Comparison of the efficacy of ambroxol hydrochloride and N‑acetylcysteine in the treatment of children with bronchopneumonia and their influence on prognosis
Affiliations: Department of Pediatrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
- Published online on: October 1, 2020 https://doi.org/10.3892/etm.2020.9260
- Article Number: 130
This article is mentioned in:
Bronchopneumonia is a common infectious disease among infants, and has a very high incidence in children (1). Mycoplasma pneumoniae, together with bacteria and viruses, is the most important cause of bronchopneumonia and there are also infections caused by both bacteria and viruses (2). The main effect of bacterial pneumonia is pulmonary parenchymal damage, whereas the main effect of viral pneumonia is interstitial involvement (2). The obstruction of ventilation is caused by the thickening of the respiratory membrane and the obstruction of the lower respiratory tract caused by pulmonary inflammation. The main signs are respiratory, such as fine rales, fever, cough, asthma and lung pain (3).
Oral antibiotics constitute the basic clinical treatment for bronchopneumonia. However, antibiotics cause great damage to the nervous system, blood system and liver function (4). In the present study, aerosol inhalation was used for the treatment of bronchopneumonia in order to convert liquid medicine into water mist through ultrasonic electronic high-frequency vibration. This method is convenient for children for active respiratory inhalation and as the drug directly targets lesions, and is also effective for expectoration, cough relief, anti-inflammation and spasmolysis (5). Intravenous injection of ambroxol hydrochloride is a common treatment for bronchopneumonia in adults (6). However, children often have fear of oral and injectable drugs, which affects treatment compliance and coordination, and requires long-term hospitalization, increasing the risk of iatrogenic infections (7). Therefore, in recent years, aerosol inhalation has been included in the treatment of pediatric bronchopneumonia, effectively reducing side effects and ensuring children's safety (8).
In clinical practice, commonly used drugs for bronchopneumonia are ambroxol hydrochloride and N-acetylcysteine, which are antitussive drugs, although N-acetylcysteine is an amino acid with strong mucus dissolution. In the present study, the efficacy of ambroxol hydrochloride and N-acetylcysteine aerosol inhalation were compared in the treatment of children with bronchial pneumonia, as well as their effect on immune function and prognosis.
Patients and methods
A total of 120 children with bronchial pneumonia admitted to The Affiliated Yantai Yuhuangding Hospital of Qingdao University (Yantai, China) from July 2015 to August 2018 were enrolled in the present study. Among them, 58 children treated with N-acetylcysteine were selected as the experimental group, and 62 children treated with ambroxol hydrochloride were selected as the control group. There were 38 boys and 20 girls in the experimental group, 1-7 years of age, with median age of 4.6±1.57 years; 39 boys and 23 girls in the control group, 1-7 years of age, with median age of 4.5±1.57 years. There was no significant difference in the general characteristics of the selected children, indicating that the two groups were comparable (P>0.05; Table I).
Inclusion and exclusion criteria
Inclusion criteria: i) Children that did not resist the treatment. The children's immediate family members and/or guardians consented to their participation in the study by signing an informed consent form; ii) diagnosis was confirmed by chest X-ray and blood routine examination, referring to clinical diagnostic criteria for infants' bronchopneumonia (9), and iii) children with normal liver and kidney function and no history of allergy.
Exclusion criteria: i) Children with other diseases affecting survival, such as tumor and immune system diseases; ii) children that resisted the treatment, and iii) children with other serious medical conditions. The study was approved by the Ethics Committee of The Affiliated Yantai Yuhuangding Hospital of Qingdao University and all immediate family members and/or guardians of the children that participated in the study were informed and signed an informed consent form.
Patients in both the experimental and control group were treated with oxygen, anti-infection and fluid replenishment therapy [anti-infection therapy can improve clinical symptoms to a certain extent, thus, the two groups were treated with the same anti-infection therapy and were given penicillin 200,000-400,000 U/(kg×day) for 3 days]. The patients in the control group received ambroxol hydrochloride (Ambroxol™, specifications: 30 mg x20 tablets, batch no. 20130507; Shanghai Boehringer Ingelheim Pharmaceutical Co., Ltd.). One tablet of ambroxol was added into 3 ml of 0.9% sodium chloride, and the solution was inserted into the mask of atomizer which was connected to the oxygen device. After the oxygen flow rate was adjusted to 7 l/min, atomization inhalation was carried out: 2 ml/time, 2 times/day, with 1 week for a course of treatment, for a total of two courses. The patients in the experimental group were treated with N-acetylcysteine (Fulushi™, specifications: 600 mg x4 tablets, batch no. 20131016; Zambon Company S.p.A.). A total of 3 ml of N-acetylcysteine were added into ~3 mg of 10% sodium chloride, and the solution was inserted into a separate mask atomizer which was connected to an oxygen device. After the oxygen flow rate was adjusted to 7 l/min, atomization inhalation was performed: 3 ml/time, 2 times/day, 1 week for a course of treatment, for a total of two courses.
Effective rate of treatments
To compare the effective rate of the clinical treatments, the following evaluation criteria of the therapeutic effects were used: Significantly effective treatment, all clinical symptoms disappeared and clinical signs basically disappeared after treatment; Effective treatment, the clinical symptoms almost disappeared and the clinical signs significantly improved after treatment; Ineffective treatment, there was no difference between the indicators before and after treatment, and there was no improvement or aggravation of the clinical symptoms and signs after treatment. Total effective rate=[(no. of significantly effective cases + no. of effective cases)/no. of total cases] x100%.
Symptoms disappearance time
The disappearance time of symptoms, such as fever, cough, lung rale, asthma and lung X-ray shadow was recorded in the two groups, and the efficacy was evaluated according to the standard literature (4).
Detection of immune function
A total of 4 ml of fasting venous blood were collected from the patients of the two groups before and after treatment, and were divided into two samples of 2 ml each. The samples were placed into an anticoagulation tube, and after centrifugation at 3,000 x g for 15 min at 4˚C, serum humoral and cellular immune functions were detected. The humoral immune function was detected by the immunorapid ejection turbidimetric method (10) and the related observation indicators immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), complement C3 and C4 were investigated. Flow cytometry was used for the detection of cellular immune function, and the related indicators CD3, CD4, CD8 and CD4/CD8 were detected and analyzed. The specific detection process was as follows: Anticoagulation treatment was first performed on the whole blood, and then 100 µl of whole blood were added into the tube. A total of 20 µl of CD4-FITC (1:500, cat. no. 561005), 10 µl of CD8-PE (1:500, cat. no. 560959) and 10 µl of CD3-PerCP (1:500, cat. no. 552851) monoclonal fluorescent antibodies (BD Biosciences) were added. The tube was placed in the dark for 15 min at room temperature, and 2 ml of hemolysin were added to dissolve the red blood cells. Each sample was mixed and left at room temperature for 10 min, and then centrifuged at 1,500 x g at 4˚C for 10 min. The supernatant was discarded and PBS buffer containing 0.1% NaN3 was added. After centrifugation at 1,500 x g at 4˚C for 10 min, the supernatant was removed. Next, the cells were resuspended and FACSCalibur flow cytometer (BD Biosciences) was used for the detection. CellQuest software (BD Biosciences) was used for analysis.
Quality of life
For the comparison of the quality of life of the patients in the two groups after 3 months of treatment, the Short Form (SF)-36 health survey (11) was used for evaluation, with 100 points in each scale (the higher the score, the higher the quality of life).
The adverse reactions of the two groups were recorded and compared, including vomiting, abdominal pain, rash, diarrhea and nausea.
Experimental data were analyzed by SPSS v20.0 statistical software (Shanghai Yuchuang Network Technology Co., Ltd.). The enumeration data were compared by χ2 test, whereas the measurement data were expressed as the mean ± standard deviation and t-test was used for their comparison between two groups. Paired t-test was used for the comparison of data at different time points. ANOVA and Least Significant Difference post hoc test were used for the comparison of data between multiple groups. The figures were generated using the GraphPad Prism 6 software (Emerald Biotech Co, Ltd.). P<0.05 was considered to indicate a statistically significant difference.
The total effective rate in the experimental group was 94.83%, which was higher than that in the control group (82.26%). The difference was statistically significant (P<0.05; Table II).
Changes in the immune function of children in the two groups
There was no significant difference in the humoral or cellular immune function indexes between the two groups before treatment (P>0.05). After treatment, IgA, IgG and complement C3 were significantly higher in both groups, compared with those before treatment (P<0.01). The experimental group had significantly higher IgM level after treatment compared with that before treatment; however, there was no significant difference between the IgM levels before and after treatment in the control group (P>0.05). In addition, there was no significant difference in complement C4 before and after treatment in the experimental group (P>0.05), whereas the complement C4 in the control group was significantly lower after treatment than that before treatment. However, there was no significant difference in C3 levels between the two groups after treatment (P>0.05; Fig. 1).
Changes of IgA, IgG, IgM, C3 and C4 in humoral immune function of children with bronchial pneumonia. The changes in the levels of (A) IgA, (B) IgG, (C) IgM, (D) C3 and (E) C4 in the humoral immune function of the children with bronchial pneumonia in the experimental and control groups are presented before and after treatment. *P<0.01. IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M.
Moreover, there was no significant difference in CD3, CD4, CD8 and CD4/CD8 between the two groups before treatment. After treatment, CD3, CD4, and CD4/CD8 were significantly increased in both groups, compared with those before treatment; however the CD8 levels were significantly decreased in both groups (P<0.05). The levels of CD3, CD4, CD4/CD8 after treatment were significantly higher in the experimental group compared with those in the control group (P<0.05), whereas CD8 was significantly lower in the experimental group than that in the control group (P<0.05; Fig. 2).
Cellular immune function changes of CD3, CD4, CD8 and CD4/CD8 in two groups of children with bronchial pneumonia. The cellular immune function changes of (A) CD3, (B) CD4, (C) CD8 and (D) CD4/CD8 in the experimental and control groups of children with bronchial pneumonia are presented before and after treatment. (E) The plots of the flow cytometry are shown. *P<0.05.
Comparison of symptom disappearance time between the two groups
The disappearance time of symptoms such as fever, cough, asthma, shadow of the lung X-ray, time of a cough disappearing and lung rales in the experimental group were significantly shorter than those in the control group (P<0.001 or <0.05; Table III).
Comparison of adverse reactions between the two groups of patients
After statistical analysis, the total number of patients with adverse reactions in the experimental group of patients, treated with N-acetylcysteine, was significantly lower than that of the control group of patients, treated with bromate hydrochloride (P<0.05; Table IV).
Comparison of quality of life between the two groups after 3 months of treatment
The quality of life of patients in the experimental and control group after 3 months of treatment was investigated, including physiological functioning, somatic pain and general health status. The scores of physiological functioning, somatic pain, general health status and vitality of the experimental group were significantly higher than those of the control group (P<0.001). However, there was no significant difference in social role functioning, emotional role functioning and mental health between the two groups (P>0.05; Table V).
Comparison of quality of life between the two groups after 3 months of treatment (mean ± SD).
In recent years, with the opening of policies, as the birth rate has increased, the incidence of bronchopneumonia in children, which is mainly related to the immature lung development and immune system (low defense ability of the body), is higher than the incidence of neonatal diarrhea. When the cough frequency caused by pneumonia is too high, patients experience pain in the bilateral costal cartilage, accompanied by the occurrence of choking and other conditions. In infants, the bronchial tissue support and rebound elasticity are relatively weak, and the ciliary movement ability is not strong, thus, the secretions in the respiratory tract cannot be discharged in time. Another important reason for obstructing the airway is that the airway smooth muscle is weak, and cough response is insufficient, further reducing secretion excretion (12). As a result, the course of disease in some children is prolonged, and even secondary complications, such as respiratory failure, heart failure or toxic intestinal paralysis pose serious threats to life. At present, the clinical treatment of bronchopneumonia in infants mainly relies on anti-infection therapies and elimination of inflammation and the curative effect is still good, although the course of treatment required for the improvement of symptoms is long. Therefore, the focus of clinical research is to effectively shorten the duration of symptoms and improve the overall curative effect of treatment (13).
The main purpose of the present study was to compare the clinical efficacy and effect on prognosis of ambroxol hydrochloride and N-acetylcysteine treatments in children with bronchopneumonia. The results showed that the clinical symptom relief time in children who received N-acetylcysteine aerosol inhalation treatment was significantly shorter than that of the control group, and the total clinical effective rate was 94.83%, which was higher than that of the control group (82.26%) (P<0.05). This result is consistent with the study of Trastotenojo et al (14), who demonstrated the distinct advantages of nebulized inhalation therapy with N-acetylcysteine. N-acetylcysteine is a derivative of acetyl group of cysteine and has a free radical scavenging effect. Because of its strong mucilage dissolving effect, N-acetylcysteine is a solution with good solubility which can be used as an expectorant in clinic (15). In-depth research has also revealed that: i) N-acetylcysteine is an antioxidant, which can effectively reduce reactive oxygen species and inhibit the activity of nuclear factor in disease-causing cells in vivo (16); and ii) the fiber in the concentrated sputum is cut off by the sulfhydryl group contained in the N-acetylcysteine molecule, so that the sputum is easily liquefied and removed from the body (15). The experimental results showed that all immune factors were significantly improved after treatment except for C3 and CD8. Hermeyer et al (17) pointed out that the key link in the occurrence and development of bronchial pneumonia was inflammatory reaction. With the aggregation of granulocytes into the inflammatory area and the release of a large number of free radicals, lipid peroxidation of the cell membrane occurs, leading to cell autolysis and tissue necrosis. N-acetylcysteine has good cell membrane penetration after entering the cell, and therefore plays an antioxidant role and doesn't cause aggravation or tissue cell damage. In clinical practice, ambroxol hydrochloride atomization inhalation has a good clinical effect in the adjuvant treatment of pediatric bronchopneumonia, indicating that atomization inhalation has a good effect in drug delivery. In the present study, the results showed that, compared with hydrochloric acid, N-acetylcysteine atomization inhalation effects are more significant. In order to further explore the curative effect of N-acetylcysteine atomization inhalation therapy the cell and humoral immunity function in the two groups of children were investigated. The results showed that the immune function of the two groups of children was obviously affected after treatment, with the immune function showing a certain degree of recovery, which was more apparent in the patients of the experimental group (18). The reason for the failure of the bronchopneumonia treatment is that the main antibody against infection is significantly reduced during the anti-inflammatory reaction and the incomplete development of the immune function in children makes it impossible to be replenished in time. In the present study the SF-36 scoring system was also used to measure the quality of life of the two groups of patients after treatment, including the assessment of physiological functioning, somatic pain, general health status, vitality, social functioning, emotional functioning and mental health. The results revealed that the patients treated with N-acetylcysteine had significantly higher scores than the patients treated with ambroxol hydrochloride. N-acetylcysteine dissolves sputum, reduces sputum adhesion force, increases the cilia movement and inhibits the growth of pathogenic bacteria, reducing the local inflammation reaction, thus, impairing the immunity system, so that the body's humoral immunity gradually returns to normal. In the present study, the number of patients selected was small, and the experimental results are therefore limited. The reliability of the presented data needs to be further verified by future studies with a greater sample size.
In summary, the present study showed that the total effective rate, cellular immune function, humoral immune function and the quality of life in the two groups of children were significantly improved after the different treatments except for C4. Inhalation of N-acetylcysteine can effectively improve the clinical symptoms and signs, as well as the immune function of children with bronchial pneumonia, and the curative effect is remarkable, suggesting that N-acetylcysteine treatment is worthy of use in clinic.
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
HL wrote the manuscript, analyzed and interpreted the patient data. WW designed the study and performed the flow cytometry and immunoturbidimetric assay. XG was responsible for the analysis and interpretation of the data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of The Affiliated Yantai Yuhuangding Hospital of Qingdao University (Yantai, China). Patients who participated in this research had complete clinical data. Signed written informed consents were obtained from all children's immediate family members and/or guardians.
Patient consent for publication
The authors declare that they have no competing interests.
Dhanapal CK, Mathew J, Madhusudhan S, Manavalan R and Roy V: A Hospital Based study on some Clinico-epidemiological aspect of bronchopneumonia among infants and young children. Int J Chem Sci, 2009 doi: 10.1234/jgpt.v1i1.37.
Zhang XL, Ji W, Ji ZH, Ding YF, Zhu H, Yan YD, Huang YP, He YX, Ye JX and Ji XQ: Epidemiological study on respiratory syncytial virus and its bronchopneumonia among children in Suzhou. Zhonghua Yu Fang Yi Xue Za Zhi. 41:371–374. 2007.(In Chinese). PubMed/NCBI
Chang CC, Cheng AC and Chang AB: Over the counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database Syst Rev. 10(CD006088)2014.PubMed/NCBI View Article : Google Scholar
Zhou WF, Chen Q, Jin MF, Ji ZH, Zhang MZ, Li HM, Liu FJ and Ji W: The diagnostic accuracy of high-mobility group box 1 protein and twelve other markers in discriminating bacterial, viral and co-infected bronchial pneumonia in Han children. Microbiol Immunol. 55:279–288. 2011.PubMed/NCBI View Article : Google Scholar
Pairet M, Engelmann P, Von Nicolai H, Champeroux P, Richard S, Rauber G and Engelhardt G: Ambroxol improves the Broncho-spasmolytic activity of clenbuterol in the guinea-pig. J Pharm Pharmacol. 49:184–186. 2011.PubMed/NCBI View Article : Google Scholar
Behrendt G, Baer K, Buffo A, Curtis MA, Faull RL, Rees MI, Götz M and Dimou L: Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. Glia. 61:273–286. 2013.PubMed/NCBI View Article : Google Scholar
Li YQ, Yuan W and Zhang SL: Clinical and experimental study of xiao er ke cuan ling oral liquid in the treatment of infantile bronchopneumonia. Zhongguo Zhong XI Yi Jie He Za Zhi. 12:719–721, 737, 708. 1992.(In Chinese). PubMed/NCBI
Chen X, Liu Z, Ge X, Luo X, Huang S, Zhou Y, Li D, Cheng H, Li L, Huang L, et al: Associations between manganese exposure and multiple immunological parameters in manganese-exposed workers healthy cohort. J Trace Elem Med Biol. 59(126454)2020.PubMed/NCBI View Article : Google Scholar
Olivieri A, Carli GFD, Panebianco R, et al: The use of SF-36 questionnaire for the evaluation of quality of life of patients with chronic bronchitis undergoing to antibiotic prophylaxis of acute exacerbations. Qual Life Res. 3:88–89. 1994.
Mosbah AA, Abdellatif NA, Sorour EI and Awadallah MF: Serum Sp-D levels as a biomarker of lung injury in Children suffering of bronchopneumonia. J Egypt Soc Parasitol. 42:25–32. 2012.PubMed/NCBI View Article : Google Scholar
Miyata T, Ishii T, Sugiyama N, Okano Y, Nishi N, Takahama K, Ogasawara S, Oda Y, Yokoyama K, Murata Y, et al: Effect of N-acetylneuraminic acid on respiratory tract secretion and inflammation in the bronchitic rabbit. Arch Int Pharmacodyn Ther. 304:277–289. 1990.PubMed/NCBI
Trastotenojo MS, Harsoyo N, Sachro AD, Soemantri AG and Said HW: Use of acetyl cysteine in respiratory tract disease in children. Paediatr Indones. 24:1–10. 1984.PubMed/NCBI
Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA and Wright PE: A trial of antioxidants N-acetylcysteine and Procysteine in ARDS. Chest. 112:164–172. 1997.PubMed/NCBI View Article : Google Scholar
Hermeyer K, Buchenau I, Thomasmeyer A, Baum B, Spergser J, Rosengarten R and Hewicker-Trautwein M: Chronic pneumonia in calves after experimental infection with Mycoplasma bovis strain 1067: Characterization of lung pathology, persistence of variable surface protein antigens and local immune response. Acta Vet Scand. 54(9)2012.PubMed/NCBI View Article : Google Scholar
Rong-Xin J, Yi Y and Pediatrics DO: Comparison of curative effects of N-acetylcysteine and ambroxol hydrochloride in treatment of children with bronchial pneumonia and the effect on immune function and clinical symptoms. Maternal Child Health Care China, 2018.