The combination of astragalus injection and ambroxol hydrochloride in the adjuvant treatment of COPD: a systematic review and meta-analysis

Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An adjunctive therapy in COPD includes the simultaneous administration of astragalus injection and ambroxol hydrochloride. Despite its widespread use, the effectiveness of this combined approach in COPD treatment has not been systematically evaluated. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of combining astragalus injection with ambroxol hydrochloride as an adjuvant treatment for COPD. Six electronic databases were used to search for relevant randomized controlled trials, and data analysis was conducted using Review Manager 5.4. A total of 14 randomized controlled trials were included, involving 1070 patients who met the criteria. The results of the meta-analysis indicated that the combination of astragalus injection with ambroxol hydrochloride as an adjuvant treatment can improve various clinical parameters in patients with COPD compared to conventional treatment alone. These parameters include the clinical effective rate (OR = 5.44, 95% CI 3.51–8.43, I2 = 0%), partial pressure of oxygen in artery (MD = 1.12, 95% CI 0.87–1.36, I2 = 5%), partial pressure of carbon dioxide in artery (MD = − 1.43, 95% CI − 1.65 to − 1.21, I2 = 0%), forced expiratory volume in one second (MD = 0.30, 95% CI 0.18–0.42, I2 = 0%), percentage of forced expiratory volume in one second (MD = 16.18, 95% CI 12.60–19.76, I2 = 82%), forced vital capacity (MD = 0.33, 95% CI 0.21–0.45, I2 = 36%), hemoglobin (MD = − 16.17, 95% CI − 20.84 to − 11.51, I2 = 29%), and the ratio of forced expiratory volume in one second to forced vital capacity (MD = 2.51, 95% CI − 0.05 to 5.06, I2 = 0%). The combination of astragalus injection and ambroxol hydrochloride could be a selection of COPD patients as an adjuvant treatment. However, further validation is required to evaluate the effectiveness of combining astragalus injection and ambroxol hydrochloride as an adjunctive treatment for patients with COPD.


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 (PaO 2 ), partial pressure of carbon dioxide in artery (PaCO 2 ), 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 I 2 > 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.

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.

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.

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 methods 3,4,7,11,12,14,15,18 , three studies used random number tables 9,10,13 , one study used random blind selection 16 , one study used a double-blind method 19 , and one study used a lottery for random allocation 17 .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.There was no heterogeneity among the fourteen studies (P = 0.97, I 2 = 0%), and a fixed-effects model was used for the meta-analysis (Fig. 3).

Hemoglobin
Three RCTs (N = 264) reported the effects of astragalus injection combined with ambroxol hydrochloride on the hemoglobin levels of patients with COPD 9,12,13 .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, I 2 = 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, PaO 2 , PaCO 2 , and the pooled odds ratio (OR) values of CER are robust.Sensitivity analysis results of FEV1% and FEV1/FVC are shown in Table 2. www.nature.com/scientificreports/

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

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, PaO 2 , PaCO 2 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.

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-rays 4,10,11,14,16,17,19 .Three studies obtained CER based on cough, sputum volume, and pulmonary rales 7,15,18 .Two studies obtained CER according to the Guidelines for Clinical Research on expectorant cough suppressants 12,13 .One study obtained the CER based on improvements in body temperature and coughing 9 .One study did not describe the method of obtaining CER 3 .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 PaO 2 and PaCO 2 in patients with COPD.
Although no adverse effects were reported in the 14 studies, early studies indicated that astragalus injection may have some side effects 20 .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 conditions 21,22 .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 symptoms 23 .Astragaloside IV, one of the main components of Astragalus injection, has anti-inflammatory, antioxidant, and immune regulatory effects 24 .Additionally, astragaloside can activate the AMPK/mTOR signaling pathway and reduce lung inflammation and injury induced by PM2.5 25 .Astragaloside IV also inhibits the cellular response of Th17 26 .In clinical studies, ambroxol hydrochloride has been shown to be an effective adjunctive therapy in reducing inflammation, alleviating clinical symptoms, and improving pulmonary function 2 .Traditional Chinese medicine believes that deficiency in the spleen and lungs is one of the causes of COPD 27 .Astragalus can tonify the qi of the lungs and spleen.Clinical studies have shown that astragalus injection can enhance lung function in patients with COPD 28 .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, www.nature.com/scientificreports/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.

Figure 1 .
Figure 1.Flow chart of the literature screening process.

Author/year Country Study design Sample size Mean age Interventions Comparator
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).

Table 1 .
Characteristics of the included studies.U Unknown, A Astragalus injection, B Ambroxol Hydrochloride, CER Clinical effective rate, PF pulmonary function, ABG arterial blood gas, HGB Hemoglobin.

Table 3 .
Quality of evidence.NS Not serious, N none.
AThe methodology of most studies has an unclear bias.B The sample size was less than 400.CThe sensitivity analysis revealed a highly sensitive profile.D Heterogeneity test I 2 > 75% (82%).EThe medication and dosage of routine therapy are unclear.