Introduction

Chronic obstructive pulmonary disease (COPD) is a global disease with 3.97 million new cases reported in China in 2019. The incidence of COPD tends to increase with age1. COPD is a preventable and treatable disease, but airflow restriction is progressive and affects patients' quality of life1. At present, the primary treatment methods for COPD include anti-infection medications, cough suppressants, expectorants, bronchodilators, and spasmolytics. Although medical technology continues to improve, COPD is still a significant medical burden1.

Ambroxol hydrochloride is a commonly used drug in the adjunctive treatment of COPD2. It can effectively alleviate the clinical symptoms and improve lung function in patients with COPD2. Astragalus injection is a traditional Chinese medicine injection that can be used in conjunction with conventional treatment to aid in the treatment of COPD3,4. The combination of traditional Chinese medicine preparation and conventional treatment can reduce the number of acute exacerbations of COPD and improve the clinical efficacy of COPD treatment5,6. Clinical researchers in China have used astragalus injection in combination with ambroxol hydrochloride as an adjuvant treatment for COPD7. However, the effects of combining astragalus injection with ambroxol hydrochloride on patients with (COPD) have never been systematically evaluated. To assess the therapeutic efficacy of astragalus injection combined with ambroxol hydrochloride as an adjuvant treatment for COPD, we conducted a systematic review and meta-analysis by summarizing relevant randomized controlled trials (RCTs).

Methods

This study followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) project, and all study procedures were conducted in accordance with PRISMA requirements8. The systematic review has been registered on the International Prospective Register of Systematic Reviews (PROSPERO), and the ID is CRD42023421010.

Information sources and search strategies

The databases used were PubMed, China Biomedical Literature Database (CBM), Wan Fang Database, Embase, Web of Science, and the China National Knowledge Infrastructure (CNKI). The literature search strategy is ("Astragalus injection") AND ("Ambroxol hydrochloride") AND ("COPD" OR "Chronic obstructive pulmonary diseases"). To ensure that no important literature is missed, we conducted a thorough literature search using the strategy shown in Supplementary Material. The retrieval date was set from the database's establishment to October 26, 2023. There were no language restrictions.

Inclusion and exclusion criteria

Inclusion criteria: (a) Type of study (S): The included study was a randomized controlled trial; (b) Type of participant (P): Adult patients clinically diagnosed with COPD and hospitalized for COPD; (c) Type of intervention (I): The experimental group was given Astragalus injection and Ambroxol hydrochloride and conventional treatment, and the administration was via an intravenous drip; (d) Type of comparator (C): The control group received conventional treatment; (e) Type of prognostic measurement (O): These studies included one of the following outcomes: clinical effective ratio (CER), lung function, and arterial blood gas analysis, hemoglobin.

Exclusion criteria: (a) Unable to extract sufficient data for statistical aggregation; (b) Outcome measurement and conclusion were inconsistent; (c) Duplicate published or duplicated data; (d) The original data was not available.

The type of the outcome measurement

The clinically effective ratio (CER) was the primary outcome, and forced expiratory volume in one second (FEV1), percentage of forced expiratory volume in one second (FEV1%), forced vital capacity (FVC), partial pressure of oxygen in artery (PaO2), partial pressure of carbon dioxide in artery (PaCO2), the ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), hemoglobin, were the secondary outcomes.

Selection of studies and extraction of data

Two reviewers (CH and ZBZ) reviewed potentially eligible studies and documented the selection process independently, and then completed the PRISMA flowchart. The data was independently extracted by (ZBZ and XBZ) using the extraction table. The information retrieved was as follows: Name of the first author, year of publication, study design, the sample size of the trial, the mean age of the participants, the interventions of the experimental group and the control group, duration, and outcomes. Differences in the retrieved information were resolved through consulting with LLY and RG.

Risk of bias assessment

The quality of the methods in each trial was scored independently scored by two evaluators (LLY and ZBZ), which included seven domains: appropriate sequence generation, hidden allocation, blinding of participants and people, incomplete outcome data, selective reporting, and other biases. Three levels were used to assess the quality of the method: "low bias risk" ( +), "high bias risk" (−), and "uncertain bias risk" (?). We discussed the differences with other researchers (CH, XBZ, and RG) to reach a consensus.

Data synthesis and analysis

The Review Manager 5.4 was used for the meta-analysis. Dichotomous data were expressed as odds ratio (OR). Continuous data were expressed as mean difference (MD) with a 95% confidence interval when the units of measurement for the outcome variable are the same. When I2 > 50% and P < 0.05, there was significant heterogeneity between studies, and a random effects model was used for meta-analysis. When there was no heterogeneity between studies, the fixed effects model was used to summarize OR and MD. Qualitative analysis of data that cannot be included in the meta-analysis.

Sensitivity analysis

Sensitivity analysis was conducted to assess the robustness of the pooled OR values and the pooled MD values by excluding each trial.

Risk of publication bias

As more than 10 studies were included, we would test for potential publication bias using a funnel plot.

Quality assessment of the evidence

Two reviewers (CH and ZBZ) used GRADE prolifer to assessed the grade of each evidence independently. A third reviewer (LLY) determined the differences in the assessments. Four levels of "high", "medium", "low", and "very low" were used to evaluate the quality of evidence. If the sample size of the trial was less than 400, or the pooled values with high sensitivity, the quality of the study would be reduced by one grade.

Results

Description of studies

We identified 1542 related studies from the databases. Thereafter, we obtained 24 articles after excluding 653 duplicated articles and 865 articles that did not meet the inclusion criteria. After further review of the full text, 14 studies were excluded and 10 randomized controlled trials (n = 1070) were finally included, all of which were from China. The literature selection process is displayed in Fig. 1, and the general characteristics of studies are listed in Table 1.

Figure 1
figure 1

Flow chart of the literature screening process.

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Table 1 Characteristics of the included studies.
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Risk of bias in the included studies

Figure 2a and Fig. 2b summarized the bias risk assessment for 14 RCTs. From the 14 RCTs, eight studies had no specific methods3,4,7,11,12,14,15,18, three studies used random number tables9,10,13, one study used random blind selection16, one study used a double-blind method19, and one study used a lottery for random allocation17. None of the 14 studies mentioned blinding the participants, personnel, or assessment outcomes. Data from the 14 studies were complete and did not exist other risks of bias.

Figure 2
figure 2

Risk of bias summary and Risk of bias graph.

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Primary outcome

Clinical effective ratio (CER)

Fourteen RCTs (N = 1070) reported the effect of astragalus injection combined with ambroxol hydrochloride on the clinical effective ratio (CER) of COPD. CER = (number of obvious effective cases + number of effective cases) / total number of people in each group × 100%. The results of the data analysis show that the combination of astragalus injection and ambroxol hydrochloride injection with conventional treatment significantly improved CER, compared to conventional treatment alone (OR = 5.44, 95% CI: 3.51–8.43, P < 0.00001). There was no heterogeneity among the fourteen studies (P = 0.97, I2 = 0%), and a fixed-effects model was used for the meta-analysis (Fig. 3).

Figure 3
figure 3

The forest plot of CER.

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Secondary outcomes

Pulmonary function: FVC, FEV1, FEV1/FVC, and FEV1%

Five RCTs (N = 422) reported FVC9,12,13,14,19. Data analysis revealed that the combination of astragalus injection and ambroxol hydrochloride with conventional treatment can improve FVC in patients with COPD compared to conventional treatment alone (MD = 0.33, 95% CI 0.21–0.45, P < 0.00001). There was no heterogeneity among the five studies (P = 0.18, I2 = 36%), and a fixed-effects model was used for the meta-analysis (Fig. 4a).

Figure 4
figure 4

The forest plots of FVC, FEV1, FEV1/FVC, FEV1%, PaO2, PaCO2, and hemoglobin.

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Five RCTs (N = 350) reported FEV14,9,11,12,14. Data analysis revealed that the combination of astragalus injection and ambroxol hydrochloride as an adjuvant treatment significantly improved FEV1 compared to conventional treatment alone (MD = 0.30, 95% CI 0.18–0.42, P < 0.0001). There was no heterogeneity among the five studies (P = 0.99, I2 = 0%), and a fixed-effects model was used for data analysis (Fig. 4b).

Four RCTs (N = 300) reported the FEV1/FVC3,10,15,18. Data analysis revealed that the combination of astragalus injection and ambroxol hydrochloride can improve the FEV1/FVC compared to conventional treatment alone (MD = 2.51, 95% CI − 0.05 to 5.06, P = 0.05). No heterogeneity was found among the four studies (P = 0.94, I2 = 0%), and data were analyzed using a fixed-effects model (Fig. 4c).

Ten RCTs (N = 794) reported FEV1%3,9,10,12,13,14,15,16,18,19. Data analysis revealed that the combination of astragalus injection and ambroxol hydrochloride with conventional treatment significantly improved patients’ FEV1% compared to conventional treatment alone (MD = 16.18, 95% CI 12.60–19.76, P < 0.00001). There was significant heterogeneity among the ten studies (P < 0.00001, I2 = 82%), and a random-effects model was used for the meta-analysis (Fig. 4d). Sensitivity analysis revealed that heterogeneity originated from the Zhang 2017 (Table 2), the source of heterogeneity may be the dosage of astragalus injection.

Table 2 Sensitivity analysis of FEV1% and FEV1/FVC.
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Arterial blood gas analysis: PaO2, PaCO2

PaO2 was reported in seven RCTs (N = 566)3,10,12,13,15,16,18. Data analysis revealed that the combination of treatments significantly improved patients' PaO2 compared to conventional treatment alone (MD = 1.12, 95% CI 0.87–1.36, P < 0.00001). There was no significant heterogeneity among the seven studies (P = 0.39, I2 = 5%), and a fixed-effects model was used (Fig. 4e).

PaCO2 was reported in seven RCTs (N = 566)3,10,12,13,15,16,18. Data analysis revealed that the combination significantly improved patients' PaCO2 compared to conventional therapy (MD =  − 1.43, 95% CI − 1.65 to − 1.21, P < 0.00001). There was no heterogeneity among the seven studies (P = 0.43, I2 = 0%), and a fixed-effects meta-analysis was used (Fig. 4f).

Hemoglobin

Three RCTs (N = 264) reported the effects of astragalus injection combined with ambroxol hydrochloride on the hemoglobin levels of patients with COPD9,12,13. Data analysis showed that, compared to conventional treatment alone, the combination therapy significantly down regulated the hemoglobin levels of patients with COPD (MD =  − 16.17, 95% CI − 20.84 to − 11.51, P < 0.00001). There was no heterogeneity among the seven studies (P = 0.24, I2 = 29%), and a fixed-effects meta-analysis was used (Fig. 4g).

Sensitivity analysis

We use sensitivity analysis to assess the robustness of merged data and investigate the sources of heterogeneity. Through sensitivity analysis, it was found that, in addition to FEV1/FVC, the pooled mean difference (MD) values of FVC, FEV1, PaO2, PaCO2, and the pooled odds ratio (OR) values of CER are robust. Sensitivity analysis results of FEV1% and FEV1/FVC are shown in Table 2.

Publication bias analysis

As shown in Fig. 5, the funnel plot of the CER is approximately symmetric, indicating no publication bias.

Figure 5
figure 5

Funnel plot of CER.

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Quality of evidence

We evaluated the quality of evidence. Due to unclear bias risk in research methods and the medication and dosage of routine therapy are unclear, the quality of evidence for CER, PaO2, PaCO2 and FVC has been downgraded by two grade. The quality of evidence for FEV1 has been downgraded by two levels due to unclear bias risk in research methods and a sample size of less than 400. Because of the unclear bias risk in research methods, a sample size of less than 400, and the high sensitivity of the pooled MD values, the quality of evidence for hemoglobin, FEV1/FVC, and FEV1% is considered to be very low. The comprehensive results are presented in Table 3, providing a clear depiction of the quality of the evaluated evidence.

Table 3 Quality of evidence.
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Discussion

In the study, we conducted a systematic evaluation of the clinical efficacy of astragalus injection combined with ambroxol hydrochloride as an adjuvant treatment for COPD. Additionally, we evaluated the therapeutic impact of this combination on pulmonary function and arterial blood gas analysis.

In terms of clinical efficacy, the combination of astragalus injection with ambroxol hydrochloride as adjuvant treatment significantly improved the CER in COPD. Seven studies obtained CER from clinical symptoms such as cough, phlegm, and shortness of breath, as well as from chest X-rays4,10,11,14,16,17,19. Three studies obtained CER based on cough, sputum volume, and pulmonary rales7,15,18. Two studies obtained CER according to the Guidelines for Clinical Research on expectorant cough suppressants12,13. One study obtained the CER based on improvements in body temperature and coughing9. One study did not describe the method of obtaining CER3. In future studies, the method of obtaining CER should be standardized, such as the COPD Assessment Test (CAT). In terms of lung function, the combination of astragalus injection and ambroxol hydrochloride can improve FVC, FEV1/FVC, FEV1, and FEV1% in COPD patients as an adjuvant treatment. However, the quality of evidence for FEV1% and FEV1/FVC is very low. In terms of arterial blood gas analysis, the combination of astragalus injection and ambroxol hydrochloride significantly improved the levels of PaO2 and PaCO2 in patients with COPD.

Although no adverse effects were reported in the 14 studies, early studies indicated that astragalus injection may have some side effects20. Hence, further research is needed to determine the safety of combining astragalus injection with ambroxol hydrochloride in COPD patients.

The pathogenesis of COPD is related to chronic inflammation, oxidative stress, and immune imbalance. Cytokine release and oxidative stress are induced by airborne particles 2.5 (PM2.5), which can exacerbate COPD conditions21,22. The Th17/Treg ratio in the lungs of COPD patients is unbalanced, and the release of the cytokine IL17 by Th17 cells leads to the exacerbation of COPD symptoms23. Astragaloside IV, one of the main components of Astragalus injection, has anti-inflammatory, antioxidant, and immune regulatory effects24. Additionally, astragaloside can activate the AMPK/mTOR signaling pathway and reduce lung inflammation and injury induced by PM2.525. Astragaloside IV also inhibits the cellular response of Th1726. In clinical studies, ambroxol hydrochloride has been shown to be an effective adjunctive therapy in reducing inflammation, alleviating clinical symptoms, and improving pulmonary function2. Traditional Chinese medicine believes that deficiency in the spleen and lungs is one of the causes of COPD27. Astragalus can tonify the qi of the lungs and spleen. Clinical studies have shown that astragalus injection can enhance lung function in patients with COPD28.These findings might explain the enhanced clinical effectiveness of combining astragalus injection with ambroxol hydrochloride in COPD.

However, this study had some limitations. First, the number of relevant studies included was only 14, all of which were published in China, and did not describe whether these patients were in a stable or acute phase of COPD. Additionally, the overall quality of these studies was not high, which diminished the credibility of the findings. Second, although all the studies used random assignment, only six studies provided specific explanations, which may increase the risk of selection bias. Thirdly, None of the studies indicated whether double-blind trials were conducted, and the overall quality of the 14 included studies was low. Fourth, the pooled mean MD value for FEV1/FVC are highly sensitive, which reduces the quality of the evidence. Furthermore, 14 of the included studies did not specify the use of conventional treatment drugs and dosages, which undermines the credibility of the evidence. In future studies, more clinical trials are needed to verify the clinical efficacy of combining astragalus injection with ambroxol hydrochloride as adjuvant therapy in patients with COPD.

Conclusion

In conclusion, as an adjuvant treatment, the combination of astragalus injection and ambroxol hydrochloride significantly improves the clinical symptoms of patients with COPD. This suggests that combining astragalus injection with ambroxol hydrochloride could be a viable adjuvant treatment option for patients with COPD. However, due to the limitations of the trials, further validation is required to evaluate the effectiveness of combining astragalus injection with ambroxol hydrochloride for patients with COPD. Additionally, future trials should preferably employ a clear randomization method and incorporate a double-blind test.