanisms underlying acupuncture therapy have not been clearly dened. Acupuncture is hypothesized to modulate the autonomic nervous system and thereby revitalize the balance of metabolism in the body (Lin and Chen, 2008). Several methods have been proposed to study beat-to-beat uctuations in heart rate in both the time and frequency domains. Power spectral analysis of heart rate variability (HRV) has recently been used as a sensitive index of autonomic nervous system activity (Pomeranz et al., 1985; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). The analysis of HRV provides quantitative information regarding autonomic control mechanisms in the body. Many acupuncture studies have evaluated its effect on HRV. Currently, however, there is no systematic review of these data available in the literature. Hence, the objective of this systematic review was to summarize and critically assess the evidence from randomized clinical trials (RCTs) regarding the effects of acupuncture on HRV. 2. Methods 2.1. Data sources The following electronic databases were searched from for all studies that had been published as of October 2009: Medline, EMBASE, CINAHL, PsycINFO, The Cochrane Library 2009 (Issue 4), and nine Asian Medical Databases (listed in Table 1). The search terms used were acupuncture AND (heart rate variability OR HRV) and the Korean and/or Chinese language terms for acupuncture AND heart

rate variability. We also manually searched our departmental les and the relevant journals FACT (Focus on Alternative and Complementary Therapies) and Forschende Komplementrmedizin und Klassische Naturheilkunde (Research in Complementary and Classical Natural Medicine) for appropriate articles that had been published as of October 2009. In addition, the references of all of the articles we identied were manually searched for other relevant articles. 2.2. Study selection All of the RCTs in which human subjects were treated with needle acupuncture with or without electric stimulation were considered for inclusion in the review. Acupuncture was dened as the insertion of needles into the skin and underlying tissues, at previously described acupuncture points, for therapeutic or preventive purposes. Trials testing forms of acupuncture other than needle acupuncture, such as laser acupuncture or moxibustion, were excluded. Trials were included if they employed acupuncture as the sole treatment being evaluated. To be included, trials had to compare needle acupuncture with any type of sham acupuncture. The trials had to use spectral analysis of HRV as the outcome measurement to be included. No language restrictions were imposed. Dissertations and abstracts were included as long as they contained sufcient detail. 2.3. Data extraction and assessment of the risk of bias Hard copies of all articles were obtained and read in full by two independent reviewers (SHL, MSL). Data from the articles were validated and extracted according to pre-dened criteria by two independent reviewers (SHL, MSL) (Table 2), who sought the opinion of other reviewers (JYC, SWL) if needed. Risk of bias was assessed using the Cochrane criteria to evaluate the following aspects of the trials: randomization, blinding, withdrawals, blinding and allocation concealment (Higgins and Altman, 2008). Considering that it is virtually impossible to blind therapists to the use of acupuncture, we assessed patient and assessor blinding separately. Discrepancies were resolved through discussions between two reviewers (SHL, MSL) and if needed, by seeking the opinion of a third reviewer (EE). There were no disagreements between the three reviewers regarding the assessment of risk of bias.

Table 1 Information about the Asian databases used to search for articles for this review. Database Korean Studies Information Service System (KISS) DBPIA Publisher Korean Studies Information Co. URL http://search.koreanstudies.net/ Search terms used 1. acupuncure AND (heart rate variability OR HRV) 2.

Nurimedia

www.dbpia.co.kr

Science Society Maul

Korea Institute of Science and Technology Information (KISTI) Korea Education & Research Information Service Korean Association of Medical Journal Editors National Assembly Library of the Republic of Korea Research Information Center for Health China National Knowledge Infrastructure (CNKI)

http://society.kisti.re.kr/main.html

Research Information Service System (RISS) KoreaMed Korean National Assembly Library Database of RICH China Academic Journals Full-text Database

http://www.riss4u.net/index.jsp http://www.koreamed.org/ www.nanet.go.kr www.richis.org http://china.eastview.com/kns50/ single_index.aspx 1. acupuncure AND (heart rate variability OR HRV) 2.

J-STAGEa

Japan Science and Technology Information Aggregator (electronic)

http://www.jstage.jst.go.jp/browse/ -char/en

acupuncture AND (heart rate variability OR HRV)

Only English search terms were used for J-STAGE because its search platform is only available in English.

Table 2 Summary of randomized clinical trials examining acupuncture and heart rate variability.
First authors (year) Origin Agelink et al. (2003) German Design Sample size conditions Intervention (Regimen) Heart rate variability Main results Inter-group differences Respiratory regulation Measuring position Measuring time n.r. Seating Before, 3rd treatment (before, 5 min and 15 min after treatment), before 10th treatment Yes Seating 1st and 12th session (before, during and after) n.r. Seating Rest, End of task (simulated driving), after AT n.r. Seating 5 min before mental stress, before and after treatment n.r. Supine Pre-stress, Post-Stress, Post-Acupuncture n.r. n.r. Before and 60 min after caffeine was ingested, after treatment n.r. n.r. Baseline, during, and after AT Risk of bias

Parallel 38 patients with minor depression or anxiety disorders

(A) AT (15 min, once daily in weekdays for 2 weeks, total 10 sessions, n = 18) (B) Sham AT (minimal penetration on non-acupuncture point, n = 20)

1) LF/HF 2) log LF 3) log HF

Backer et al. (2008) German

Parallel 30 migraine patients

Li et al. (2005) China

Parallel 29 healthy subjects with fatigue (after 3 h driving workout) Parallel 40 healthy subjects with mental stress

Kang and Kim (2009) Korea

(A) AT (30 min, 12 sessions, n= 17) (B) Sham AT (minimal penetration on non-acupuncture point, supercial stimulation, n = 13) (A) AT (15 min, n = 10) (B) Sham AT (minimal penetration on non-acupuncture points, n = 10) (C) AT without driving (A) AT (15 min, n = 19) (B) Sham AT (minimal penetration on non-acupuncture point, 15 min, n = 18) (A) AT (15 min, n = 12) (B) Sham AT (minimal penetration on non-acupuncture point, 15 min, n = 12) (A) AT (20 min, n = 13) (B) Sham AT (minimal penetration on non-acupuncture point, 20 min, n = 14)

1) HF 2) LF

1) A, B: P b 0.05, at 5 min after 3rd treatment; NS at 15 min after 3rd treatment; NS: before 10th treatment 2) A, B: NS, both acutely and after 10 sessions 3) A, B: NS, both acutely and after 10 sessions 1) A, B: P b 0.008, during 1st and 12th session 2) A, B: NS, during 1st and 12th session

Y,N.Y.Y,U

Y,Y,Y,Y,U

1) LF/HF 2) LFn 3) HFn 1) LF/HF 2) LFn 3) HFn 1) LF/HF 2) LF 3) HF 1) LF 2) HF

1)2) A, B: P b 0.05 3) A, B: P b 0.05

U,N,Y,U,U

S. Lee et al. / Autonomic Neuroscience: Basic and Clinical 155 (2010) 513

1) A,B: NS 2) A,B: NS 3) A,B: NS 1) A, B: P b 0.05 2) A , B: P b 0.05 3) A, B: NS 1) A,B: NS 2) A,B: NS

Y, Y,Y,N,N

Park et al. (2008) Korea

Parallel 24 healthy men with mental stress

Y,N,N,N,N

Jeong et al. (2008) Korea

Parallel 26 healthy subjects after caffeine consumption

Y, Y,Y,Y,N

Chang et al. (2005) Taiwan

Cross-over 15 healthy subjects

Haker et al. (2000) Denmark

Cross-over 12 healthy subjects

Wang et al. (2002) Taiwan

Cross-over 9 healthy subjects

A) EA (2 Hz, 30 min, n = 15) B) Sham EA (minimal penetration on non-acupuncture point, no electric stimulation, n = 15) C) EA plus atropine injection Sessions A, B, C in a randomized order with 3 days between sessions. (A) AT (25 min, n = 12) (B) Sham AT (minimal penetration on acupuncture points, n = 12) (C) AA (25 min, n = 12) (A) AT (24 min, n = 9) (B) Sham AT (24 min, penetration on non-acupuncture points, n = 9) (A) AT (20 min, n.r., n = 39) (B) Sham AT (penetration on non-acupuncture points, n = 38) (C) No treatment (n = 34) (A) AT (15 min, n = 12) (B) Sham AT (minimal penetration on non-acupuncture point, 15 min, n = 10) (A) AT (10 min., n = 20) (B) Sham AT (10 min, non-penetration on non-acupuncture point, n = 38)

1) LF/HF 2) LF 3) HF

1) A, B: NS 2)3) A, B: NS

U,N,Y,U,U

1) LF 2) HF

1) A, B: NS 2) A, B: NS

No regulation Supine Baseline, during, and after AT n.r. supine Baseline, during, and after AT n.r. n.r. n.r. Before and after AT n.r. Supine 10 min before treatment, during treatment, after treatment n.r. n.r. Before and during AT

U,N.Y.U,U

1) LFn 2) HFn

1) A, B: P b 0.05 2) A, B: P b 0.05

U,N,Y,U,U

Huang et al. (2005) Taiwan

Parallel 111 healthy subjects

1), 2) A, B: NS 3) A, B: NS

U,Y,Y,U,U

Rheu et al. (2006) Korea Streitberger et al. (2008) German

Parallel 22 healthy men Cross-over 20 healthy acupuncture-nave subjects

1) A, B: NS 2) A, B: NS 3) A, B: NS 1) A, B: NS, except 2nd min during treatment (P b 0.05) 2) A, B: NS, except 1st min during treatment (P b 0.05)

U,N,N,N,N

U,N,Y,U,U

AA: auricular acupuncture; AT: acupuncture: n.r.: not reported; : signicantly increased compared with baseline; : signicantly decreased compared with baseline: : no change; NS: not signicant; LF: low frequency power; HF: high frequency power; LFn: normalized low frequency power; HFn: normalized high frequency power; aRisk of bias (sequence generation, incomplete data, patient-blinded, assessor blinded, allocation concealment performed), Y: appropriate; N: not reported or inappropriate; U:unclear.

S. Lee et al. / Autonomic Neuroscience: Basic and Clinical 155 (2010) 513

2.4. Data synthesis The mean change in outcome measures compared with baseline was used to assess differences between the intervention groups and the control groups. Weighted mean differences (WMDs) were used when studies measured the outcome on the same scale, and standardized mean differences (SMDs) were used when studies measured the outcome on different scales. WMDs or SMDs and 95% condence intervals (CIs) were calculated using the Cochrane Collaboration's software (Review Manager Version 5.0 for Windows, Copenhagen: The Nordic Cochrane Centre). For studies with insufcient information, we contacted the primary authors to acquire and verify data where possible. Summary estimates of the treatment effect were calculated using the more conservative approach of a random effects model. Differences compared with sham control were considered relevant in the context of this study. The variance of the change was inferred using a correlation factor of 0.5 (Follmann et al., 1992). The Chi-squared test, tau2 and the Higgins I2 test were used to assess heterogeneity. We attempted to assess publication bias using a funnel plot, whereby effect estimates of the common outcome measure were plotted against sample size. Post hoc sensitivity analyses were performed to test the robustness of the overall effect.

3. Results 3.1. Study description The searches identied 135 potentially relevant articles. A total of 123 studies were excluded, 25 of which were RCTs. The reasons that articles were excluded during the selection process are described in Fig. 1. Key data regarding the 12 RCTs that were found to meet our inclusion criteria are summarized in Table 2. A total of 354 participants were included in these trials. Three RCTs originated from Germany (Agelink et al., 2003; Backer et al., 2008; Streitberger et al., 2008), four studies were conducted in Korea (Kang and Kim, 2009), three studies were from Taiwan (Chang et al., 2005; Huang et al., 2005; Wang et al., 2002), one trial was from China (Li et al., 2005), and one trial was from Denmark (Haker et al., 2000). Ten RCTs included healthy subjects who were either at their normal baseline state or under conditions of stress (Kang and Kim, 2009), while the other studies included patients with minor depression and anxiety disorders (Agelink et al., 2003) or migraine headaches (Backer et al., 2008). Manual acupuncture was used in 11 trials (Agelink et al., 2003; Backer et al., 2008; Haker et al., 2000; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006;

Fig. 1. Flowchart of trial selection process. RCT: randomized clinical trial; CCT: non-randomized clinical trial; UOS: uncontrolled observational study.

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Streitberger et al., 2008; Wang et al., 2002), and electroacupuncture (EA) was employed in 1 trial (Chang et al., 2005). Eight RCTs employed minimal acupuncture at non-acupuncture points as the control intervention (Agelink et al., 2003; Backer et al., 2008; Chang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006). One RCT used minimal acupuncture on acupuncture points (Haker et al., 2000), two RCTs (Huang et al., 2005; Wang et al., 2002) employed penetration at non-acupuncture points, and one RCT (Streitberger et al., 2008) employed non-penetrating acupuncture at non-acupuncture points. Eight of the included trials adopted a parallel group study design (Agelink et al., 2003; Backer et al., 2008; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006) and four used a cross-over design (Chang et al., 2005; Haker et al., 2000; Streitberger et al., 2008; Wang et al., 2002). Four RCTs utilized a supine position for measurement of HRV (Haker et al., 2000; Park et al., 2008; Rheu et al., 2006; Wang et al., 2002) and four measured HRV from a seated position (Agelink et al., 2003; Backer et al., 2008; Kang and Kim, 2009; Li et al., 2005). The other trials (Chang et al., 2005; Huang et al., 2005; Jeong et al., 2008; Streitberger et al., 2008) did not report details regarding the position from which HRV was measured. Only one study (Backer et al., 2008) controlled for respiratory frequency.

3.3. Outcomes 3.3.1. Dysfunctional states Two RCTs tested the effects of acupuncture (total 10 sessions or 12 sessions) on HRV as compared to minimal penetrating acupuncture on non-acupuncture points in patients with minor depression or anxiety disorders (Agelink et al., 2003) or patients who suffered from migraine headaches (Backer et al., 2008). The acupuncture group exhibited a decrease in the LF/HF ratio at 5 min after the third treatment relative to the sham control, but acupuncture did not inuence overall LF and HF power in these patients with minor depression or anxiety disorders (Agelink et al., 2003). However, there were no signicant differences identied with regard to the LF/HF ratio, LF power, and HF power among patients who were treated with acupuncture as compared to the sham controls at 15 min after 3rd acupuncture treatment and before 10th treatment. In migraine patients, acupuncture signicantly decreased HF power, but not LF power, relative to sham acupuncture. Additionally, it is notable that the patients who were clinical responders in both the treatment and sham groups exhibited a decrease in LF power during treatment sessions, but no changes in HF power (Backer et al., 2008). 3.3.2. Healthy subjects in stressed states Four RCTs tested the effect of acupuncture on HRV among healthy patients under several conditions of stress, including fatigue after driving (Li et al., 2005), mental stress (Kang and Kim, 2009; Park et al., 2008), and caffeine consumption (Jeong et al., 2008). Statistical or clinical heterogeneity among the studies prohibited us from pooling data for analysis. One RCT (Li et al., 2005) found that individuals treated with acupuncture exhibited a signicant increase in HF power and a decrease in the LF power and the HF/LF ratio as compared to the individuals in the sham control group after all participants had fatigue induced with a 3 h driving simulation. Two RCTs assessed the effects of acupuncture after a period of mental stress in healthy subjects (Kang and Kim, 2009; Park et al., 2008). One RCT (Park et al., 2008)

3.2. Risk of bias Five RCTs described the methods of randomization that were used (Agelink et al., 2003; Backer et al., 2008; Jeong et al., 2008; Kang and Kim, 2009; Park et al., 2008). Details regarding patients who dropped out or withdrew from the study were described in four trials (Backer et al., 2008; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009). None of the 12 trials reported details regarding allocation concealment. All of the included trials used subject blinding and three trials (Agelink et al., 2003; Backer et al., 2008; Jeong et al., 2008) employed both subject and assessor blinding.

Fig. 2. Forest plot of the effects of acupuncture on (A) high frequency power (HF); (B) low frequency power (LF); (C) LF/HF ratio as compared to sham acupuncture after induction of mental stress in healthy subjects.

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showed signicant differences in the LF/HF ratio and the LF power between the acupuncture group and the control group, while the other RCT (Kang and Kim, 2009) failed to do so. The meta-analysis of these two trials did not indicate that acupuncture had favorable effects on HF power (n = 61, SMDs 0.07; 95% condence intervals (CIs) 0.43 to 0.58, P = 0.78; heterogeneity: 2 = 0.00, 2 = 0.73, P = 0.39, I2 = 0%, Fig. 2A). Regarding LF power and the LF/HF ratio,

our meta-analysis also failed to show signicant differences between two groups despite the present of a high degree of heterogeneity (LF: n = 61, SMDs 0.79; 95% CIs 1.93 to 0.36, P = 0.18; heterogeneity: 2 = 0.52, 2 = 4.21, P = 0.04, I2 = 76%, Fig. 2B; LF/HF: n = 61, WMDs 0.56; 95% CIs 1.60 to 0.47, P = 0.29; heterogeneity: 2 = 0.53, 2 = 17.53, P b 0.0001, I2 = 94%, Fig. 2C). The other RCT, which compared the effects of acupuncture versus sham acupuncture on HRV

Fig. 3. Forest plot of the effects of acupuncture on (A) high frequency power (HF); (B) low frequency power (LF); (C) LF/HF ratio in normal healthy subjects after acupuncture; (D) high frequency power (HF); (E) low frequency power (LF); (F) LF/HF ratio during acupuncture as compared to sham acupuncture.

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after caffeine consumption, reported no signicant differences between the two groups (Jeong et al., 2008). 3.3.3. Healthy subjects in normal states The other six RCTs examined the impact that manual acupuncture or electroacupuncture (EA) (as compared to sham acupuncture) had on HRV in healthy subjects (Chang et al., 2005; Haker et al., 2000; Huang et al., 2005; Rheu et al., 2006; Streitberger et al., 2008; Wang et al., 2002). Five studies failed to show statistical differences in HRV between the acupuncture (Haker et al., 2000; Huang et al., 2005; Rheu et al., 2006; Streitberger et al., 2008) or EA groups (Chang et al., 2005) and the sham control groups. Three of the included RCTs could be combined into a meta-analysis (Chang et al., 2005; Huang et al., 2005; Rheu et al., 2006). When we compared the effects of acupuncture versus sham acupuncture on HF and LF power, and the LF/HF ratio, our meta-analysis revealed no signicant differences in either parameter (HF: n = 129, SMDs 0.11; 95% CI 0.24 to 0.46, P = 0.53; heterogeneity: 2 = 0.00, 2 = 0.01, P = 1.0, I2 = 0%, Fig. 3A; LF: n = 129, SMDs 0.15; 95% CIs 0.26 to 0.56, P = 0.48; heterogeneity: 2 = 0.03, 2 = 2.51, P = 0.28, I2 = 20%, Fig. 3B; LF/HF: n = 129, WMDs 0.07; 95% CIs 0.73 to 0.87, P = 0.87; heterogeneity: 2 = 0.26, 2 = 4.25, P = 0.12, I2 = 53%, Fig. 3C). Two RCTs reported the values of HRV recorded during acupuncture (Chang et al., 2005; Rheu et al., 2006). Meta-analysis did not show signicant differences in HF power (n = 52, SMDs 0.06; 95% CIs 0.48 to 0.61, P = 0.83; heterogeneity: 2 = 0.00, 2 = 0.05, P = 0.82, I2 = 0%) and LF power (n = 52, SMDs 0.48; 95% CIs 1.72 to 0.75, P = 0.44; heterogeneity: 2 = 0.62, 2 = 4.51, P = 0.03, I2 = 78%). The same applied for LF/HF ratio with high heterogeniety (n = 52, WMDs 0.95; 95% CIs 3.47 to 1.57, P = 0.46; heterogeneity: 2 = 2.89, 2 = 7.56, P = 0.0006, I2 = 87%). 4. Discussion Few sham-controlled RCTs have tested the effects of acupuncture on HRV. The majority of the existing studies fail to suggest that acupuncture is an effective modality for modulating HRV. Five of the twelve RCTs that were included in this review assessed various patient populations in various states (i.e., stressed state versus normal state) suggested that acupuncture had changes in the pattern of LF/ HF, HF, or LF patterns in HRV as compared to sham acupuncture (Agelink et al., 2003; Backer et al., 2008; Li et al., 2005; Park et al., 2008; Wang et al., 2002). Our meta-analysis also did not show signicant differences between sham acupuncture and acupuncture with regard to HRV among healthy patients under stress and in their

normal states. Overall, our ndings provide no convincing evidence that acupuncture has signicant effects on HRV. All of the included RCTs employed a single-blinded (patientblinded) methodology. Three RCTs were double-blinded (i.e., both the patient and the assessor were blinded) (Agelink et al., 2003; Backer et al., 2008; Jeong et al., 2008), while the other nine trials (Chang et al., 2005; Haker et al., 2000; Huang et al., 2005; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006; Streitberger et al., 2008; Wang et al., 2002) did not provide clear information regarding assessor blinding. These latter studies were therefore subject to performance and detection bias. The concealment of treatment allocation was not reported in any of the included trials. Trials with inadequate blinding and/or inadequate allocation concealment may be subject to selection bias and would therefore be likely to generate exaggerated treatment effects. Details regarding patient drop-out and withdrawal were described in four of the included RCTs (Backer et al., 2008; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009). Additionally, most of the RCTs had small sample sizes, and their results were therefore prone to type II errors. Five RCTs that assessed the effects of acupuncture on HRV showed signicant differences between the acupuncture group and the sham control group (Agelink et al., 2003; Backer et al., 2008; Li et al., 2005; Park et al., 2008; Wang et al., 2002). Two RCTs showed that acupuncture had a changes in pattern of HF or LF in HRV in patients with mild depression or anxiety disorders (Agelink et al., 2003) or migraine headaches (Backer et al., 2008). A third RCT (Li et al., 2005), which tested the effects of acupuncture after a 3 h stress exposure showed that acupuncture had signicant effects on HRV. The fourth RCT reported signicant differences between acupuncture and sham acupuncture with regard to HRV in healthy patients who were experiencing mental stress (Park et al., 2008). Another RCT (Wang et al., 2002) assessed effects of acupuncture on Sishencong points (EX-HN1) in healthy subjects and reported that acupuncture had point-specic effects on HRV. Only one trial (Backer et al., 2008) measured patients' respiratory frequency, a parameter that can affect cardiac autonomic activities. Another potential confound is the position in which the HRV parameters were measured. Four RCTs (Haker et al., 2000; Park et al., 2008; Rheu et al., 2006; Wang et al., 2002) measured HRV in the supine position and four trials (Agelink et al., 2003; Backer et al., 2008; Kang et al., 2009; Li et al., 2005) measured it in the seated position. Patient positioning during measurement can inuence autonomic activities, and it is therefore important to consider patient positioning when assessing the function of the autonomic nervous system. The rationale for acupuncture point selection was stated in 10 RCTs (Agelink et al., 2003; Backer et al., 2008; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu

Table 3 Summary of acupuncture treatments administered in the included studies. First author (year) Agelink et al. (2003) Backer et al. (2008) Li et al. (2005) Kang et al. (2009) Park et al. (2008) Jeong et al. (2008) Chang et al. (2005) Haker et al. (2000) Experience of acupuncturist n.r. n.r. n.r. 3 years n.r. 1 year n.r. n.r. Acupuncture points GV20, Sishencong points, and bilateral HT7, PC6, BL62 GB20, Ex-HN5, TE23, TE5, LR3, GB41 (bilateral for all of the above points), GV20 PC6, LI4 (bilateral) HT7 PC6, SP4 PC6 ST36 (bilateral) (A) LI4 (right) (B) LI4 (left) (C) LU1 in the Left ear Sishencong points PC6 (Bilateral) PC6, SP4 LI4 De-qi n.r. Considered Considered Considered Considered Considered Considered Considered Manipulation n.r. Yes Yes Yes Yes Yes Yes Yes Rationale for acupuncture point selection Previous study TCM theory Previous studies TCM theory Previous studies Previous studies n.r. n.r

Wang et al. (2002) Huang et al. (2005) Rheu et al. (2006) Streitberger et al. (2008)

n.r. n.r. n.r. 10 years

n.r. Considered Considered n.r.

No Yes Yes Yes

Previous Previous Previous Previous

studies studies studies studies

n.r.: not reported, TCM: traditional Chinese Medicine.

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et al., 2006; Streitberger et al., 2008; Wang et al., 2002) (Table 3). The authors quoted previous studies or expert consensus to justify their point selection. Only three RCTs reported the experience level of the acupuncture practitioners (Jeong et al., 2008; Kang and Kim, 2009; Streitberger et al., 2008). Needle stimulation causing a typical needle sensation has been claimed to be an important factor in obtaining the optimal effects of acupuncture. This needle sensation (de-qi) was assessed in nine RCTs (Backer et al., 2008; Chang et al., 2005; Haker et al., 2000; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006). The other three trials did not report these details. Eleven RCTs reported the manipulation methods used by the acupuncture practitioners (Backer et al., 2008; Chang et al., 2005; Haker et al., 2000; Huang et al., 2005; Jeong et al., 2008; Kang and Kim, 2009; Li et al., 2005; Park et al., 2008; Rheu et al., 2006; Streitberger et al., 2008; Wang et al., 2002). In the present data set, it is not evident whether the presence or absence of de-qi had an important inuence on HRV. One problem with acupuncture clinical trials is nding a suitable placebo control. Several sham acupuncture methods have been proposed for use in acupuncture trials. They generally range from non-/minimal/normal needle penetration at non-acupuncture points to minimal needle penetration at acupuncture points. In the present systematic review, none of the studies identied strong evidence of the effects of real acupuncture as compared with sham acupuncture, regardless of the acupuncture technique employed. In a previous study, however, non-penetrating sham acupuncture was reported to have signicant effects on placebo tablets at treating subjective pain complaints (Kaptchuk et al., 2006). This suggests that the effects of needle acupuncture with or without electric stimulation may be nonspecic in nature. However, there is no universally accepted placebo, and an ideal placebo cannot be designed before the exact mechanism by which acupuncture works is elucidated. Therefore, a range of methods have been used in these types of studies, some of which may not be adequate. The fact that, overall, there is no good evidence regarding the effect of acupuncture on HRV could have several possible interpretations. First, acupuncture could be an ineffective modality for modulating cardiac autonomic activity. Alternatively, acupuncture could be effective, but may have been administered sub-optimally (e.g., inappropriate acupuncture points could have been used) in these studies. A third interpretation is that sham acupuncture may also be effective and may be the reason that no inter-group differences could be demonstrated. Penetrating acupuncture, regardless of the site at which it is administered, could potentially induce physiological modulations that might inuence various symptoms, including pain and autonomic nervous system-related symptoms. The nding that penetrating sham acupuncture performed at non-acupuncture points had similar outcomes to acupuncture might be due to a physiological effect of needle penetration or the therapeutic relationship between the practitioner and the patient. A fourth interpretation is that acupuncture may only be effective in pathologic conditions, which could explain why no benecial effects could be demonstrated in normal healthy subjects. Much of the clinical literature on acupuncture shows that sham acupuncture has superior clinical effects than non-treatment does. Thus, it would be interesting to further analyze the two RCTs that employed a no-treatment control group (Huang et al., 2005; Zhou and Chen, 2008 One RCT (Huang et al., 2005), which was included in this review, showed no signicant differences in HRV between the real acupuncture, sham acupuncture, and no-treatment groups, all of which comprised healthy subjects. The other RCT, which was excluded from this review because of the absence of sham control group, reported signicant effects of acupuncture on LF and LF/HF power as compared to no treatment among patients with hypertension (Zhou and Chen, 2008). However, these results may also be explained by any of the four hypotheses discussed above, and we cannot therefore completely elucidate the non-specic effects of acupuncture.

Our review has a number of important limitations. We tried to reduce bias in this systematic review, through extensive search, the use of multiple reviewers, and inclusion of non-English studies. Although we made a strong effort to retrieve all RCTs on the subject, we cannot be absolutely certain that we succeeded. Moreover, selective publishing and reporting are other major causes of bias that must be considered (Ernst and Pittler, 1997 Pittler et al., 2000; Rothstein et al., 2005). It is conceivable that several negative RCTs remain unpublished, thereby distorting the overall picture. Further limitations include the paucity and the often suboptimal methodological quality of the primary data. While HF power is associated with parasympathetic activity (assuming regulated breathing patterns), the association between sympathetic activity and LF power as well as the LF/HF ratio remains unclear. In total, these facts limit the conclusiveness of this systematic review considerably. In conclusion, these results provide no convincing evidence for the effectiveness of acupuncture in modulating HRV in dysfunctional or stressful states or in normal states in healthy subjects. However, the number, size, and quality of the RCTs that are available are too low to draw rm conclusions. Further rigorous RCTs seem warranted to further examine this topic, but they must overcome the many limitations present in the current literature. Acknowledgements S.H. Lee was supported by the Program of Kyung Hee University for the Young Researcher in Medical Science (KHU-20071513). References
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