Study Protocol Systematic Review Medicine ®

OPEN

Effects of Guizhi decoction for diabetic cardiac

autonomic neuropathy
A protocol for a systematic review and meta-analysis
Junmin Chen, MMa , Jiawei Cai, MMa, Mengya Wei, MMa, Xiaoran Zhang, MDa, Min Zhong, MMa,
∗ ∗
Min Liu, MMa, Yang Yu, MDb, , Qiu Chen, PhDa,

Abstract
Background: Diabetic cardiac autonomic neuropathy (DCAN) is one of the serious complications of diabetes. The pathogenesis of
DCAN has not been fully elucidated. There is currently no effective treatment for such chronic disease. Traditional Chinese medicine
has a long clinical history for the prevention and treatment of diabetes and chronic complications, and it also shows certain
advantages in the treatment of DCAN. Many clinical studies have confirmed that Chinese medicine Guizhi decoction can reduce the
clinical symptoms and improve neuronal function of patients with DCAN. So we intend to conduct a systematic review further clarified
the effectiveness and safety of Guizhi decoction for DCAN.
Methods: We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library,
PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database.
Simultaneously we will retrieval clinical registration tests and grey literatures. In this study, only the clinical randomized controlled trials
(RCTs) were selected to evaluate the efficacy and safety of Guizhi decoction in the treatment of DCAN. The 2 researchers
independently conducted literature selection, data extraction, and quality assessment. Statistical heterogeneity among studies will be
evaluated using the Cochran Q test (x2) and the I2 statistical value. We will utilize the Review Manage software V5.3.0 (The Nordic
Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark) to statistically analyze all data.
Ethics and dissemination: This study is a protocol for a systematic review of Guizhi decoction as a treatment of DCAN patients.
Results: This study will provide high-quality synthesis of effectiveness and safety of Guizhi decoction for DCAN.
Conclusion: This systematic review aims to provide new options for Guizhi decoction treatment of DCAN in terms of its efficacy
and safety.
Registration number: INPLASY202080018.
Abbreviations: CANs = Cardiac autonomic nerves, CI = confidence interval, DCAN = diabetic cardiac autonomic neuropathy,
MD = mean difference, RCT = randomized controlled trial, RR = risk ratio, SMD = standardized mean difference.
Keywords: diabetic cardiac autonomic neuropathy, Guizhi decoction, meta-analysis, protocol, systematic review

JC and JC contributed equally to this work as co-first authors.

This study was supported by the Key R & D plan of the Ministry of science and technology of the people’s Republic of China: Research on the Academic Viewpoints,
Unique Diagnostic and Treatment Methods and Major Diseases Prevention and Treatment Experience of Illustrious Senior Traditional Chinese Medicine Practitioners in
Western China (No. 2018YFC1704104).
Taking into account the systematic review of this protocol, ethical ratification is not required. In this study, participants were not recruited and data were not collected
from participants. The review will be disseminated through peer-reviewed publications.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
a
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, b College of acupuncture and massage, Chengdu University of Traditional Chinese Medicine
, No 37 Shi-er-qiao Road, Chengdu, Sichuan Province, PR China.
∗
Correspondence: Qiu Chen, Medical Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, No 39 Shi-er-qiao Road, Chengdu
610072, Sichuan Province, PR China (e-mail: chenqiu1005@cdutcm.edu.cn); Yang Yu, College of acupuncture and massage, Chengdu University of Traditional Chinese
Medicine , No 37 Shi-er-qiao Road, Chengdu 610075, Sichuan Province, China (e-mail: zj110110@163.com).
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Chen J, Cai J, Wei M, Zhang X, Zhong M, Liu M, Yu Y, Chen Q. Effects of Guizhi decoction for diabetic cardiac autonomic neuropathy: A
protocol for a systematic review and meta-analysis. Medicine 2020;99:39(e22317).
Received: 19 August 2020 / Accepted: 20 August 2020
http://dx.doi.org/10.1097/MD.0000000000022317

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Chen et al. Medicine (2020) 99:39 Medicine

1. Introduction (RCTs) about Guizhi decoction for DCAN based on the basis of
Cardiac autonomic nerves (CANs) include the sympathetic nerve evidence-based medicine, and conduct a meta-analysis of its
and the vagus nerve, which check and balance each other and efficacy and safety to provide higher quality clinical evidence for
play important roles in the regulation of heart rate, conduction, Chinese medicine treatment of DCAN.
and cardiac contractility. Diabetic cardiac autonomic neuropathy
(DCAN) is one of the severe complications of diabetes mellitus; 2. Methods
damage of CANs in a high glucose environment causes
sympathetic-vagal imbalance,[1,2] which thus causes abnormal 2.1. Protocol registration
neurotransmitter signaling and increased asynchronization of The systematic review protocol has been registered on the
cardiac electrophysiology.[3,4] About 2.5% to 50.0% of diabetic LNPLASY website as INPLASY202080018. (https://inplasy.
patients have cardiac autonomic neuropathy.[5] It is reported that com/inplasy-2020-8-0018/). It is reported following the guide-
diabetic cardiac autonomic neuropathy is easy to be ignored in lines of Cochrane Handbook for Systematic Reviews of
many complications of diabetes. Because the balance of cardiac Interventions and the Preferred Reporting Items for Systematic
autonomic nerves is broken, the incidence of myocardial Reviews and Meta-analysis Protocol (PRISM).[20]
ischemia, painless myocardial infarction and sudden cardiac
death is increased,[6] and the mortality rate within 5 years is as
2.2. Eligibility criteria
high as 50%, of which sudden cardiac death accounts for 2.2.1. Study design. This study only included RCTs of Guizhi
28%.[2,7,8] Compared with the patients without DCAN, the decoction for DCAN. However, animal experiments, reviews,
mortality increased 3 to 4 times.[9,10] The time variability of left case reports, and non-randomized controlled trials are excluded.
ventricular repolarization in DCAN patients increased, and the
proportion of malignant arrhythmia caused by it in the cause 2.2.2. Participants. DCAN patients must meet the World
analysis of sudden death was 50% to75%.[11] According to a Health Organization (WHO) “diabetes” diagnosis standard
research, strict blood sugar control could slow the progression of in 1999.[21] The diagnosis standard of cardiac autonomic
CAN diseases but could not reverse CAN pathological neuropathy shall refer to Toronto standard and European
changes.[12] Therefore, in addition to protecting the sympathetic cardiovascular disease prevention guidelines,[22,23] regardless of
and vagus nerves from further damage, regulation of the race, gender, and age. Special patients with severe diabetic
imbalance of these 2 nerves is even more important for the complications, severe cardiac insufficiency, pregnancy, etc. are
treatment of diabetic CAN diseases. Because the pathogenesis of not included.
the disease has not been fully elucidated, western medicine lacks
the corresponding treatment plan, some drugs interfere with 2.2.3. Interventions. Both groups were cured with conventional
glycolipid metabolism, drug target is single, the safety, and diabetes treatments recommended by the American Diabetes
effectiveness need to be further confirmed.[13] Our previous Association (ADA) guidelines, including diet, exercise, and
studies have shown that based on the treatment methods of hypoglycemic, and lipid-lowering therapies.[24] The experiment
balancing yin and yang and harmonizing Ying and Wei in group used Guizhi decoction or modified Guizhi decoction, while
Chinese medicine theory, taking Xinhe granule and Tiaoxin the control group applied for placebo, nutritional neurological
decoction containing Guizhi decoction can improve the symp- drugs, or no treatment. In addition, the 2 groups did not take any
toms of autonomic neuropathy of coronary heart disease.[14,15] drugs that interfered with the outcome indicators. Trials will be
Traditional Chinese medicine suggests that diabetic cardiac included at least 4 weeks of treatment.
autonomic neuropathy belongs to the category of “chest 2.2.4. Outcomes. The primary outcomes include patient before
obstruction” and “palpitation”. Guizhi decoction can effectively and after treatment: markedly effective: symptoms improved
play the role of regulating Ying Wei, reverse the remodeling of significantly >70%; effective: symptoms reduced by 30% to
myocardial collagen, inhibit inflammatory factors, inhibit the 70%; ineffective: symptom improvement is <30% or no
abnormal remodeling of sympathetic nerve, and maintain the improvement, or even worse. In addition to Heart rate variability
balance of autonomic nerve.[16] Studies also confirmed that (HRV) recognized as the most accurate and sensitive index
Guizhi decoction decreased the accumulation of inflammatory to judge whether diabetic patients have autonomic nervous
factors including nuclear factor k B (NF-k B), interleukin-1 (IL-1), system damage, fasting blood glucose (FBG) and 2 hours
tumor necrosis factor-a (TNF-a), and endothelin (ET-1) in the Postprandial Blood Glucose (2 hours PBG) were also included.
heart of streptozocin (STZ) rats; reversed spontaneous myocar- Secondary outcomes included glycosylated hemoglobin and
dial collagen remodeling in diabetic rats; significantly reduced adverse events.
myocardial basement membrane thickness; prevented damage
and thickening of the myocardial basement membrane; and
improved oxygen diffusion barriers,[17,18] thus to prevent and 2.3. Study search
treat diabetic myocardial damage. We will search each database from the built-in until July 2020.
In recent years, the advantages of traditional Chinese medicine The English literature mainly searches Cochrane Library,
in the prevention and treatment of this kind of chronic diseases PubMed, EMBASE, and Web of Science, while the Chinese
have been widely recognized around the world.[19] The literature comes from CNKI, CBM, VIP, and Wangfang
prescription of Guizhi decoction firstly recorded in the book of database. Simultaneously we will retrieval clinical registration
Shanghan Lun written by Zhang Zhongjing, is composed of tests and grey literatures. According to the PICOS principle, the
Ramulus Cinnamomi (Guizhi), Paeonia lactiflora (Shaoyao), keywords of our search terms were: (“Guizhi Tang” OR “Guizhi
Rhizoma Zingiberis Recens (Shengjiang), Licorice (Gancao), and Decoction”) AND (“diabetic cardiac autonomic neuropathy”
Jujube (Dazao). We intend to collect randomized controlled trials OR “DCAN”).

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2.4. Study selection 2.5. Data extraction and management

We will manage the electronic citations we downloaded from the According to the characteristics of the study, we prepared excel
above databases in Endnote X8 for Mac (Thomson Reuters, table for data acquisition before data extraction. The results of
USA). First of all, 2 independent reviewers initially screened the the qualified study were extracted independently by 2 reviewers
literatures that did not meet the pre-established standards of the and the data extraction form was filled in. Duplicate literature
study by reading the title and abstract. Secondly, download the will be removed. If there is any dispute, the 2 reviewers can
remaining literatures and read the full text carefully to further discuss or consult the third party to reach an agreement. The
decide whether to include or not. Finally, the results were cross- main data extracted are as follows: first author, year of
checked repeatedly by reviewers. A final decision will be made publication, source of funds, intervention measures in experi-
through consensus when there were discrepancies. Details of the mental group, intervention measures in control group,
selection process were shown in the flow chart (Fig. 1). treatment time, course of disease, number of patients in each

Figure 1. Flow diagram of study selection.

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group, age, gender, prognosis, and safety of patients. If you omitting each of the RCT, or excluding the RCTs with high risk
find something unclear in the study, you can contact the of bias, or excluding the RCTs with missing data.
author of the communication directly for more detailed
information. The above information was finally cross checked 2.8.3. Reporting bias. If there are more than 10 studies in meta-
by 2 reviewers. analysis, the symmetry of the funnel plot will be evaluated to
check for publication bias and to interpret the results carefully,
grading the quality of evidence. In this systematic review, the
2.6. Risk of bias assessment evidence quality of the whole study was assessed by the
Two review authors will independently evaluate the design, “recommended assessment, formulation and evaluation (grade)”
execution, and reporting of the included RCTs based on the standard developed by the World Health Organization and
Cochrane risk of bias tool. The following 7 items affiliated with international organizations to achieve transparency and simplifi-
bias risk, including random sequence generation, allocation cation. The quality of evidence was divided into 4 levels: high,
concealment, blinding of participants and personnel, blinding of medium, low, and very low. Slope profiler 3.2 will be used for
outcome assessment, incomplete outcome data, selective outcome analysis.
reporting, and other biases, will be evaluated by 2 reviewers.
Each item is classified as “Low risk”, “High risk” or “Unclear 3. Discussion
risk”. The discrepancies will get a consistent conclusion by
discussing between both reviewers or seeking the third-party DCAN is a common chronic complication of diabetes. At present,
consultation. drug treatment is universally used in the treatment of this disease,
and there are some shortcomings, such as little effect or large side
effects. Therefore, both clinicians and patients hope to seek a new
2.7. Statistical analysis treatment to improve symptoms with low adverse reactions.
The risk ratio (RR) for dichotomous data will be calculated, Traditional Chinese medicine has been used to treat diabetes and
respectively, along with 95% CI, the weighted mean difference diabetic complications in China for many years.[25,26] It has not
(WMD). For continuous data, the mean difference (MD) or only outstanding efficacy, but also has few side effects and low
standardized mean difference (SMD) with 95% CI will be economic costs. Clinical studies have shown that Guizhi
estimated. If we use the same scale to measure an outcome in Decoction can alleviate the symptoms of DCAN and improve
different studies, we will use MD. Similarly, if we use different the overall clinical efficacy.[27–29] However, there is no evidence-
scales to measure the same outcome, we will use SMD. If an based medicine to confirm the efficacy of Guizhi Decoction for
outcome measure contains less than 2 trials, we will summarize DCAN. So we attempt to perform this meta-analysis to provide
the results descriptively. Statistical heterogeneity among studies high-quality evidence for the clinical efficacy and safety of Guizhi
will be evaluated using the Cochran Q test (x2) and the I2 Decoction. Finally, we will classify the existing evidence to
statistical value. We will categorize the heterogeneity using the provide a better guide for clinical use.
following rules. I2 of 0% to 25% indicates low heterogeneity. I2
of 25% to 50% represents moderate heterogeneity. And I2 of Author contributions
75% to 100% represents high heterogeneity. When the P value
from a x2 test is more than .10 or I2 50%, we will adopt the fixed- Conceptualization: Junmin Chen, Jiawei Cai, Qiu Chen, Yang
effects model. Otherwise, there will be perceptible differences Yu.
between the studies. Subgroup analysis will be performed to Data curation: Mengya Wei, Xiaoran Zhang.
identify possible explanations for statistical heterogeneity, taking Funding acquisition: Qiu Chen, Yang Yu.
into account pre-specified factors. Investigation: Min Zhong, Min Liu.
We will utilize the Review Manage software V5.3.0 (The Methodology: Junmin Chen, Jiawei Cai, Qiu Chen.
Nordic Cochrane Center, The Cochrane Collaboration, 2014, Project administration: Qiu Chen, Yang Yu.
Copenhagen, Denmark) to statistically analyze all data. The Software: Junmin Chen, Jiawei Cai.
overall RR with its 95% CI for dichotomous data will be Supervision: Xiaoran Zhang.
estimated. The MD or SMD with 95% CI will be calculated for Validation: Junmin Chen.
continuous data in different situations. The fixed-effects model Writing – original draft: Junmin Chen, Jiawei Cai.
will be employed as appropriate for analysis. If the heterogeneity Writing – review & editing: Qiu Chen, Yang Yu.
in the study is significant, subgroup analysis will be conducted to
investigate possible sources of statistical heterogeneity. When a References
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