Ambroxol hydrochloride and clenbuterol hydrochloride oral solution versus ambroxol hydrochloride injection for pediatric lower respiratory tract infection with mucoid sputum: a multicenter, non-randomized observational study in China

Introduction

Lower respiratory tract infection (LRTI) is a common disease in pediatric patients, primarily manifesting as cough, fever, headache, and mucoid sputum (1,2). Among these symptoms, mucoid sputum is particularly concerning to clinicians due to its possible consequences, such as exacerbation of cough, expectoration difficulty, and dyspnea; most notably, suffocation can occur in pediatric patients with LRTI and severe symptoms of mucoid sputum (3-5). Hence, timely expectoration and effective reduction of mucoid sputum viscosity are critical to improving the prognosis of pediatric patients with LRTI complicated by mucoid sputum.

Ambroxol hydrochloride, an N-demethylated active metabolite of bromhexine hydrochloride, is a classical mucoactive agent that exerts multiple effects, including secretolytic, anti-inflammation, antioxidant, and local anesthetic activity (6). It has also been demonstrated to alleviate sputum, cough, cyanosis, and respiratory distress (7-10). Clenbuterol hydrochloride, a direct-acting sympathomimetic agent with a highly selective function on β2 receptor, exerts its principal pharmacological effect by inducing relaxation of bronchial smooth musculature and mitigating bronchoconstriction (11). Notably, there is a synergistic effect between ambroxol and clenbuterol, in which ambroxol improves the spasmolytic activity of clenbuterol to alleviate respiratory symptoms of bronchospasm (12). Moreover, their concomitant use adheres to first-order kinetics in pharmacokinetics without exhibiting mutual interference (13,14). However, most existing evidence regarding ambroxol and clenbuterol is derived from small-scale or single-center studies, and there remains a lack of large-scale comparative data evaluating combination therapy versus monotherapy in pediatric LRTI.

Ambroxol hydrochloride and clenbuterol hydrochloride oral solution [AHCHOS (or Yitanjing)] is a compound preparation consisting of ambroxol hydrochloride and clenbuterol hydrochloride, indicated for expelling sputum, arresting coughing, and attenuating expectoration difficulties in pediatric patients (15,16). AHCHOS not only exerts the mucokinetic, antioxidant, and anti-inflammatory effects of ambroxol hydrochloride but also exhibits the bronchodilatory activity of clenbuterol hydrochloride; moreover, their synergistic action further enhances mucus clearance and effectively alleviates clinical manifestations such as cough and mucoid sputum associated with respiratory diseases (6,11,12,15,16).

In clinical practice in China, ambroxol hydrochloride injection (AHI) is commonly used as an expectorant therapy in hospitalized pediatric patients with LRTI. Therefore, it serves as a practical comparator for evaluating the effectiveness of alternative treatment strategies. In addition, given the practical challenges of conducting randomized controlled trials in pediatric populations, real-world observational studies may provide valuable complementary evidence for clinical decision-making. Therefore, we conducted a China-wide, multicenter study to compare AHCHOS and AHI in terms of clinical outcomes and safety in the treatment of pediatric patients with LRTI complicated by mucoid sputum, representing combination oral therapy versus single-agent injectable therapy in real-world practice. We present this article in accordance with the TREND reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0271/rc).

Methods

Patients

A total of 407 pediatric patients with LRTI complicated by mucoid sputum treated across 30 Chinese institutions from May 2018 to July 2019 were consecutively included in this national-wide, multicenter study. All data were collected from routine clinical practice at each participating hospital, based on medical records and clinical assessments during hospitalization. The inclusion criteria were as follows: (I) diagnosis of LRTI, including acute bronchitis, pneumonia, bronchial asthma with infection, and acute infectious bronchiolitis; (II) hospitalized patients aged ≤14 years; (III) symptoms of mucoid sputum; (IV) respiratory symptom scale-sputum amount subscale score ≥2 or respiratory symptom scale-expectoration difficulty score ≥2; and (V) imminent administration of AHCHOS or AHI treatment. Meanwhile, the exclusion criteria were as follows: (I) contraindications, intolerance, or allergy to any component of the study-related drugs; (II) use of expectorants within 2 days before enrollment; (III) other conditions that could affect therapeutic assessment as determined by the investigators. Informed consent was obtained from the legal guardians of the pediatric patients (age ≤14 years). The study was approved by the Institutional Review Board of the Children’s Hospital of Chongqing Medical University (No. 2018-2) and conformed to the principles outlined by the Declaration of Helsinki and its subsequent amendments. All participating hospitals/institutions were informed of and agreed to this study. No formal sample size calculation was performed, and the sample size was determined based on the number of eligible patients consecutively enrolled during the study period across participating centers.

Baseline data collection

Clinical characteristics of patients were collected after enrollment and included the demographics of patients, demographics of guardians, medical history, smoking-related history, disease-related characteristics, physical examination indices, and laboratory examination indices.

Treatment

This was a multicenter, non-randomized observational study, and treatment allocation was not randomized but determined by clinical practice and guardian preference. Patients received AHCHOS (n=254) or AHI (n=153) treatment for 7 days according to the disease conditions and guardian preference, and they were divided into the groups corresponding to the treatment they received. The oral dosage of AHCHOS (Yitanjing, Beijing Hanmi Pharmaceutical Co., Beijing, China) was determined according to age. (I) For patients ≤12 years, a dose of 2.5–15 mL was administered twice a day, which was adjusted according to age and weight as follows: 2.5 mL for pediatric patients younger than 8 months with a weight of 4–8 kg, 5.0 mL for pediatric patients older than 8 months and younger than 1 year of age who weighed between 8 and 12 kg, 7.5 mL for pediatric patients aged 2–3 years with a weight of 12–16 kg, 10.0 mL for pediatric patients aged 4–5 years with a weight of 16–22 kg, and 15.0 mL for pediatric patients aged 6–12 years with a weight of 22–35 kg. (II) For pediatric patients over 12 years of age, a dose of 20 mL was administered twice a day; after significant improvement in symptoms, it was reduced to 10 mL administered 2–3 times a day; for patients with severe respiratory distress, 20 mL was administered 3 times a day for the first 2–3 days. An injectable dose of AHI was administered according to the instructions of the respective manufacturers (Mucosolva, Boehringer Ingelheim Espana SA, Barcelona, Spain; Lansu, Shiyao Pharmaceutical Co., Changzhou, China; Yinuoshu, Pharmaceutical Research Institute Pharmaceutical Co., Tianjin, China). The selection of treatment was based on clinical judgment and guardian preference, reflecting real-world practice. This was an open-label study conducted under real-world clinical conditions. Due to the differences in routes of administration between oral and injectable treatments, blinding (e.g., double-blind or double-dummy design) was not feasible. Outcome assessments were performed by treating clinicians and were not blinded to treatment allocation. Caregivers were instructed on the proper administration of medications, and treatment adherence was monitored by clinicians during hospitalization.

Evaluation

The primary outcome was the change in total respiratory symptom score from baseline to Day 7 (D7). Secondary outcomes included changes in the respiratory symptom subscale scores (cough, sputum amount, expectoration difficulty, and wheezing rale), the percentage change in total respiratory symptom score, the change in visual analog scale (VAS) score for self-reported symptom severity, and safety outcomes. An overall respiratory symptom scale including four subscales (cough, sputum amount, expectoration difficulty, and wheezing rale) was recorded at baseline and on the 7th day of treatment (D7). Each subscale was scored between 0 and 3 (with a higher score indicating greater symptom severity); the scoring criteria are detailed in Table S1. The total respiratory symptom score was the sum of four subscale scores (range, 0–12). Subsequently, the decrease in total respiratory symptom score and the decrease in the scores of subscales from baseline to D7 were calculated as follows: decrease in score = score at D7 – score at baseline. Meanwhile, the decrease in percentage of total respiratory symptom score was calculated as follows: decrease in percentage = score at D7 – score at baseline/score at baseline × 100%.

A VAS of self-reported symptom severity was also recorded at baseline and D7, the scoring criteria of which are presented in Figure S1. The decrease in VAS self-reported symptom severity score was calculated as follows: decrease in score = score at D7 – score at baseline.

Additionally, safety outcomes were assessed through routine clinical monitoring during hospitalization, including vital signs, physical examination findings, laboratory evaluation, and electrocardiography. Adverse reactions were recorded based on clinically observed abnormalities and physician judgment, rather than a predefined systematic checklist or protocol-driven active surveillance. However, no standardized adverse event reporting checklist or structured surveillance protocol was implemented, and safety data collection relied on routine clinical practice. All clinical assessments were performed by trained clinicians using standardized criteria to ensure consistency across study sites.

Statistical analysis

The unit of analysis was the individual patient, consistent with the unit of assignment. All data were analyzed with SAS 9.4 statistical software (SAS Institute Inc., Cary, NC, USA). Measurement data are expressed as the mean ± standard deviation (SD) or as the median and interquartile range (IQR). According to the normality and homoscedasticity, the t-test or rank-sum test was used for comparisons. Count data are expressed as the number with percentage and were compared with the Chi-squared test. A P value <0.05 was considered statistically significant. The efficacy analyses were conducted based on the full analysis set (FAS), while safety analyses were performed on the safety set (SS). Missing data were not imputed, and analyses were conducted based on available data. Given the observational nature of the study, the statistical analyses were primarily descriptive and exploratory, and no adjustment for potential confounders or center effects was performed.

Results

Participant inclusion

A total of 4,452 patients were initially screened, among whom 3,304 were excluded due to the following reasons (some patients met more than one of following items): cough score <1 (n=65), sputum amount score <1 (n=475), ambulatory patients (n=1,130), use of glucocorticoids/budesonide (n=1,868), and use of other Chinese patent medicine as expectorants (n=948). Consequently, 1,148 patients were eligible for further screening. Subsequently, 741 patients were further excluded due to the following reasons (some patients met more than one of following items): no use of AHCHOS or AHI (n=525), use of AHCHOS plus other drugs (n=105), use of AHI plus other drugs (n=122), and use of a noninjection type of ambroxol (n=111). Finally, 407 patients (pediatric patients with LRTI complicated by mucoid sputum) were deemed eligible for inclusion in this study, with 254 cases in the AHCHOS group and 153 cases in the AHI group (Figure 1). No major protocol deviations from the planned study procedures were identified during the study. All analyses were conducted based on the predefined study design.

Figure 1 Flowchart of patient inclusion. AHCHOS, ambroxol hydrochloride and clenbuterol hydrochloride oral solution; AHI, ambroxol hydrochloride injection; QS, quantitative symptom.

Clinical characteristics

The median age of participants in the AHCHOS group was 1.25 years (IQR: 0.57–3.41 years), and there were 100 (39.37%) female and 154 (60.63%) male patients. In the AHI group, the median age was 1.96 years (IQR: 0.78–4.07 years), and there were 65 (42.48%) female and 88 (57.52%) male patients. The AHCHOS group and AHI group differed significantly in terms of family history of respiratory disease (P<0.001) and type of the episode (P=0.02); however, there were no differences for any other characteristics (Table 1).

AHCHOS improved total respiratory symptom

The total respiratory symptom score at baseline was not different between the AHCHOS group and AHI group (5.57±1.84 vs. 5.36±1.74; P=0.17; Figure 2A), indicating the two-group comparability. After 7-day treatment, the total respiratory symptom score decreased in both the AHCHOS and AHI groups. Importantly, the reduction in total respiratory symptom score was greater in the AHCHOS group than in the AHI group at D7 (−4.35±2.25 vs. −3.56±1.89; P<0.001; Figure 2B). Accordingly, the decrease in the percentage of total respiratory symptom score was also greater in the AHCHOS group than in the AHI group at D7 (−77%±30% vs. −65%±28%; P<0.001; Figure 2C).

Figure 2 Assessment of total respiratory symptom score. Comparison between the AHCHOS group and AHI group in terms of the total respiratory symptom score at baseline (A), the decrease in total respiratory symptom score from baseline to D7 (B), and the decrease in percentage of total respiratory symptom score from baseline to D7 (C). AHCHOS, ambroxol hydrochloride and clenbuterol hydrochloride oral solution; AHI, ambroxol hydrochloride injection; D7, day 7 of treatment.

AHCHOS attenuated cough, sputum amount, and wheezing rale

At baseline, the AHCHOS group and AHI group had similar scores for the respiratory symptom subscales including cough (1.70±0.61 vs. 1.64±0.62; P=0.33), sputum amount (1.53±0.55 vs. 1.52±0.6; P=0.70), and expectoration difficulty (1.69±0.66 vs. 1.77±0.67; P=0.23), but the AHCHOS group had a higher wheezing rale score at baseline (0.65±0.84 vs. 0.42±0.76; P=0.002) (Figure 3A). After 7-day treatment, the score of each subscale decreased in both the AHCHOS and AHI groups. Notably, the AHCHOS group, as compared to the AHI group, had a greater decrease in scores for cough (−1.15±0.77 vs. −0.75±0.81; P<0.001), sputum amount (−1.21±0.79 vs. −1.06±0.67; P=0.03), and wheezing rale (−0.58±0.8 vs. −0.37±0.67; P=0.008), but the decrease in expectoration difficulty score was not significantly different (−1.41±0.77 vs. −1.38±0.82; P=0.90) (Figure 3B). The scores of the respiratory symptom subscales at baseline and D7 are presented in Table 2.

Figure 3 Assessment of respiratory symptom subscale scores. Comparison between the AHCHOS group and AHI group in terms of respiratory symptom subscale scores at baseline (A), and the decrease in respiratory symptom subscale scores from baseline to D7 (B). The respiratory symptom subscales included cough, sputum amount, expectoration difficulty, and wheezing rale. AHCHOS, ambroxol hydrochloride and clenbuterol hydrochloride oral solution; AHI, ambroxol hydrochloride injection; D7, day 7 of treatment.

AHCHOS reduced the VAS score for self-reported symptom severity

The VAS score for self-reported symptom severity at baseline was not significantly different between the AHCHOS group and AHI group (5.16±1.76 vs. 5.27±1.71, P=0.56; Figure 4A). After 7-day treatment, the VAS score for self-reported symptom severity decreased in both the AHCHOS and AHI groups. Moreover, the decrease in the VAS score for self-reported symptom severity was greater in the AHCHOS group than in the AHI group at D7 (–4.12±2.04 vs. –3.51±1.78; P=0.006; Figure 4B).

Figure 4 Assessment of the VAS for self-reported symptom severity score. Comparison between the AHCHOS group and AHI group in terms of the VAS for self-reported symptom severity score at baseline (A) and the decrease in VAS for self-reported symptom severity score from baseline to D7 (B). AHCHOS, ambroxol hydrochloride and clenbuterol hydrochloride oral solution; AHI, ambroxol hydrochloride injection; D7, day 7 of treatment; VAS, visual analog scale.

Adverse reactions

Over the whole study period, no clinically significant adverse reactions were reported in either group during the study period. Additionally, no clinically significant abnormalities in vital signs were observed, as shown in Table S2.

Discussion

The anatomy of the respiratory system in pediatric patients is distinct: the trachea and bronchus are relatively narrow, and the bronchial wall elasticity, cilia movement function, and lung elastic tissue development are relatively poor (3,17,18). When LRTI occurs, the increase in respiratory secretions leads to a high susceptibility for airway stenosis, which adversely affects ventilation function and causes breathing difficulties (19). An increase in airway resistance can contribute to persistent airway hyperreactivity, which further leads to air exchange disorders, hypoxia, carbon dioxide retention, pulmonary vasoconstriction, and increased pulmonary circulation resistance (19). Furthermore, the mucoid sputum can further aggravate respiratory difficulty, and if the viscosity of mucoid sputum is high, it may even increase the risk of suffocation (20). Hence, expectoration and reduction of the viscosity of the mucoid sputum in these pediatric patients are critical. AHCHOS, a compound of ambroxol hydrochloride and clenbuterol hydrochloride that can be administered orally to pediatric patients, has been applied in Chinese pediatric patients with respiratory diseases such as pneumonia and acute bronchitis. It can effectively relieve respiratory symptoms, including cough, sputum production, and wheezing rale (16,21,22). However, large-scale validation for the application of AHCHOS in treating pediatric LRTI is lacking. There is limited evidence for its use among pediatric patients with LRTI complicated by mucoid sputum. In this study, AHI was selected as the comparator because it was widely used in hospitalized pediatric patients with LRTI in China. The comparison between AHCHOS and AHI reflected two different but commonly used clinical strategies: combination oral therapy versus single-agent injectable therapy. Therefore, the findings of this study provided clinically relevant evidence for real-world treatment decision-making rather than a strictly controlled efficacy comparison.

We conducted a large-scale investigation involving 30 institutions across different regions in China and compared AHCHOS and AHI in terms of efficacy and safety in 407 pediatric patients with LRTI complicated by mucoid sputum. We observed that AHCHOS provided greater improvement in respiratory symptoms including cough, sputum amount, and wheezing rale as compared with AHI. Meanwhile, the VAS score of self-reported symptom severity corroborated the superiority of AHCHOS over AHI. These findings could be explained as follows:

Ambroxol has high lung affinity and strong anti-infection and antioxidation effects, which can regulate the chemotactic function of alveolar macrophages and promote the synthesis of pulmonary surfactant. Meanwhile, ambroxol modifies the secretion of bronchial mucus glands, reduces the viscosity of sputum, increases the ciliary movement of the bronchus, and facilitates mucoid sputum expectoration (6,23-25). Furthermore, clenbuterol is a bronchial relaxant, which effectively dilates bronchial smooth muscle, relieves bronchospasm, and increases the movement of respiratory cilia (26,27). Hence, combining ambroxol and clenbuterol can provide greater improvement in respiratory symptom relief as compared to AHI.

Ambroxol can improve the spasmolytic activity of clenbuterol to ameliorate the symptoms of bronchospasm, which could exert a synergistic effect with clenbuterol. This endows AHCHOS with better outcomes as compared to AHI (12).

Finally, AHCHOS suppresses inflammation and restores immune balance and blood oxygen in pediatric patients with respiratory diseases (28-30).

Safety is also another crucial concern in the treatment of pediatric patients. In one study, an ambroxol-based regimen demonstrated a good safety profile in patients with severe pneumonia (31). In another study, an ambroxol-based regimen produced few adverse reactions in patients with chronic bronchitis (32). Meanwhile, in a study on AHCHOS (33), there were no obvious adverse events caused by AHCHOS in pediatric patients with LRTI. This is in line with our finding of no adverse reactions in either the AHCHOS or AHI groups of pediatric patients with LRTI complicated by mucoid sputum. Overall, these results indicate that AHCHOS has a favorable tolerability profile under routine clinical observation. However, given that safety monitoring was not based on a standardized adverse event reporting system, the possibility of under-reporting, particularly for mild or transient events, cannot be excluded.

Other highlights of this study are as follows: (I) the age of pediatric patients with LRTI in the AHCHOS group was low, and the median age was only 1.25 years, with the youngest age being 0.05 years. This suggests that AHCHOS could be used in patients at a young age and provide satisfactory outcomes and safety; (II) different from the tablet formular of ambroxol and clenbuterol, AHCHOS has an aromatic and sweet taste, which may be more suitable for pediatric patients; (III) when administered to pediatric patients, AHI might damage blood vessels and induce panic and pain. However, the oral solution form of AHCHOS is not associated with any of these adverse reactions; (IV) similar to previous studies, the most common disease type of LRTI in this study was pneumonia, which accounted for more than 90% of patients. Pneumonia is the most common infectious disease in childhood and one of the most common reasons pediatric patients are hospitalized. These findings support the application and popularization of AHCHOS among pediatric patients.

As a non-randomized observational study, the findings should be interpreted as associations rather than causal effects. Certain limitations related to this study should be acknowledged: (I) we employed an observational design, which could have introduced potential bias. A randomized, controlled study should be conducted to verify the study’s findings; (II) a few of the baseline characteristics differed between the AHCHOS and AHI groups, and thus potential confounding could have occurred; (III) the follow-up period was insufficiently extensive to determine the long-term efficacy of AHCHOS in these patients; (IV) safety data in this study were based on routine clinical observations rather than systematic adverse event monitoring using predefined criteria. Therefore, mild or transient adverse reactions may have been underreported; (V) the absence of reported adverse events may reflect under-reporting of mild or transient symptoms rather than their true absence; (VI) the open-label nature of the study, along with the lack of blinded outcome assessment, and the use of subjective outcome measures (e.g., symptom scores and VAS), may have introduced assessment bias; (VII) the statistical analyses were primarily based on univariate comparisons without adjustment for potential confounders. In addition, no propensity score methods or multivariable models were applied, and center-level clustering effects were not accounted for. Therefore, residual confounding may exist, and the findings should be interpreted as associative rather than causal. The generalizability of our findings is supported by the multicenter design involving 30 institutions across diverse regions in China and the inclusion of a broad pediatric population with LRTI under real-world clinical conditions.

Conclusions

AHCHOS is associated with greater improvement in respiratory symptoms and similar tolerance when compared with AHI in treating pediatric LRTI complicated by mucoid sputum.

Acknowledgments

The authors thank the following 30 Chinese institutions for their contribution to patient enrollment and data collection: Children’s Hospital, Tianjin University/Tianjin Children’s Hospital; Yichun People’s Hospital; Children’s Hospital of Chongqing Medical University; General Hospital of Ningxia Medical University; The Second Hospital of Tianjin Medical University; Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University; Baotou Central Hospital; Children’s Hospital of Soochow University; The Affiliated Hospital of Qingdao University; Xiangya Hospital Central South University; Ganzhou Women and Children’s Health Care Hospital; The Third Affiliated Hospital of Sun Yat-sen University; Xiamen Medical College Affiliated Haicang Hospital; Zhongshan Hospital, Xiamen University; Xiamen Hospital (Xiamen Children’s Hospital), Children’s Hospital of Fudan University; Children’s Hospital of Nanjing Medical University; Children’s Hospital, Zhejiang University School of Medicine; Shenzhen Children’s Hospital; Quanzhou Municipal Children’s Hospital; Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University; The First Affiliated Hospital of Fujian Medical University; Dongfang Hospital, Beijing University of Chinese Medicine; Shanghai Tenth People’s Hospital; The First Affiliated Hospital of Xiamen University; The First People’s Hospital of Foshan; Chengdu Women and Children’s Central Hospital; West China Second University Hospital, Sichuan University; Shanxi Children’s Hospital; Chongqing University Three Gorges Hospital; The Second Affiliated Hospital of Harbin Medical University.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0271/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0271/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0271/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0271/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Institutional Review Board of the Children’s Hospital of Chongqing Medical University (No. 2018-2) and adhered to the principles of the Declaration of Helsinki and its subsequent amendments. All participating hospitals/institutions were informed of and agreed to this study. Informed consent was obtained from the legal guardians of the pediatric patients (age ≤14 years).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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