Chronic obstructive pulmonary disease (COPD) is a global disease and is predicted to be the fourth leading cause of death in 2030 [
Exacerbations of COPD are commonly treated with drugs such as bronchodilators, corticosteroids, and antibiotics and in more severe cases may require oxygen therapy and ventilator support. These therapies are beneficial; however they can lead to some significant side effects such as headache, insomnia, nausea, and pneumonia [
Chinese herbal medicine (CHM) showed potential beneficial effect for AECOPD in a recent systematic review; lung function, arterial blood gases, and clinical effective rate were improved by a Chinese herbal formula
Clinical trials have demonstrated that
Included studies were randomized controlled trials (RCT) investigating
Several broad outcome measures were selected to provide critical data on measuring different aspects of AECOPD. The outcome measures include lung function; dyspnoea; health related quality of life, emergency department or hospital admissions; length of hospital stay; arterial blood gases—partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2); biomarkers, tumour necrosis factor alpha (TNF-
Studies were excluded if they combined
The search was conducted in five English (PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and AMED) and four Chinese (Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chongqing VIP information (CQVIP)) databases. The search time frame ranged from the databases’ inception until 9 June 2013. No restrictions were applied. To ensure the largest sample of herbal formulae was included,
Two independent researchers (Shaonan Liu and Xuhua Yu) screened the studies according to the eligibility criteria and disagreement was resolved by a third researcher (Xiankun Chen).
Recorded information on study characteristics included first author, publication year, location, setting, study design, population characteristics, sample size,
The methodological quality was assessed by three independent researches (Shaonan Liu, Xiankun Chen, and Xuhua Yu) according to the Cochrane Collaboration’s risk of bias tool [
All data were analysed and synthesized using RevMan 5.2 software. Dichotomous data were calculated and presented as risk ratio (RR) with 95% confidence intervals (95% CI), and continuous data were reported as mean difference (MD) and 95% CI, and standardized mean difference (SMD) was used when studies reported different scales of the same outcome measure. Statistical heterogeneity was evaluated using Chi-square test and
The search identified 15,128 publications. After duplicates were removed, 9,309 studies were screened and 1,506 full texts were reviewed. After full-text review 537 RCTs using Chinese herbal medicine were reviewed. Only 15 of these studies used
Flow chart of the study selection process.
All studies used one packet of
Characteristics of included studies.
First author, publication year, |
Treatment duration | Severity; duration of condition | Number of participants randomised/assessed | Age (mean (SD) or range); |
Intervention* | Control (pharmacotherapy) |
---|---|---|---|---|---|---|
Chen et al., 2008 [ |
2 w | NS; I: 9.8 (5.0) y |
I: 36/36 |
I: 65.7 (8.3); 24/12 |
|
Routine care (oxygen therapy, bronchodilators, antibiotics, mucolytics plus nutritional therapy) not specified |
|
||||||
Jing et al., 2007 [ |
1 w | Mild-moderate; I: 17.2 (3.5) y |
I: 30/30 |
I: 66.3 (5.4); 22/8 |
Qian jin |
Routine care (bronchodilators, antibiotics, mucolytics plus nutritional therapy) not specified |
|
||||||
Liu et al., 2006 [ |
10 d | I: mild-very severe; 16.86 (10.97) y |
I: 30/30 |
I: 69.17 (7.53); 21/9 |
Jia wei qian jin |
Routine care (oxygen, antibiotics plus nutritional therapy) not specified |
|
||||||
Chen and Qiu, 2012 [ |
2 w | I: NS; 16.79 (10.53) y/ |
I: 30/30 |
I: 72.07 (8.39); 20/10 |
Qian jin |
Oxygen therapy, Methylxanthines (Doxofylline 0.3 g iv qd); Ventolin 2 spray inhaled, Ipratropium 10 mL qd inhaled, Levofloxacin, 0.4 g, IV, qd; ambroxol hydrochloride, 30 mg, IV, tid; |
|
||||||
Shi et al., 2007 [ |
2 w | I: mild: 4, moderate: 29, severe: 7, 16.34 (9.53) y/ |
I: 40/40 |
I: 61.4 (6.8); 27/13 |
|
Oxygen therapy, antibiotics (Cefmetazole 1 g iv bid) plus methylxanthines (Aminophylline 0.1 g, bid) plus mucolytic (Mucosolvan 30 mg bid) |
|
||||||
Zhang et al., 2009 [ |
10 d | NS | I: 30/30 |
I: 65.21 (6.02); 25/5 |
Qian jin |
Oxygen therapy, antibiotics plus methylxanthines (Theophylline 0.2 g, bid) plus mucolytic (Mucosolvan 30 mg tid) |
|
||||||
Chen and Wang, 2009 [ |
15 d | NS | I: 31/31 |
I: 62.5 (NS); 23/8 |
|
Oxygen therapy, Cefalexin, 3 g, qd-bid; ipratropium, 2 mL, inhaled, tid; salbutamol, 1 mL, inhaled, tid; theophylline, 0.2 g, bid; Mucosolvan, 30 mg, tid |
|
||||||
Li, 2009 [ |
10 d | I: mild: 5, moderate: 25; 9.94 (3.62) y/ |
I: 30/30 |
I: 63.87 (8.64); 19/11 |
Qian jin |
oxygen therapy, Levofloxacin, 0.3 g, IV, qd; salbutamol, 200 ug, inhaled tid, ipratropium, 20 ug, inhaled, tid, theophylline, 0.2 g, PO, bid; ambroxol hydrochloride, 30 mL, tid |
|
||||||
Shi et al., 2010 [ |
10 d | NS | I: 20/20 |
Total: 52–83; 31/9 |
|
Routine care (oxygen therapy, bronchodilators, antibiotics, mucolytics, and others) not specified |
|
||||||
Jing et al., 2006 [ |
10 d | mild-moderate; I: 13.2 (3.7) y |
I: 30/30 |
I: 64.7 (5.2); 21/9 |
Qian jin |
Routine care (bronchodilators, antibiotics, mucolytics plus nutritional therapy) not specified |
|
||||||
Xu, 2012 [ |
2 w | I: NS; 12.24 (3.79) y/ |
I: 40/40 |
I: 65.82 (11.73); 23/17 |
Qian jin |
Oxygen therapy, antibiotics plus methylxanthines (Aminophylline) plus mucolytic (Mucosolvan) |
|
||||||
Zang, 2010 [ |
2 w | Mild-severe; I: 11.6 (NS) d |
I: 35/35 |
I: 62.3 (NS); 23/12 |
Qian jin |
Routine care (bronchodilators, antibiotics, mucolytics plus nutritional therapy) not specified |
|
||||||
Zhang, 2011 [ |
10 d | NS | I: 40/40 |
Total: 67.7 (7.1); 59/21 | Qian jin |
Routine care (oxygen therapy, bronchodilators, antibiotics, mucolytics) not specified |
|
||||||
Zhan, 2008 [ |
10 d | I: mild: 5, moderate: 13, severe: 12; 15.46 (8.37) y/ |
I: 30/30 |
I: 65.7 (8.54); 25/5 |
|
Oxygen therapy, Levofloxacin, 0.3 g, IV, qd methylxanthines (Aminophylline 0.1 g, bid) plus mucolytic (ambroxol, 30 mg, tid) |
|
||||||
Guo, 2010 [ |
15 d | I: NS; 8.9 y |
I: 56/56 |
I: 63.5; 30/26 |
|
Oxygen therapy, antibiotics plus methylxanthines (Theophylline 0.2 g, bid) plus mucolytic (Mucosolvan 30 mg tid) |
I: intervention; C: control; IV: intravenous; NS: not specified; d: day; w: week; y: year.
*In all studies the same pharmacotherapy was used in the intervention group as in the control group.
All studies were described as randomized. However only four reported the details of random sequence generation using appropriate methods such as a random number table [
Assessment of risk of bias.
Studies reporting FEV1% and effective rate were evaluated for publication bias. Visual inspection was unclear (Figures
For lung function FEV1 percentage predicted (FEV1%), nine studies were included.
Forest plot of
Forest plot of
Sensitivity analysis after removal of studies at high or unclear risk of bias for random sequence generation showed positive effects of
Sensitivity analysis.
Outcome | Number of studies | Effect estimate MD/RR (95% CI) |
---|---|---|
FEV1 |
3 (Li 2009 [ |
MD 0.25 (0.14, 0.36) |
FEV1% | 2 (Li 2009 [ |
MD 4.02 (0.38, 7.65) |
PaO2 | 2 (Li 2009 [ |
MD 13.83 (0.05, 27.60) |
PaCO2 | 2 (Li 2009 [ |
MD −5.10 (−11.28, 1.08) |
Effective rate | 4 (Li 2009 [ |
RR 1.29 (1.14, 1.45) |
Sensitivity analysis removed studies with unclear or high risk of bias for sequence generation.
Arterial blood gases were reported as millimetres mercury (mmHg) except for one study that used kilopascals (Kpa) [
Forest plot of
Forest plot of
Effective rate was assessed and based on clinician’s judgment of symptom improvement, mostly using the “Guiding Principles of Clinical Research on New Drugs of Traditional Chinese Medicine” [
Forest plot of
Funnel plot of publication bias using FEV1%.
Funnel plot of publication bias using effective rate.
Four studies were included in the sensitivity analysis. The result was similar with the larger pool of studies (RR 1.29, 95% CI 1.14 to 1.45,
Four studies were included in the analysis of serum TNF-
Four predefined outcomes were not reported in any of the included studies. These outcomes were dyspnoea, health related quality of life, emergency department or hospital admissions, and length of hospital stay.
Seven out of the 15 studies reported adverse events [
This review based on published RCT revealed that
In terms of lung function,
Effective rate assessed by clinician’s judgment of symptom improvement is a common outcome used in Chinese medicine clinical trials. In this review effective rate was evaluated in all but one study and pooled data showed a significant difference between the groups, in favour of
Findings from this review are comparable with previous systematic reviews that evaluated Chinese herbal medicine combined with RP for AECOPD [
Although previous reviews have been published, this review evaluated a commonly used and recommended oral herbal formula for AECOPD.
Several limitations should be considered when interpreting this study. There were methodological shortfalls in the included studies. Only a small number of trials included information on randomization and blinding of participants and personnel was not performed in any of the trials. The effects shown by the result of sensitivity analysis were similar to the total analysis; however, the methodological shortfalls may cause potential risk of bias and influence the reliability of the conclusion. Therefore, CONSORT statement was also recommended for RCTs. Sample sizes were also small and a calculation of sample size was not performed in included studies. The predefined outcomes dyspnoea, health related quality of life, emergency department or hospital admissions, and length of hospital stay were not reported in any of the included studies. These outcomes especially dyspnoea and health related quality of life are useful when assessing and monitoring outcomes in patients with AECOPD and can be good predictors of future mortality risk [
Despite methodological limitations of the included studies,
#2: Traditional Chinese Medicine OR Chinese Traditional Medicine OR Chinese Herbal Drugs OR Chinese Drugs, Plant OR Medicine, Traditional OR Ethnopharmacology OR Ethnomedicine OR Ethnobotany OR Medicine, Kampo OR Kanpo OR TCM OR OR Medicine, Ayurvedic OR Phytotherapy OR Herbology OR Plants, Medicinal OR Plant Preparation OR Plant Extract OR Plants, Medicine OR Materia Medica OR Single Prescription OR Herbs OR Chinese Medicine Herb OR Herbal Medicine.
#3: Randomized controlled trial or controlled clinical trial or randomized or placebo or drug therapy or randomly or trial or groups.
#4: #1 AND #2 AND #3.
#2: Zhong Yi (Traditional Chinese Medicine) OR Zhong Xi Yi (Integrative medicine) OR Zhong Yi Liao Fa (Chinese Medicine Therapeutics) OR Bian Zheng Lun Zhi (syndrome differentiation and treatment) OR Bian Zheng (syndrome differentiation) OR Han Fang (Kampo) OR Zu Guo Yi Xue (Chinese Medicine) OR Chuan Tong Yi Xue (traditional medicine) OR Chuan Tong Zhi Liao (traditional treatment) OR Ti Dai Yi Xue (Complementary disease) OR Ti Dai Zhi Liao (complementary treatment) OR Zhong Guo Chuan Tong Yi Xue (traditional Chinese medicine) OR Min Zu Yi Yao (Ethnomedicine) OR Cao Yao (herbal medicine) OR Zhong Cao Yao (Chinese herb medicine) OR Zhong Yao Liao Fa (Chinese herb medicine therapeutics) OR Zhong Xi Yao (Chinese and western medicine) OR Zhong Cheng Yao (Chinese patent medicine).
#3: Lin Chuang Guan Cha (clinical observation) OR Lin Chuan Shi Yan (clinical trial) OR Lian Chuang Yan Jiu (clinical research) OR Qian Zhan Xing (prospective) OR Dui Zhao (control) OR Sui Ji (random) Duo Zhong Xin (multiple centres) OR Bing Li Bao Gao (case report).
#4: #1 AND #2 AND #3.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Shaonan Liu, Johannah Shergis, Xiankun Chen, Xuhua Yu, Xinfeng Guo, Anthony Lin Zhang, Chuanjian Lu, and Charlie Changli Xue conceived and designed the study. Shaonan Liu, Xiankun Chen, Xuhua Yu, and Xinfeng Guo searched and selected the articles, and Shaonan Liu and Johannah Shergis analysed and interpreted the data. Shaonan Liu, Johannah Shergis, Xiankun Chen, Xuhua Yu, Xinfeng Guo, Anthony Lin Zhang, Chuanjian Lu, and Charlie Changli Xue wrote and revised the paper. All authors approved the final version of the paper.
This study is funded by a Project Grant from the Guangdong Provincial Science & Technology Department and the Guangdong Provincial Academy of Chinese Medical Sciences (GPACMS) (Project Grant no. 2012A032500009). The study is partially supported by a Grant from the International Science & Technology Cooperation Project of the Ministry of Science and Technology of China (Project Grant no. 2012DFA31760) and the China-Australia International Research Centre for Chinese Medicine, funded by the Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine (GPACMS & GPHCM), Guangdong, China, and RMIT University, Australia.