w.sciencedirect.com

i n t e r n a t i o n a l j o u r n a l o f nu r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3

HOSTED BY Available online at ww

ScienceDirect

journal homepage: ht tp: / /www.elsevier .com/journals / internat ional -journal -of -nursing-sciences/2352-0132

Original Article

Efficacy of combining traditional Chinese medicinefumigation with Western medicine for diabeticperipheral neuropathy: A systematic review andmeta-analysis

Lei Zhang a, Xu Tian a, Yue Ma b, Ying-Hui Jin c, Fan-Jie Meng d,*

a Graduate College, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, Chinab Department of Nursing, Shijiazhuang College of Medicine, Shijiazhuang 050061, Chinac School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, Chinad Department of Teachers' Development and Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin

300193, China

a r t i c l e i n f o

Article history:

Received 25 May 2015

Received in revised form

12 July 2015

Accepted 27 July 2015

Available online 18 September 2015

Keywords:

Fumigation

Diabetic

Peripheral neuropathy

Traditional Chinese medicine

* Corresponding author.E-mail address: mfj127@tjutcm.edu.cn (F

Peer review under responsibility of Chinesehttp://dx.doi.org/10.1016/j.ijnss.2015.08.0042352-0132/Copyright © 2015, Chinese Nursinarticle under the CC BY-NC-ND license (http

a b s t r a c t

Objective: A systematic review and meta-analysis was conducted to evaluate the effec-

tiveness of supplementing Western medicine with Traditional Chinese medicine (TCM)

fumigation in patients with diabetic peripheral neuropathy.

Methods: The China Biomedical Literature, Chinese full-text periodical, China National

Knowledge Infrastructure, WanFang, PubMed, EMbase, and Cochrane Library databases

were searched for relevant randomized controlled trials published from inception through

May 2015. The methodological quality of eligible studies was evaluated using the Cochrane

Risk Bias Assessment tool, and summarized effects were calculated using Reviewer Man-

ager 5.1 software. Subgroup analysis was conducted based on the duration of intervention.

Results: The initial search identified 312 relevant studies, of which 40 randomized

controlled trials involving 3497 patients were eligible for analysis. The results indicated

that TCM fumigation significantly improved the curative effects [risk ratio (RR) ¼ 1.34, 95%

CI (confidence interval): 1.29e1.39], common peroneal motor nerve conduction velocity

[standard mean difference (SMD) ¼ 2.93, 95% CI: 2.26e3.61], common peroneal sensory

nerve conduction velocity (SMD ¼ 2.23, 95% CI: 1.46e3.01), and plasma viscosity

(SMD ¼ �1.02, 95% CI: �1.35e0.69) compared to Western medicine alone (all p < 0.01). A

subgroup analysis indicated that the curative effects were significant after 15 days

(RR ¼ 1.31, 95% CI: 1.21e1.42), 30 days (RR ¼ 1.33, 95% CI: 1.26e1.40), and 60 days (RR ¼ 1.50,

95% CI: 1.32e1.71) of combined treatment (all p < 0.01).

.-J. Meng).

Nursing Association.

g Association. Production and hosting by Elsevier (Singapore) Pte Ltd. This is an open access://creativecommons.org/licenses/by-nc-nd/4.0/).

i n t e r n a t i o n a l j o u rn a l o f n u r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3296

Conclusion: TCM fumigation significantly improves the clinical outcomes of diabetic pe-

ripheral neuropathy, though further confirmatory studies are needed.

Copyright © 2015, Chinese Nursing Association. Production and hosting by Elsevier

(Singapore) Pte Ltd. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Diabetic peripheral neuropathy (DPN) is the most common

chronic complication of diabetes mellitus [1]. It is the main

contributor to diabetic foot ulcers, which are responsible for

the majority of non-traumatic amputations, and ultimately

increases the risk for mortality in diabetic patients [2,3]. The

pathogenesis of DPN is not well understood, and current

Western medicines fail to adequately treat this condition [4].

However, Traditional Chinese medicine (TCM) offers consid-

erable advantages overWesternmedicine for the treatment of

chronic diseases and their associated complications. For

example, previous work has shown that TCM fumigation

promotes local circulation of blood and lymphatic fluids via

stimulation of blood vessels and nerves [5]. Nonetheless, data

demonstrating the benefits obtained from TCM fumigation in

DPN patients are inconclusive. This systematic review and

meta-analysis of randomized controlled trials was conducted

in order to evaluate the efficacy of TCM fumigation compared

to Western medicine alone in the treatment of patients with

DPN.

2. Materials and methods

The search and screening of all potential studies, extraction of

data, assessment of study quality, and analysis and reporting

of results in this study were all in accordance with the

Preferred Reporting Items for Systematic Review and Meta-

analysis [6] and Cochrane Handbook for Systematic Reviews

of Interventions Version 5.1.0 [7]. All analyses were conducted

on data extracted from previously published studies; there-

fore, ethical approval and informed consent were not

required.

2.1. Literature search

Two investigators (L. Zhang and X. Tian) independently

searched for potential studies that compared Western medi-

cine and TCM fumigation with Western medicine alone for

treatment of DPN listed in PubMed, EMBASE, the Cochrane

Central Register of Controlled Trials, Google Scholar,

Clinicaltrials.gov (http://clinicaltrials.gov), China Biomedical

Literature, Chinese full-text periodical, Wanfang, and China

National Knowledge Infrastructure databases up through May

2015. The following search terms were used: “diabet*” OR

“diabetes mellitus” (Mesh) AND “peripheral neuropathy” OR

“neuritis” (Mesh) OR “peripheral nerve” OR “peripheral neur*”

AND “Traditional Chinese medicine fumigation” OR “fumiga-

tion*” OR “fumigation” (Mesh) OR “embalm wash” OR “drug

fumigation” AND “randomized controlled trial” (publication

type) OR “randomized controlled trials as topic” (Mesh) OR

“random*” AND human NOT animal. The reference lists of

topic-related reviews and eligible studies were also searched

to include any latent articles and guarantee the recall ratio.

Only studies published in English or Chinese languages were

eligible. Any discrepancies that occurred during the search

and selection of literature were resolved by discussion with a

third investigator (Y. Ma).

2.2. Selection criteria

Selection criteria were specified a priori according to the PICOS

acronym: population, all diabetic patients with DPN were

eligible [8]; interventions and comparisons, studies comparing

the efficacy of Western medicine (methycobal, alprostadil,

alpha lipoic acid, ligustrazine, vitamin B1, vitamin B6, or

epalrestat) plus TCM fumigation or alone; outcomes, the

outcomes included in this study were total effect rate (defined

as self-conscious symptom and tendon reflection improve-

ment, electromyography nerve conduction velocity increase

<5 m/s, or the traditional Chinesemedicine syndrome integral

reduce 30% or higher), nerve conduction velocity, vibration

perception threshold, and plasma viscosity; study design, only

randomized controlled trials were included. Any discrep-

ancies that occurred between authors concerning the eligi-

bility of a studywere resolved by consulting a third author (Y.-

H. Jing) or by consensus.

2.3. Data extraction

The total effective rate and nerve conduction velocity were

extracted as primary outcomes, and vibration perception

threshold and plasma viscosity were specified as secondary

outcome measures of interest in this study. Relevant data

were independently extracted from eligible full-text articles

by two investigators (L. Zhang and F.-J. Meng) using a pre-

designed standardized data extraction form. If essential in-

formation from an included study was incomplete, the cor-

responding author of the original study was contacted. Any

discrepancies that occurred between authors concerning the

extracted data were resolved by consulting a third author (L.

Zhang).

2.4. Quality assessment

The Cochrane Risk of Bias tool released by the Cochrane

Collaboration was used to assess the methodological quality

of each of eligible study [7]. Six domains, including selection,

performance, detection, attrition, reporting, and other biases,

i n t e r n a t i o n a l j o u r n a l o f nu r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3 297

were critically assessed to judge the level of risk of bias of each

included study. Each domainwas rated as “high,” “unclear,” or

“low” bias risk depending on the degree of matching between

information extracted from the study and the assessment

criteria [7].

2.5. Statistical analysis

All analyses and estimations of summary effects were per-

formed using Review Manager 5.3 software (Copenhagen: The

Nordic Cochrane Centre, The Cochrane Collaboration, 2013).

The pooled effect estimates of dichotomous outcomes were

expressed as relative risk (RR) with corresponding 95% confi-

dence intervals (CIs), and the standard mean difference (SMD)

with 95% CI was used to express continuous outcomes such as

nerve conduction velocity. The heterogeneity across studies

was assessed using the Cochrane's Q statistic with corre-

sponding p value and quantified as an I2 statistic; I2 �50% in-

dicates substantial heterogeneity. Meta-analyses was

performed using a random effects model based on the Man-

teleHaenszel method, or a fixed effects model based on an

inverse variance statistical approach according to the clinical

characteristics and methodologies of the pooled studies. A

subgroup analysis was conducted according to duration of

intervention. Stata 12.0 software (StataCorp, LP, College Sta-

tion, TX, USA)was used to perform an Egger's linear regressionanalysis and construct a funnel plot to assess publication bias.

For all results, a p < 0.05 was considered statistically

significant.

3. Results

3.1. Study identification and selection

The initial search identified 312 articles, which were system-

atically sorted using EndNote (version 7.1) software (Thomson

Reuters, New York, NY, USA). Of these, 112 articles were

eliminated due to duplication and 103 were excluded after

screening the title and abstract. The full-text of the remaining

studies were examined, and 57 studies were excluded because

their topic of study did not meet our inclusion criteria. Thus,

40 studies [9e48] were eligible for inclusion in the meta-

analysis (Fig. 1).

3.2. Study characteristics

The characteristics of the included studies are shown in Table

1. The studies were published between 2007 and 2015, and all

were planned and performed by researchers in China. The

sample size of each study ranged from 50 to 320 for a total of

3497 patients.

3.3. Risk of bias

Of all included studies, 14 [9,12,17,24,27,35e39,43e45,48] con-

ducted appropriate randomization methods, such as the use

of random number table; one study [38] utilized a sealed

opaque envelope and a specific coordinator to carry out the

randomization of group assignment. Only one study [45]

utilized blinding of the investigators. Although the number

and reason for study dropout were reported in three studies

[17,38,39], intention-to-treat was not adopted to analyze the

results. Nine [9,12,13,16,22e25,30] studies did not report the

results of the outcomemeasures of interest. An assessment of

risk of bias indicated that the overall quality of the included

studies was low (Table 1).

3.4. Total effective rate

A total of 37 studies [9e11,13e33,35e47] comprising 3289 pa-

tients reported the total effective rate. A fixed effects model

was used to calculate the summary effect estimate, as no

clinical characteristics or methodological differences were

detected among these studies and there was no significant

heterogeneity (I2 ¼ 0%, p ¼ 0.53). The results indicated a sig-

nificant difference between groups treated with Western

medicine plus TCM fumigation and Western medicine alone

(RR ¼ 1.34; 95% CI: 1.29e1.39; p < 0.01).

Subgroup analyses of this outcome were conduced based

on the duration of intervention (Fig. 2). Nine studies

[11,13e17,42,46,47] comprising 627 patients reported the 15-

day total effective rate. There was no significant heterogene-

ity among these studies (I2 ¼ 0%, p ¼ 0.52), therefore, a fixed

effects model was used. The pooled result indicated that the

addition of TCM fumigation significantly improved the treat-

ment of DPN patients (RR ¼ 1.31, 95% CI: 1.21e1.42; p < 0.01).

Similar results were found with additional subgroup analyses

for treatments after 20 days, 30 days, 40 days, and 60 days (all

p < 0.01). Only one study [10] determined the total effective

rate 10 days after implementing interventions and found no

significant difference between TCM fumigation and Western

medicine alone.

3.5. Nerve conduction velocity

Common peroneal motor nerve conduction velocity was re-

ported in twelve of the included studies [19,28,29,31e38,40],

which were divided into three subgroups according to when

the evaluations were conducted after implementing in-

terventions: 30 days [19,28,29], 40 days [31e33], and 60 days

[34e38]. Significant heterogeneity was only detected in the 30-

day subgroup (I2 ¼ 94%, p < 0.01), thus the random effects

model was used for this evaluation. The results of thesemeta-

analyses showed that supplementation of Western medicine

with TCM fumigation significantly improved common pero-

neal motor nerve conduction velocity in patients with DPN (all

p < 0.05) (Table 2). Similar effects were found with studies

evaluating the conduction velocities in the median and tibial

nerves (both p < 0.01).

Sensory nerve conduction velocity was evaluated in the

common peroneal nerve after 40 days in two studies [31,32]

and after 60 days of treatment in six studies [34e38,40]. No

statistical heterogeneity was detected, therefore, a fixed ef-

fects model was used. The results indicated that TCM fumi-

gation significantly improved common peroneal sensory

nerve conduction velocity in patients with DPN (both p < 0.01)

(Table 2). Similar effects were found with studies evaluating

the conduction velocities in the median sensory nerve (both

p < 0.01).

Records iden fied through database searching

(n = 306)

Screen

ing

Includ

edEligibility

Iden

fica

on

Addi onal records iden fied through other sources

(n = 6)

Records a er duplicates removed

(n = 200)

Records screened(n = 97)

Records excluded(n = 103)

Full-text ar cles assessed for eligibility

(n = 40)

Full-text ar cles excluded:

non-RCTs (n = 19)Duplica ons (n = 21)Interven on did not conform with inclusion criteria (n = 17 )

Studies included in qualita ve synthesis

(n = 40)

Studies included in quan ta ve synthesis

(meta-analysis)(n = 39)

Fig. 1 e Flowchart of the study selection. RCT ¼ randomized controlled trial.

i n t e r n a t i o n a l j o u rn a l o f n u r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3298

3.6. Vibration perception threshold

Two studies [14,48] including 128 patients reported vibration

perception thresholds assessed 15 days after initiating ther-

apy. There was no significant heterogeneity between the

studies (I2 ¼ 0%, p ¼ 0.58), therefore, a fixed effects model was

used. The results showed that there was no significant dif-

ference between TCM fumigation and Western medicine

compared to Western medicine alone in reducing the vibra-

tion perception threshold (mean difference ¼ �1.53, 95% CI:

�3.65e0.59; p ¼ 0.16).

3.7. Plasma viscosity

Two studies [35,39] including 175 patients reported on plasma

viscosity. There was no significant heterogeneity between the

studies (I2 ¼ 0%, p ¼ 0.44), therefore, a fixed effects model was

used. The results indicated that, compared with Western

medicine alone, the addition of TCM fumigation significantly

decreased plasma viscosity in patients with DPN

(SMD ¼ �1.02, 95% CI: �1.35e0.69; p < 0.01).

3.8. Publication bias

A funnel plot was constructed to evaluate the potential for

publication bias with regard to the total effective rate. The

results of an Egger's linear regression indicated that there was

no significant publication bias (t ¼ 1.29; p ¼ 0.21) (Fig. 3).

4. Discussion

The increase in the prevalence of diabetes mellitus has led to

an increase in the incidence of DPN [5]. This loss of sensation

from the neuropathy can seriously reduce the patient's qualityof life, as well as lead to diabetic foot ulcers and gangrene, or

even amputation [49]. Although the pathogenesis of DPN is

complex, it is influenced by factors such as metabolism, blood

vessels, neurotrophins, and oxidative stress [50]. As a conse-

quence, effective treatments are urgently needed.

A multitude of Western medicines have been developed to

control DPN. These include such compounds as a methycobal

[51], which can reduce limb numbness and pain, alpha lipoic

Table 1 e Characteristics and quality of included studies.

Study Number ofpatients (T/C)

Interventions Outcomes Risk of bias

T C Adequatesequencegeneration

Allocationconcealment

Blinding Incompleteoutcome

data

Selectivereporting

Otherbias

Kong C X et al., 2011 [10] 25/25 A þ B B( ) I U U U Yes Yes U

Xiao J H et al., 2013 [11] 30/30 A þ B B( ) I þ II U U U Yes Yes U

Song H L et al., 2011 [12] 40/40 A þ B B( ) II Yes U U Yes No U

Wan L et al., 2008 [13] 30/30 A þ B B( ) I þ II U U U Yes No U

Liu T et al., 2012 [48] 34/34 A þ B B( ) IV Yes U U Yes Yes U

Xiong XD et al., 2013 [14] 30/30 A þ B B( ) I þ IV U U U Yes Yes U

Hu G et al., 2012 [15] 25/25 A þ B B( ) I U U U Yes Yes U

Che S S et al., 2010 [16] 60/58 A þ B B( ) I U U U Yes No U

Shen et al.,L X 2012 [17] 34/30 A þ B B( ) I þ II Yes U U No Yes U

Huang et al., P 2008 [27] 64/64 A þ B B( ) I þ II Yes U U Yes Yes U

Chen J et al., 2009 [18] 30/30 A þ B B( ) I U U U Yes Yes U

Gao M S et al., 2011 [19] 42/42 A þ B B( ) I þ II U U U Yes Yes U

Zhang XN et al., 2013 [20] 20/20 A þ B B( ) I þ III þ IV U U U Yes Yes U

Hu X J et al., 2013 [21] 160/160 A þ B B( ) I þ IV U U U Yes Yes U

Hao D et al., 2011 [22] 51/47 A þ B B( ) I U U U Yes No U

Huang Z et al., 2007 [23] 40/38 A þ B B( ) I U U U Yes No U

Zhang S F et al., 2013 [24] 60/60 A þ B B( ) I Yes U U Yes No U

Hu X L et al., 2007 [25] 40/38 A þ B B( ) I U U U Yes No U

Wang Y F et al., 2011 [26] 30/30 A þ B B( ) I U U U Yes Yes U

Zhu N et al., 2012 [9] 56/56 A þ B B( ) I Yes U U Yes No U

Chen J Y et al., 2009 [28] 40/40 A þ B B( ) I þ II U U U Yes Yes U

Li Q et al., 2009 [29] 150/150 A þ B B( ) I þ II U U U Yes Yes U

Li Q et al., 2010 [30] 30/30 A þ B B( ) I U U U Yes No U

Ding Y et al., 2011 [31] 50/50 A þ B B( ) I þ II U U U Yes Yes U

Fan G J et al., 2010 [32] 34/28 A þ B B( ) I þ II U U U Yes Yes U

Meng QH et al., 2010 [33] 40/40 A þ B B( ) I þ II U U U Yes Yes U

Wang ZX et al., 2012 [34] 30/30 A þ B B( ) II U U U Yes Yes U

Qiu X T et al., 2013 [35] 80/40 A þ B B( ) I þ II þ III Yes U U Yes Yes U

Hou S F et al., 2010 [36] 30/30 A þ B B( ) I þ II Yes U U Yes Yes U

Xu Q S et al., 2009 [37] 30/30 A þ B B( ) I þ II Yes U U Yes Yes U

Li M D et al., 2009 [38] 31/30 A þ B B( ) I þ II Yes Yes U No Yes U

Guan Y H et al., 2009 [39] 28/27 A þ B B( ) I þ III þ IV Yes U U No Yes U

Wu X et al., 2014 [40] 40/40 A þ B B( ) I þ II U U U Yes Yes U

Shao G J et al., 2015 [41] 35/33 A þ B B( ) I U U U Yes Yes U

Su W B et al., 2014 [42] 42/42 A þ B B( ) I þ II U U U Yes Yes U

Qin Y et al., 2015 [43] 34/34 A þ B B( ) I þ IV Yes U U Yes Yes U

Pan Z W et al., 2014 [44] 60/60 A þ B B( ) I Yes U U Yes Yes U

Li Y X et al., 2015 [45] 30/30 A þ B B( ) I Yes No Yes Yes Yes U

Liu M et al., 2015 [46] 36/35 A þ B B( ) I U U U Yes Yes U

Chen Y F et al., 2015 [47] 30/30 A þ B B( ) I U U U Yes Yes U

A ¼ traditional chinese medicine fumigation; B¼ common therapy including foundational treatments (insulin, diet, sports, health education) andWestern medicine; C¼ control group; I¼ total effect

rate; II ¼ nerve conduction velocity; III ¼ blood viscosity; IV ¼ vibration perception thresholds; T ¼ experimental group; U ¼ unclear.

Western Medicines: Oral methycobal; Intramuscular methycobal; Intravenous drip alprostadil; Intravenous drip alpha lipoic acid; Intravenous drip methycobal; Intravenous drip lig-

ustrazine; Intravenous push note methycobal; Intramuscular vitamin B1; Intramuscular vitamin B6; Oral vitamin B1; Oral vitamin B6; Oral epalrestat.

internatio

naljo

urnalofnursin

gscie

nces

2(2

015)295e303

299

Fig. 2 e Forest plots showing results of meta-analyses comparing patients treated with Traditional Chinese and Western

medicines (experimental) and Western medicine alone (control).

i n t e r n a t i o n a l j o u rn a l o f n u r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3300

Table 2 e Meta-analyses on nerve conduction velocity.

Outcomes Included studies No.of patients

Effect size Heterogeneity Test for overall effect

n Ref. MD/SMD (95%CI) c2 value p value I2 Z value p value

Motor nerve conduction velocity

Common peroneal nerve

After 30 days of treatmenta 3 [19,28,29] 464 4.72 (0.41e9.03) 32.40 <0.01 94% 2.15 0.03

After 40 days of treatment 3 [31e33] 242 3.45 (2.85e4.05) 0.80 0.67 0% 11.30 <0.01After 60 days of treatment 6 [34e38,40] 441 2.93 (2.26e3.61) 8.75 0.12 43% 8.52 <0.01Median nerve

After 15 days of treatment 2 [11,13] 120 10.23 (8.74e11.72) 0.50 0.48 0% 13.45 <0.01Tibial nerve

After 30 days of treatmenta 3 [19,28,29] 464 4.73 (2.18e7.28) 10.27 <0.01 81% 3.64 <0.01Sensory nerve conduction velocity

Common peroneal nerve

After 40 days of treatment 2 [31,32] 168 2.30 (1.30e3.30) 0.08 0.78 0% 4.50 <0.01After 60 days of treatment 6 [34e38,40] 441 2.23 (1.46e3.01) 2.61 0.76 0% 5.64 <0.01Median nerve

After 40 days of treatment 2 [31,32] 168 2.50 (1.29e3.71) 1.10 0.29 9% 4.05 <0.01After 60 days of treatment 4 [35e37,40] 320 2.63 (1.68e3.58) 2.56 0.46 0% 5.41 <0.01

CI ¼ confidence interval; MD ¼ mean difference; SMD ¼ standard mean difference.a Random-effects model.

i n t e r n a t i o n a l j o u r n a l o f nu r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3 301

acid [52], an antioxidant that helps restore nerve function, and

alprostadil [53], which improves circulation and thus pro-

motes recovery of nerve function. Interestingly, a recent

meta-analysis concluded that supplementation of Western

medicines with TCM decoction significantly improved treat-

ments for DPN [54]. The results of the current meta-analysis

support these findings, showing that TCM fumigation can

also significantly improve patient outcomes, specifically, the

total effective rate and limb sensory and motor nerve con-

duction velocities.

Diabetes mellitus belongs to the “Xiaoke” category within

TCM, with corresponding neurologic complications classified

as “Bizheng,” “Xuebi,” and “Weizheng.” In the TCM system,

DPN is characterized by pain, numb, stasis, and stubborn, and

is termed “Xiaoke-Bizheng.” [5] It is further divided into five

subtypes based on various pathogeneses, such as “deficiency

of both qi and yin,” “phlegm stasis Bizu,” “blood stasis

obstructing the collaterals,” “yang deficiency and cold,” and

“liver-wind stirring” [55]. According to the principle of dia-

lectic therapy, TCMs, such as safflower, cassia twig, ferlate,

angelica, and tougucao, were the ones commonly used in the

studies included in this meta-analysis. The reported effects of

Fig. 3 e Funnel plot for publication bias.

these are as follows: safflower activates the blood and

removes stasis, cassia twig warms channels and dredges

collaterals, thus activating yang-fluidizing chi, dispelling the

cold, and relieving pain; angelica alsowarms and activates the

blood to regulate the channels, relieve pain, and can be used

for blood deficiency and stasis; tougucao promotes dehu-

midification, relaxation of the muscles, stimulates blood cir-

culation, and acts as an analgesic [56]. Combinations of these

TCMs have a synergistic effect [57]. Moreover, pharmacologic

research has confirmed that safflower [58,59], cassia twig

[60e62], ferlate [63,64], angelica [65], and tougucao [66] have

analgesic, anti-inflammatory, antianaphylactic, antibacterial,

and antioxidant effects, and reduce blood lipids levels and

viscosity and reduce peripheral vascular resistance.

The results presented here show significant improvement

in almost all outcomes measured. In particular, nerve con-

duction velocities and plasma viscosity were significantly

improved in groups who also received TCM fumigation.

However, two studies [14,48] evaluated vibration perception

thresholds, and found that there was no significant effect of

TCM fumigation. It is possible that the lack of significance was

due to the early assessment (after 15 days), which may not

have been sufficient time to effectively influence vibration

perception thresholds.

There are some limitations of the currentmeta-analysis that

should be noted. First, the TCM fumigation regimes varied

among the included studies, which could potentially influence

the results. Second, assessment of bias was difficult inmany of

the studies because of unclear and inadequate descriptions of

methodologies. Overall, thequality of the studieswasquite low.

Thus, additional, high-quality studies are needed to more

accurately assess the benefits of TCM fumigation.

5. Conclusion

The results of this systematic review andmeta-analysis show

that supplementation of Western medicine with TCM

i n t e r n a t i o n a l j o u rn a l o f n u r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3302

fumigation significantly improves DPN patient outcomes.

TCM fumigation improved the total effective rate, nerve con-

duction velocity, and plasma viscosity within 15 days of

treatment. However, these results should be interpreted with

caution due to the low quality of included studies. Additional,

high-quality, large-scale randomized controlled trials are

warranted to confirm these beneficial effects.

Contributors

Lei Zhang, Xu Tian, Yue Ma, Ying-Hui Jin, and Fan-Jie Meng

conceived of and designed the protocol. Lei Zhang, Xu Tian,

and Yue Ma searched and selected the studies. Lei Zhang and

Xu Tian collected and analyzed the data. Lei Zhang, Xu Tian,

and Ying-Hui Jin wrote the manuscript. All authors carefully

reviewed the manuscript and approved this submission.

Competing interests

These authors have declared that there are no competing

interests.

r e f e r e n c e s

[1] Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM,et al. The prevalence by staged severity of various types ofdiabetic neuropathy, retinopathy, and nephropathy in apopulation-based cohort: the Rochester Diabetic NeuropathyStudy. Neurology 1993;43:817e24.

[2] Prompers L, Schaper N, Apelqvist J, Edmonds M, Jude E,Mauricio D, et al. Prediction of outcome in individuals withdiabetic foot ulcers: focus on the differences betweenindividuals with and without peripheral arterial disease. TheEURODIALE Study. Diabetologia 2008;51:747e55. http://dx.doi.org/10.1007/s00125-008-0940-0.

[3] Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL,Freeman R, et al. Diabetic neuropathies: a statement by theAmerican Diabetes Association. Diabetes Care2005;28:956e62.

[4] Liu GW. Effect of cobamamide on diabetic neuropathies.Chin Med J Engl 1998;38:14e7.

[5] Li JH. Study on the curative effects and mechanisms ofwenjingtongluo xunxifang to diabetes mellitus peripheralneuropathy disease patients. Guangzhou University ofTraditional Chinese Medicine; 2008.

[6] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferredreporting items for systematic reviews and meta-analyses:the PRISMA statement. Int J Surg 2010;8:336e41. http://dx.doi.org/10.1016/j.ijsu.2010.02.007.

[7] Higgins JPT, Green S. Cochrane handbook for systematicreviews of interventions version 5.1.0 (updated March 2011).2008.

[8] Lv RH. The diagnosis and treatment of Chinese and westernmedicine of II-diabetic and complications. 1997. p. 390e4.

[9] Zhu N, Cao XM, Fang CH. The observation of Chinesemedicine embalm wash party coalition cobamamide treatingdiabetic peripheral neuropathy 56 cases. Yunnan J TraditChin Med 2012;33:32e3.

[10] Kong CX, Chen W. The clinical effect of the treatmenttraditional Chinese medicine medicated bath of diabeticperipheral neuropathy. Seek Med Ask Med 2011;9:347.

[11] Xiao JH, Wang X, Qiao P. The clinical experience oftraditional Chinese medicine fumigation treatment ofdiabetic peripheral neuropathy of 60 cases. Cap Med2013;7:82e3.

[12] Song HL. Clinical observation on treating lower extremitydiabetic peripheral neuropathy by TCM fumigation. Clin JChin Med 2011;3:1e2.

[13] Wan L, Pan SB. The Chinese medicine fumigation auxiliarytreatment of diabetic peripheral neuropathy. Hubei J TraditChin Med 2008;30:30e1.

[14] Xiong XD. Efficacy of Chinese medicine fumigationcombination of alpha lipoic acid of vibration sensorythresholds in patients with diabetic peripheral neuropathy.World Heal Dig Med Period 2013;10:402e3.

[15] Hu G. The treatment of Tougu scattered fumigationcombined a cobamamide of diabetic peripheral neuropathy.Shanxi J Tradit Chin Med 2012;28:42e3.

[16] Che SS. The nursing experience of Chinese medicinefumigation auxiliary in treating diabetic peripheralneuropathy. J Emerg Tradit Chin Med 2010;12:528e9.

[17] Shen LX. The clinical observation a cobamamide combinedtraditional Chinese medicine for the treatment of diabeticperipheral neuropathy. J Pract Diabetol 2012;8:42e4.

[18] Chen J, Sang W, Zheng CH. The clinical observation oftongluo fumigation on treatment of diabetic peripheralneuropathy. J Pract Tradit Chin Intern Med 2009;23:58e9.

[19] Gao MS, Peng C, Tan Y. A summary of Chinese medicinefumigation combined with cobamamide of treating diabeticperipheral neuropathy in 42 cases. Guid J Tradit Chin MedPharm 2011;17:52e3.

[20] Zhang XN, Zhang XK, Li RY. Chinese medicine fumigation inthe treatment of type 2 diabetes peripheral neuropathy 40cases. J Shanxi Coll Tradit Chin Med 2011;4:61e2.

[21] Hu XJ, Yang HX, Li T, Li XH. Tongluo Zhitong No.1 fumigationtreatment of 320 cases of diabetic peripheral neuropathy. JShanxi Tradit Chin Med 2013;34:44e6.

[22] Hao D. Chinese fumigation treatment of 98 cases of diabeticperipheral neuropathy. J Pract Tradit Chin Intern Med2011;25:63e4.

[23] Huang Z. Chinese medicine fumigation auxiliary treatmentof 40 cases of diabetic peripheral neuropathy. J ZhejiangTradit Chin Med 2007;42:435.

[24] Zhang SF, Pan ZW, Qian CF, Tan XD, Liang HM. Xibifangfumigation combined with western medicine inrandomized parallel control study on treatment of diabeticperipheral neuropathy. J Pract Tradit Chin Intern Med2013;27:95e6.

[25] Hu XL. The observation and nursing of traditional Chinesemedicine fumigation for diabetes peripheral neuropathy oflower limbs. Tianjin J Nursin 2007;15:275e6.

[26] Wang YF. The curative effect of Yiqi huoxue tongluofumigation of diabetic peripheral neuropathy. Chin ForeignMed Res 2011;9:59e60.

[27] Huang P, Zheng JH. The western medicine combinedtraditional Chinese medicine fumigation for the treatment of64 cases of type 2 diabetes peripheral neuropathy. J PractMed 2008;24:853e4.

[28] Chen JY, Ying ZH. Chinese medicine fumigation incombination with cobamamide: a clinical observation ontreatment of diabetic peripheral neuropathy. J Emerg TraditChin Med 2009;19:901.

[29] Li Q, Wu Q, Wu WD, Cao YY, Xiong L. The treatment ofChinese medicine fumigation of 150 cases diabeticperipheral neuropathy. Yunnan J Tradit Chin Med2009;30:26e8.

[30] Li Q, Xu YP. Chinese medicine fumigation care for thetreatment of diabetic peripheral neuropathy. Yunnan J TraditChin Med 2010;31:73e4.

i n t e r n a t i o n a l j o u r n a l o f nu r s i n g s c i e n c e s 2 ( 2 0 1 5 ) 2 9 5e3 0 3 303

[31] Ding Y. Chinese medicine wash outside on treatment of 50cases of diabetic peripheral neuropathy: a clinicalobservation. J Trait Med 2011;23:140e1.

[32] Fan GJ, Tang XY, Liu ZH, Wei H, He L, Zou DY, et al. Theclinical observation of traditional Chinese medicinecombination of cobamamide on treatment of diabeticperipheral neuropathy. J New Chin Med 2010;42:27e8.

[33] Meng QH, Chen JL. The cobamamide combined withtraditional Chinese medicine bubble foot in treatment ofdiabetic peripheral neuropathy: a clinical observation. Clin JTradit Chin Med 2010;22:675e6.

[34] Wang ZX, Qian Q, Liang YW, Hu J, Xia WW, Jin J. Study theeffect of huangqi guizhi wuwu tang fumigation treatment ofdiabetic peripheral neuropathy. Mod Hosp 2012;12:21e4.

[35] Qiu XT, Zhang YJ. A clinical observation on traditionalChinese medicine fumigation treatment of diabeticperipheral neuropathy. Chin J Chin Med Inf TCM2013;20:74e5.

[36] Hou SF, Huang SL, Guan GD. Fracture lotion fumigation No.1combined with cobamamide: a clinical observation of 30cases of diabetic peripheral neuropathy. Guang Ming J ChinMed 2010;25:1063.

[37] Xu QS, Lu LY, Zhang HL. The medicated bath foot combinedwith cobamamide treatment of diabetic peripheralneuropathy 30 cases. J Jiangxi Tradit Chin Med 2007;40:33e4.

[38] Li MD, Lin L, Sun SC, Ni Q, Su H. Clinical study of Chineseherb formula tangtongfang by bathing the affected feet withdiabetic peripheral neuropathy. Chin J Rehabil Theory Pract2009;15:553e5.

[39] Guan YH. The observation of clinical effect tougusanfumigation therapy on patients with deficiency of both Qiand Yin with blood stasis and diabetic peripheralpolyneuropathy. Nanjing University of Chinese Medicine;2009.

[40] Wu X, Luo DZ, Wang QH. A research of Chinese medicinewith prostaglandin for diabetic peripheral neuropathy. JPract Tradit Chin Med 2014;30:535e6.

[41] Shao GJ, Wang XJ. TCM fumigation and epalrestat intreatment of diabetic peripheral neuropathy. Liaoning JTradit Chin Med 2015;42:291e2.

[42] Su WB, Li ZY, Liu XC. A clinical research of TCM fumigationfor diabetic peripheral neuropathy. Lishizhen Med MaterMedica Res 2014;25:2714e6.

[43] Qin Y, Hu XJ. Western medicine combined dredgingcollaterals analgesic powder no. 2 for diabetic peripheralneuropathy of 68 patients. J Pract Tradit Chin Med2015;30:410.

[44] Pan ZW, Zhang SF, Tan XD. The effect of Xiaobifang intreatment of 2-diabetes mellitus peripheral neuropathy. NewJ Tradit Chin Med 2014;46:128e9.

[45] Li YX. TCM fumigation for the treatment of Xiaokebizheng.Res Integr Tradit Chin West Med 2015;7:23e4.

[46] Liu M, Zhang XK. TCM fumigation witha-lipoic acid for thetreatment of diabetic peripheral neuropathy of 36 patients. JPract Tradit Chin Med 2015;31:232e3.

[47] Chen YF, Du YH, Huo Y. The effect of TCM fumigation fordiabetic peripheral neuropathy of 30 patients. Yunnan JTradit Chin Med Mater Medica 2015;36:39e40.

[48] Liu T, Huang Z, Wei AS, Mai WH, Liang XF. The randomparallel control study of total symptoms score (TSS) andvibration perception threshold in diabetic peripheralneuropathy patients treated with Chinese herb fumigationcombined with alpha lipoic acid. J Pract Med Tradit ChinIntern Med 2012;26:57e9.

[49] Lu ZQ. Progress in diagnosis and treatment of diabeticperipheral neuropathy. Drug Eval 2013;10:35e45.

[50] Liu YL. A review of pathogenesis and treatment of diabeticperipheral neuropath. Youjiang Med J 2011;33:356e8.

[51] Li G. Effect of mecobalamin on diabetic neuropathies. Beijingmethycobal clinical trial Collaborative group. Zhonghua NeiKe Za Zhi 1999;38:14e7.

[52] Scaramuzza A, Giani E, Redaelli F, Ungheri S, Macedoni M,Giudici V, et al. Alpha-lipoic acid and antioxidant diet help toimprove endothelial dysfunction in adolescents with type 1diabetes: a pilot trial. J Diabetes Res 2015;2015:474561. http://dx.doi.org/10.1155/2015/474561.

[53] Luo C, Li T, Zhang C, Chen Q, Li Z, Liu J, et al. Therapeuticeffect of alprostadil in diabetic nephropathy: possible roles ofangiopoietin-2 and IL-18. Cell Physiol Biochem2014;34:916e28. http://dx.doi.org/10.1159/000366309.pii:000366309.

[54] Xu ZY. Effect of Chinese decoction therapy for diabeticperipheral neuropathy: a meta-analysis. Liaoning Universityof Chinese Medicine; 2013.

[55] Wu Y. Clinical effects of quyutongluo washing decoction onpatients with diabetic peripheral neuropathy. HubeiUniversity of Chinese Medicine; 2011.

[56] Gao XM. Traditional Chinese pharmacology. 2002.[57] Liu Y, Ding HS. Class tougucao progress in the study of

traditional Chinese medicine. Inf Tradit Chin Med1999;16:10e2.

[58] Yang ZF, Mei QB, Jiang YP. Active constituents andpharmacological effects of safflower. Northwest Pharm J2001;16:131e3.

[59] Zhao G, Wan AH. Safflower resource and its medicinal value.Chin Wild Plant Resour 2004;23:24e5.

[60] Zhao JH, Liu SY. Pharmacological action and clinical of cassiatwig. Med Inf 2011;24:1575.

[61] Zhao JY. New pharmacological research and clinical use ofcassia twig. Guang Ming J Chin Med 2010;25:1546.

[62] Zhao Y. A discussion of cassia twig of modern pharmacologyand clinical application. Chin Med Mod Distance Educ China2009;7:77e8.

[63] Li QY, Gan GP, Liu YW. Chemical components andpharmacological research progress of rhizoma ligusticiwallichii. Lishizhen Med Mater Med Res 2006;17:1298.

[64] Qu P. Ligustici wallichii pharmacological effects: a review.Inn Mong J Tradit Chin Med 2010;29:78e9.

[65] Xia Q, Zhang P, Zhang SP, Wang YT. Pharmacological effectsof angelica sinennsis: a review. Lishizhen Med Mater MedRes 2004;15:164e6.

[66] Wang X, Xiao ZP. Comparative studies of Chinese drugtougucao on anti-inflammatory and analgesic effects. JBeijing Med Univ 1998;30:145e7.