Seo et al.

Trials 2014, 15:348

TRIALS
http://www.trialsjournal.com/content/15/1/348

STUDY PROTOCOL Open Access

Acupuncture in subjects with cold hands

sensation: study protocol for a randomized
controlled trial
Jung-Chul Seo1†, Hyun-jong Lee2†, Min-Ah Kwak3, Sung-Hoon Park1, ImHee Shin4, Woo-Sung Yun5
and Kihyuk Park5*

Abstract
Background: Cold hands sensation is a common disorder within the Korean population. Many Korean family
physicians believe that it is a mild early manifestation of Raynaud’s phenomenon (RP), or may be related to RP.
RP is characterized by reversible digital vasospasm provoked by cold temperatures and/or emotional stress, and
doctors often prescribe medications that are used in treatment of RP for subjects with cold hands. However, this
has not shown a clear benefit, and these medications can cause unwanted side effects. It is also reported that
traditional Korean medicine, including acupuncture, is widely used to treat cold hands, although the current level of
evidence for this approach is also poor and to date, there have been no published randomized controlled clinical
trials (RCTs) evaluating the efficacy and safety of acupuncture for cold hands. We have therefore designed a pilot
RCT to obtain information for the design of a further full-scale trial.
Methods/Design: The proposed study is a five-week pilot RCT. A total of 14 subjects will be recruited and randomly
allocated to two groups: an acupuncture plus medication group (experimental group) and a medication-only group
(control group). All subjects will take nifedipine (5 mg once daily) and beraprost (20 mg three times daily) for three
weeks. The experimental group will receive additional treatment with three acupuncture sessions per week for three
weeks (nine sessions total). The primary outcome will be measured using a visual analogue scale. Secondary outcomes
will be measured by blood perfusion in laser Doppler perfusion imaging of the hands, frequency and duration of
episodes of cold hands, and heart rate variability. Assessments will be made at baseline and at one, three, and five
weeks thereafter.
Discussion: This study will provide an indication of the feasibility and a clinical foundation for a future large-scale trial.
Trial registration: This study was registered at Korean Clinical Research Information Service (CRIS) registry on 5 August
2013 with the registration number #KCT0000817.
Keywords: Acupuncture, Cold hands sensation, Laser Doppler perfusion image

Background and complaints of cold hands sensation are very common

One of the normal physiological responses to cold tempera- among the general population [1]. Cold hands sensation is
tures or emotional stress is a reduction of the skin defined as hands that become intolerably cold when
temperature to preserve body heat and maintain a normal exposed to normal temperature, in which most individuals
body core temperature. Reactions characterized by exces- feel no cold. There can be a confusion between cold hands
sive peripheral vasospasm may evoke clinical symptoms, sensation and Raynaud’s phenomenon (RP), as both have
cold hands as a symptom. The signs of RP include cold and
* Correspondence: [email protected]
†
numb hands when exposed to cold temperatures, with
Equal contributors
5
Division of Vascular Surgery, Department of sugery, School of Medicine,
subsequent pain and skin becoming blue in colour [2]. In a
Catholic University of Daegu, 3056-6 Daemyeong 4-dong, Nam-gu, Daegu community-based survey of approximately 7,000 people,
705-718, Republic of Korea almost 12% responded that they had experienced unusual
Full list of author information is available at the end of the article

© 2014 Seo et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Seo et al. Trials 2014, 15:348 Page 2 of 7
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sensitivity to cold temperatures in their fingertips or toes Hypotheses

[3,4]. This may be due to a mild, early manifestation of In this randomized controlled two-arm clinical trial, we
Raynaud’s phenomenon (RP) or may be related to RP [1,5], will evaluate the acupuncture treatment as an adjunct
which is characterized by a reversible digital vasospasm therapy to cold hands sensation. The hypothesis is that
provoked by cold temperatures and/or emotional stress [6]. the addition of acupuncture treatment to medication
A study by Choi et al. [7] found that in South Korea, 43% reduces the severity of cold hands sensation (measured
of patients with an abnormal cold sensation in the hands or using a visual analogue scale (VAS)) significantly more
feet had RP, and that primary RP represented 73% of cases than medications alone.
of RP, and many family physicians prescribe medications
for cold hands sensation based upon treatment recommen-
dations for RP [8]. Methods/Design
The exact prevalence of primary RP is unknown. It is Design
a common disorder, especially in the general practice The study is a randomized controlled pilot clinical trial.
setting [9], and its prevalence is thought to be high com- It is designed to obtain basic information of a further
pared with the low number of patients who seek treat- full-scale trial about acupuncture treatment in subjects
ment for it [10]. The treatment is mostly dependent on with cold hands sensation. The protocols to be used ad-
the etiology of the disorder and on the presence and se- here to the principles of the Declaration of Helsinki and
verity of the individual symptoms. Lifestyle modifications have been approved by the Institutional Review Board of
including avoidance of cold exposure and caffeine, dis- Daegu Catholic University Hospital (approval number
continuation of smoking, and sufficient body insulation, IORG0004453), where the study will take place. The
are the first line of treatment for the prevention of trial is registered with the Korean Clinical Research
vasospasm [11,12]. If these modifications are insufficient, Information Service (CRIS) registry. Written informed
calcium channel blockers are the most widely used pharma- consent will be obtained from each participant before
cological agents for treatment [4,13,14], and in severe any treatment is given.
forms of RP, prostaglandins, endothelin-1 receptor an- The outcome assessments and statistical analyses will
tagonists, and specific inhibitors of phosphodiesterase- be performed by professionals blinded to the assign-
5 are the treatments of choice [6]. Although a wide ment of subjects. The trial process is presented in
variety of medications are used for treatment of RP, Figure 1. The trial will run for five weeks. Subjects will
none have been shown to have a clear benefit, and all be randomly allocated to one of two groups, a control
may be associated with unwanted side effects including group, in which subjects will receive only medication
headache, flushing, and dizziness. There is currently for three weeks, and an experimental group, in which
no gold standard or universal guideline for the treat- subjects will receive the same medication as well as
ment of RP [6,15]. nine acupuncture sessions (three sessions per week for
In Korea, traditional treatments including acupuncture three weeks). Assessments will be made at baseline and
and herbal medications have been widely used to treat again at one, three, and five weeks thereafter. The five-
cold hands for many years, and there are a number of week assessment will be performed two weeks after
published reports regarding these treatments for cold treatment cessation. This study will be conducted be-
hands [16-18]. Nonetheless, the present level of evidence tween late November 2013 to February 2014 which is
is poor because of small sample sizes or short durations winter season in South Korea. We will record room
of these published studies. In addition, even though temperature to control for temperature bias in this
there are a few published randomized controlled trials clinical trial.
(RCT) regarding acupuncture and RP [19,20], there is
no published RCT evaluating the efficacy and safety of
acupuncture in subjects with cold hands sensation. Recruitment
The need remains for more rigorous studies that will Participants will be recruited through advertisements
elucidate the efficacy and safety of acupuncture for on hospital websites and on bulletin boards. If subjects
subjects with cold hands sensation. The aim of the are interested in participating, they will be invited to
present study was to collect preliminary data on acu- the hospital for a screening meeting. Eligibility will be
puncture compared with conventional pharmaceutical determined by a vascular surgeon based on the results
agents alone for the treatment of cold hands sensation. of physical and photoplethysmography examinations.
The results of this study will provide evidence for the If eligible, subjects will be guided through the informed
feasibility of this trial design as well as basic data for a consent process. After written consent is obtained, a
large-scale RCT of acupuncture for subjects with cold study researcher will randomly allocate each partici-
hands sensation. pant to one of the two treatment groups.
Seo et al. Trials 2014, 15:348 Page 3 of 7
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Identify patients with cold hands sensation

and confirm their eligibility (target number
of patients = 14)

Randomize the participants

Experimental group (n = 7) Control group (n = 7)

Acupuncture plus medication medication only

Acupuncture: 3
Medication:
sessions per week
nifedipine 5 mg
Medication:
daily + beraprost 20
nifedipine 5 mg daily
mg three times daily
+ beraprost 20 mg

three times daily

Duration of treatment: 3 weeks

Assess outcomes at baseline and at 1, 3,

and 5 weeks thereafter

Figure 1 Flow chart of the pilot randomized controlled trial.

Participants and/or drug abuse, pregnant, lactating, or planning

A target sample size of 14 subjects with cold hands sensa- pregnancy, any individual deemed ineligible by a phys-
tion has been set. One of the main objectives of this study ician, refusal to participate in the trial or to provide
is to provide an estimate of the sample size required for the informed consent, or an inability to comprehend or
full-scale randomized controlled clinical trial. express oneself in the Korean language.

Inclusion criteria
Randomization
Participants must meet the following criteria for inclusion
Subjects will be randomized using a computerized random
in the study: cold hands sensation or RP, photoplethysmo-
number generator by an independent statistician who is
graphy showing decreased arterial pulse amplitude or
blinded to subject assignment. The method which we use
abnormal ischemic pulse waveform such as biphasic or
for randomization concealment is sequentially numbered,
monophasic wave, aged between 20 and 75 years, VAS
opaque sealed envelopes. Block randomization will be
score of >3 for cold hands sensation, symptom duration of
performed once a participant’s eligibility is confirmed and
least one month, available for follow-up during the entire
written informed consent has been obtained. Treatments
trial period, and provide written informed consent.
will be scheduled after randomization.
Exclusion criteria
Participants will be excluded from the study if they meet Interventions
any of the following criteria: one or more ulcerated Subjects will be randomly divided into two treatment
fingers, acute ischemic disease requiring reperfusion groups: an experimental group (acupuncture plus medi-
surgery, high bleeding tendency due to anticoagulant cation group) and a control group (medication only
medications, significant renal or hepatic disease, severe group). The medication will be administered every day
psychiatric or psychological disorders, known hyper- for three weeks and the acupuncture sessions performed
sensitivity reaction to acupuncture treatment, alcohol three times per a week for three weeks (nine times in
Seo et al. Trials 2014, 15:348 Page 4 of 7
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total). There are no other interventions such as moxi- imaginable. VAS measurements will be made at baseline
bustion, exercises, or lifestyle advice in this study. and at one, three, and five weeks thereafter.

Medications Secondary outcome measurements

Oral nifedipine (calcium channel blocker, 5 mg once Blood perfusion Laser Doppler perfusion imaging (LDPI)
daily) and beraprost (prostaglandin analog, 20 mg three with a Perimed AB LDPI system (Perimed AB, Jaerfaella,
times daily) will be prescribed for all subjects in both Sweden) will be used to measure the perfusion of microcir-
groups. culation in the skin of the hands. The LDPI system has a
moving laser beam that scans the tissue in steps and a
Acupuncture treatment photo detector that measures the backscattered light. The
The following acupoints will be used based on previ- frequency shift of the light has a direct relation to the per-
ously published work [21]: unilateral GV20, bilateral fusion of the lighted area of skin, according to the Doppler
ST36, PC6, TE5, LI4, and EX-UE9 (extra points). In total, principle [22].
17 acupoints will be used. Sterilized disposable acupuncture The largest scanning image is 64 × 64 (4096) points and
needles (DongBang Acupuncture Inc., Korea) 0.25 × 40 low, medium, and high resolution modes are available.
mm in size will be manually inserted into each of the The largest scanning area is about 20 × 20 cm. Measur-
acupoints. After needle insertion, the deqi sensation will ing time is about 50 milliseconds per point, and 4
be induced by manual stimulation. The needles will be minutes for a 64 × 64 image. A normal photo is taken
inserted for 20 ± 5 minutes and then removed. Acupunc- along with the blood perfusion scan in order to localize
ture will be practiced by Korea Medical Doctors (KMD) the area of interest. When the scan is completed, the
who are licensed by Ministry of Health and Welfare. region of interest is selected for analysis of the mean
blood perfusion and its changes using the built-in LDPI
Data collection windows 2.5 software.
In this study, the primary outcome will be measured by
VAS. The secondary outcomes are changes in micro- Frequency and duration of cold hands sensation
vascular blood perfusion, frequency and duration of cold episodes The subjects will record the frequency and
hands sensation episodes, and heart rate variability duration of each episode of cold hands sensation. The
(HRV) measurements. Both primary and secondary out- average frequency and duration of attacks will be calcu-
comes will be assessed at baseline and at one, three, and lated weekly by dividing the total number of attacks and
five weeks after initiation of treatment. The treatment their duration by the number of a given weekly interval
and outcomes measurement schedules are presented in (observation period). The frequency and duration cold
Table 1. hands sensation episodes will be measured at baseline
and at one, three, and five weeks thereafter. We will rec-
Primary outcome measurements ord the frequency and duration of cold hands sensation
VAS The severity of cold hands sensation episodes episodes by patient diaries.
ranges across a continuum of values but cannot easily be
measured directly. Therefore, we will use a 10-cm VAS Heart rate variation The pathogenesis of cold hands
as the measurement instrument to determine the sever- sensation is still unclear. Neural and intravascular mech-
ity of cold hands sensation. Each subject will rate each anisms are thought to be involved in the pathological
episode of cold hands sensation on a scale of 0 to 10, progress. The role of the autonomic nervous system is
where 0 indicates the absence of the cold hands sensa- most often discussed, with particular attention to sympa-
tion and 10 indicates the worst cold hands sensation thetic over-reactivity. HRV analysis is a reliable non-

Table 1 Schedule of treatments and outcome measurements throughout the five-week randomized controlled trial
Baseline Treatment period Follow-up period
Week 0 Week 1 Week 2 Week 3 Week 4 Week 5
Measurement VAS √ √ √ √
Blood perfusion √ √ √ √
Frequency and duration of cold hands episodes √ √ √ √
HRV √ √ √ √
Treatment Medication √ √ √
Acupuncture √ √ √ √ √ √ √ √ √
HRV: Heart rate variability, VAS: visual analogue scale.
Seo et al. Trials 2014, 15:348 Page 5 of 7
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invasive test that is used assess autonomic nervous trial protocol. The trial will be stopped if the principal
system function [23]. investigator believes that there are unacceptable risks of
HRV will be measured using a Medicore SA-2000E serious adverse events.
analyzer (Medicore Co., Ltd., Seoul, South Korea) with
four limb electrodes. To minimize the influence of con- Statistical analysis
founding factors, all subjects were prohibited from using The statistical significance level will be set at 5%, and
drugs, caffeine, tobacco, and alcohol for eight hours the data will be processed with the last observation car-
before HRV testing. The frequency domain methods of ried forward method for the intention-to-treat analysis.
HRV analysis will be used. Low frequency (LF), high Statistical analysis in this study will be performed using
frequency (HF), LF:HF ratio, LF in normalized units, and IBM SPSS Windows version 19.0 statistical software
HF in normalized units will be measured. LF reflects the (IBM Co., Armonk, NY, USA) and will be based on the
sympathetic influence, whereas HF reflects the parasym- Korean Clinical Trial Statistics Guidelines.
pathetic influence. The LF:HF ratio reflects the inter- The study will identify the comparative equivalence of
action between sympathetic and vagal activity. LF in demographic variables and clinical characteristics be-
normalized units and HF in normalized units are the tween the experimental and control groups by perform-
respective values of LF and HF divided by the sum of LF ing the two sample t-test or Mann-Whitney U test if
plus HF and multiplied by 100; thus, the sum of LF in normality test is satisfied or not for continuous data,
normalized units and HF in normalized units is 100 [24]. chi-square test for categorical data.
HRV measurements will be conducted at baseline and at A repeated measure two-factor analysis will be per-
one, three, and five weeks thereafter. formed to identify differences in VAS, blood perfusion,
frequency and duration of cold hands sensation attacks
Safety and HRV scores between the experimental and control
The safety of this trial will be determined by red group based on time (baseline, weeks one, three, and
blood cell (RBC) count, hemoglobin level, platelet count, five). If the interaction between group and time is statis-
mean corpuscular volume (MCV), mean corpuscular tically significant, the point at which the pattern of re-
hemoglobin (MCH) level, mean corpuscular hemoglobin sults between the two groups changes will be checked
concentration (MCHC), hematocrit (Hct), total white using the contrast analysis. To compare groups and the
blood cell (WBC) count, erythrocyte sedimentation rate incidence frequency of adverse events related to acu-
(ESR), aspartate aminotransferase (AST), alanine amino- puncture and medication, the chi-square test will be
transferase (ALT), blood urea nitrogen (BUN), and cre- used.
atinine level, serum sodium level, serum potassium level,
and serum chloride level. All subjects are evaluated Discussion
twice, first at the screening visit and once more after Cold hands sensation is a common disorder within the
the termination of acupuncture treatments. To monitor Korean population. In Korea, many physicians believe
the safety of the acupuncture treatment, we will monitor the phenomenon is related to RP, and they may pre-
the occurrence of edema, hemorrhage, and pain as adverse scribe pharmaceutical treatments similar to those used
events. for patients with RP [5,8]. However, there is no estab-
Any reported adverse events will be recorded through- lished guideline for RP therapy, and many of the agents
out the study and vital signs will be monitored at each most frequently used in the treatment of RP are used
visit. The subjects will be asked to voluntarily report off-label [15] and consist mainly of vasodilators, in par-
information about adverse events, and the researcher ticular calcium channel antagonists such as nifedipine.
will confirm the occurrence of adverse events through While these agents have proven useful in some reports
methods such as a medical interview. Details about [14], in about 50% of patients, there is no beneficial
adverse events, such as the date of occurrence, degree of effect [15]. Furthermore, their use has often been associ-
severity, causal relationship with the treatment, other ated with an unacceptably high incidence of side effects
treatments or medications that are suspected to cause including edema, flushing, erythema, dizziness, nausea,
the adverse event, and treatment of the adverse event palpitations, and drowsiness [25,26]. Beraprost is the
will be recorded in detail. first oral prostaglandin analog with vasodilatory and
antiplatelet effects which has been used in the treatment
Withdrawal and dropout of RP. To date, one double blind study has indicated that
All subjects will have the right to withdraw from the there was no difference between oral beraprost and pla-
study at any time. Participation will be ended at any cebo in the treatment of primary RP, and the same study
stage if the subject refuses to continue, withdraws con- found that patients in the beraprost group reported a
sent, or violates the inclusion or exclusion criteria or the significantly higher incidence of side effects including
Seo et al. Trials 2014, 15:348 Page 6 of 7
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doi:10.1186/1745-6215-15-348
Cite this article as: Seo et al.: Acupuncture in subjects with cold hands
sensation: study protocol for a randomized controlled trial. Trials
2014 15:348.

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