Clinical Practice of Nebulized Therapy in China:A National Questionnaire Survey

Zheng Zhu, MMed, Jinping Zheng, MD, FCCP, Zhongping Wu, MB,Yanqing Xie, PhD, Yi Gao, MMed, Liping Zhong, MB, and Mei Jiang, MMed

Abstract

Background: Despite having been used in the clinical practice of respiratory diseases for decades in China, theoverall description of nebulized therapy has not been reported to date. The purpose of this study was toinvestigate the basic characteristics and information on the application of nebulized therapy in the clinicalpractice of respiratory diseases in China.Methods: A questionnaire survey with 17 questions relating to nebulized therapy was carried out in three levels(tertiary, secondary, and primary) of hospitals throughout mainland China. The perspectives of various pro-fessional degrees of the medical staffs from different levels of hospitals were further studied.Results: A total of 6,449 effective questionnaires were collected from 1,328 hospitals or clinics located in 27provinces or autonomous regions of mainland China. Nebulized therapy was applied in 91.1% of the hospitals,significantly more in tertiary and secondary levels of hospitals than in the primary level of hospitals. Jet andultrasonic nebulizers were used in 53.3% and 47.7% of the hospitals, respectively. Only 50.8% of the re-sponders identified the brands of the devices. 82.5 Percent of the responders had prescribed nebulized therapy.68.8 Percent and 41.5% of responders agreed that nebulized therapy can be used for the treatment of asthma andCOPD, respectively. 86.5 Percent of responders agreed that nebulized therapy can be used for patients withacute exacerbation, whereas 27.5% stated that it can be used for stable patients. The most commonly usedmedicines were short-acting bronchodilators, followed by corticosteroids, mucolytics, and antibiotics. 17.2Percent of the responders reported adverse events of nebulized therapy experienced by the patients. Continuousmedical education and training on nebulized therapy were required by 72.1% of responders.Conclusions: The present national survey, firstly, provided the basic characteristics and information on theapplication of nebulizer therapy in the clinical practice of respiratory diseases in China. Certainly, this will helpfacilitate nebulized therapy, especially in the community hospitals. Continuous medical education and technicaltraining are essential to improve the clinical application of nebulized therapy.

Key words: inhalation therapy, nebulizer, clinical application, questionnaire survey, China

Introduction

Inhalation therapy with the advantages of rapid onset,low administered dose, and less systemic adverse effects

over routine administrations (oral or intravenous routes) hasbeen used for decades.(1) Three major types of inhalationdevices are available nowadays, i.e., metered dose inhalers(pMDIs), dry powder inhalers (DPIs), and nebulizers.(2)

When used with proper technique, the various devices areequally efficacious.(3) Inhalation therapy by pMDIs and DPIs

remain the first-line choice for maintenance treatment ofasthma and chronic obstructive pulmonary disease (COPD);nevertheless, for those with severe illness, the weak, the el-derly, or those with poor compliance in the usage of pMDI orDPI, treatment with a nebulizer does present user-friendlybenefits and provides better treatment effects. Nebulizers alsocan deliver higher doses and more kinds of drugs at the sametime for the treatment of COPD, asthma, and other respira-tory diseases. Medicine will be delivered when patientsuse general or natural tidal-volume breathing.(4) Although

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital ofGuangzhou Medical University, Guangzhou 510120, China.

JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERYVolume 27, Number 5, 2014ª Mary Ann Liebert, Inc.Pp. 386–391DOI: 10.1089/jamp.2013.1053

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nebulized therapy has been used for decades, the overalldescription of the application of nebulized therapy in Chinahas not been reported to date.

The purpose of this national questionnaire survey is toprovide the basic characteristics and information on the ap-plication of nebulized therapy in the clinical practice of re-spiratory diseases in China, including but not limited to asthmaand COPD. Certainly, this should help facilitate the applicationof nebulizer aerosol inhalation therapy by chest physicians,respiratory patients, and nebulizer device producers in China,and will also provide evidence for the development of theChinese guidelines for aerosol therapy used in COPD, asthma,and other respiratory diseases in the near future.

Methods

Organized by the steering committee of the RespiratoryTherapy and Pulmonary Function Testing Division, ChineseThoracic Society, the cross-sectional questionnaire survey wascarried out in three levels of hospitals (tertiary: provincialhospitals or teaching hospitals; secondary: district hospitals orclinics; and primary: community hospitals or clinics). Aquestionnaire consisting of 17 questions relating to the basicinformation of the hospitals or clinics, devices, commonly usedmedicines, indications, adverse events, and attitudes toward theuse of nebulized therapy, etc., was developed (Table 1). Theperspectives of medical staff with various professional degreesand from different levels of hospitals were further studied.Descriptive statistical analysis was applied to the study data.

Results

Overall description

A total of 6,449 effective questionnaires were collectedfrom 1,328 hospitals or clinics located in 27 provinces orautonomous regions of mainland China. The survey wascarried out between March and June 2012. The hospitalswere located in the following areas of mainland China:19.4% in the north, 11.5% in the northeast, 20.3% in theeast, 27.7% in the south and middle, 11.3% in the southwest,and 9.8% in the northwest of China. They were evenlydistributed regarding the geography, population distribution,and availability of medical facility (Fig. 1). Among all of thecollected questionnaires, 4,812 (74.6%) were from tertiaryhospitals, 1,088 (16.9%) were from secondary hospitals, and549 (8.5%) were from primary hospitals. It was reported thatnebulized therapy had been used in 91.1% of the hospitals.The application of nebulized therapy in primary hospitals(47.3%) was significantly less than that in tertiary (95.8%)and secondary (92.1%) levels of hospitals ( p < 0.001).Nebulized therapy has been used for more than 20 years in10.8% of hospitals, and for less than 5 years in 9.8% ofhospitals. The basic characteristics and information of theinvestigated hospitals or clinics is presented (Table 2).

Devices

Jet and ultrasonic nebulizers were used in 53.3% and 47.7%of hospitals, respectively. No vibrating mesh nebulizer use wasreported. Only 50.8% (3,274/6,449) of responders identifiedthe brand of the nebulizers. The most commonly used brandsof the devices were as follows: PARI (made in Germany),23.0% (1,484/6,449); OMRON (made in China), 2.2%: GINA

(made in China), 1.7%: YUYUE (made in China), 1.0%; aswell as some other brands. Photos of the four popular nebu-lizers are shown in Figure 2.

Medicines

The most frequently used medicines were bronchodilators,followed by corticosteroids, mucolytics, and antibiotics. In-haled salbutamol, ipratropium, and terbutaline were used in63.5%, 43.4%, and 18.1% of hospitals or clinics, respectively.Budesonide suspensions (available in doses of 0.25mg/2mL,0.5mg/2mL, and 1mg/2mL in China) were the most com-monly prescribed inhaled corticosteroids (used in 56.7% ofhospitals), but dexamethasone, a systemic corticosteroid, wasalso prescribed for nebulized therapy in 6.3% of hospitals.Ambroxol hydrochloride, gentamicin, and tobramycin wereused in 10.8%, 3.7%, and 0.4% of hospitals, respectively.Nebulized therapy with combination medication was reportedby 63.9% of responders. The commonly prescribed combi-nation formulations were reported as follows: short-acting b2-agonist (SABA) combined with corticosteroids (GCS) was

Table 1. Questionnaire Administeredto The Study Sample

1. Please name the hospital or clinic you work in.2. The level of the hospital or clinic:

2.1. Tertiary2.2. Secondary2.3. Primary

3. Is it a specialized or general hospital or clinic?4. What is your professional level: professor or chief

physician, attending, resident, or intern?5. Medical specialty:

5.1. Respiratory medicine5.2. Emergency department5.3. Pediatrics5.4. Surgical departments5.5. General internal medicine5.6. ICU5.7. Others, please indicate

6. Has nebulized therapy been used in your hospital? (Ifnot, answer the 16th question directly.)

7. How long has it been used?8. Please clarify the nebulizer devices used in your hospital:

8.1. Jet8.2. Ultrasonic8.3. Others

9. Please identify the brand and manufacture of thedevices used in your hospital.

10. Do you agree that nebulized therapy is one of theessential drug delivery methods for respiratory diseases?

11. Please state the indications for nebulized therapy.12. In which situation is the nebulized therapy used: acute

exacerbation, stable, or both conditions of the diseases?13. What are the drugs you often prescribe for nebulized

therapy?14. What are the combination forms you often use for

nebulized therapy?15. What are the adverse events reported by your patients

during the nebulized therapy?16. Please explain the reasons if nebulized therapy has not

been used in your hospital.17. Do you require continuous medical education and

training of nebulized therapy?

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reported by 39.6% (2,552/6,449); SABA combined withshort-acting muscarinic antagonists (SAMA) by 13.5% (868/6,449); antibiotics combined with GCS by 5.1% (331/6,449);SAMA combined with GCS by 10.2% (659/6,449); SABAcombined with expectorant by 3.4% (220/6,449); GCScombined with expectorant by 5.0% (323/6,449); and anti-biotics combined with expectorant by 1.7% (107/6,449).Triple therapy of SABA and SAMA combined with GCS wasreported by 15.6% (1,008/6,449) of responders.

The frequently prescribed medicines and their combina-tion formulations in different levels of hospitals are dis-played in Table 3.

Indications

83.3 Percent of responders agreed that nebulized therapyshould be considered as one of the major routes of drugdelivery for respiratory diseases, and it had been prescribed

by 82.5% of responders. The agreement of the indication ofnebulized therapy for asthma was 68.8% of responders,which was much higher than that of COPD (41.5% of re-sponders). Other indications suggested by responders were:lung infection (29.6%), laryngopharyngitis (16.7%), upperairway infection (5.2%), eosinophilic bronchitis (9.0%),and bronchiectasis (3.4%). 86.5 Percent of respondersagreed that nebulized therapy could be used for the treat-ment of patients with acute exacerbation, whereas only27.5% of responders stated that it can be used for stablepatients.

Adverse events

17.2 Percent of responders reported adverse events ex-perienced by their patients. Complaints of adverse eventswere: tremor, 17.2% (1,110/6,449); palpitation, 16.2%(1,044/6,449); arrhythmia, 10.8% (695/6,449); shortness of

FIG. 1. The area distribu-tion of recruited hospitals inmainland China.

Table 2. Basic Information Of Responders From Departments And Their Professional Levels

Tertiary (n = 4,812) Secondary (n = 1,088) Primary (n = 549)

DepartmentsRespiratory department 42.8% (2,060) 42.8% (466) 4.7% (26)Pediatric department 34.5% (1,658) 33.3% (362) 6.4% (35)Emergency department 3.0% (142) 2.2% (24) 0.4% (2)Internal medicine (excluding Respiratory) 5.2% (250) 13.1% (142) 65.8% (361)Surgery 2.2% (108) 0.6% (7) 1.6% (9)Intensive care unit 2.0% (95) 0.8% (9) 0 (0)Other departments 10.3% (499) 7.1% (78) 20.8% (114)

Doctor levelsChief physician 33.7% (1,622) 26.6% (289) 5.8% (32)Attending physician 37.7% (1,813) 44.2% (481) 47.2% (259)Resident physician 28.5% (1,373) 27.1% (295) 39.0% (214)Intern 0.1% (4) 2.1% (23) 8.0% (44)

388 ZHU ET AL.

breath, 8.4% (542/6,449); nausea or vomiting, 5.4% (349/6,449); irritating cough, 4.9% (316/6,449); uncomfortabletaste, 4.4% (284/6,449); allergic reaction to the drugs, 4.0%(262/6,449); and cross infection, 2.4% (152/6,449).

Reasons for nebulized therapy not being used

Several reasons were given by the responders. The lack ofmedicines and devices were reported by 76.2% (577/757)and 75.7% (573/757) of responders, respectively. In addi-tion, the lack of knowledge about how to use nebulizerscorrectly was reported by 72.1% (546/757) of responders.7.9 Percent of responders (60/757) reported that the cost ofthe devices and drugs for nebulized therapy was expensive.The necessity for technical training and continuous medicaleducation of nebulized therapy was addressed by most of theresponders; even 75.4% of them were from tertiary hospi-tals.

Discussion

The present study was the first national survey on theclinical application of nebulized therapy in China. It wasadministered by a wide-ranging (27 provinces of mainlandChina) and large number of responders (6,449) from dif-ferent levels (tertiary, secondary, and primary) of hospitals(1,328). About one third of the responders that came fromtertiary hospitals were chief physicians, whereas most of theresponders from the secondary and primary levels of hos-

pitals were attending and resident physicians. The answersto the questionnaire might be influenced by the knowledgeand experience of the responders, which should be takeninto account when interpreting the results of the study.Certainly, the basic and essential information on the appli-cation of nebulized therapy provided by this survey will behelpful by providing real-life evidence of nebulized therapythat may be useful in adjusting the treatment policies ofhealth authorities, medical staffs, as well as medicine andnebulizer device producers.

In this survey, we found that nebulized therapy was usedmuch less in the primary or community hospitals. In China,around 80% of the patients were treated in the primary orcommunity hospitals that are equipped with basic medicalfacilities. It is important to transfer the knowledge of neb-ulized therapy to community hospitals, as most patients willbe treated there. This might be one of the most importantfindings in the present survey.

National and international guidelines(2,3,5–7) recommendinhalation therapy as one of the preferred routes of drugdelivery for the treatment of respiratory diseases, such asasthma and COPD. However, prior to inhalation therapybeing prescribed, the doctors should take into account themedicines (e.g., available formulation, combined use), de-vices (jet, ultrasonic, or vibrating mesh nebulizer), compli-ance of the patient (child, elderly, or the weak), diseasesituation (stable or exacerbated), as well as adverseevents.(5–8)

FIG. 2. Photos of four popular neb-ulizers. (A) PARI (from Germany),(B) OMRON (from China), and (C)GINA (from China) are jet nebulizers.(D) YUYUE (from China) is an ul-trasonic nebulizer.

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Not all medicines are appropriate for nebulized therapy.For instance, dexamethasone, a nontopical corticosteroidwith less effective and long half-life that can be harmful tothe hypothalamic–pituitary–adrenal axis, was prescribed asa nebulized medicine by 6.5% of responders in the presentsurvey. Theoretically, topical steroids such as budesonideare preferred as the ideal inhaled corticosteroid, as revealedby Brogden and McTavish.(9) In terms of antibiotics, onlya few antimicrobial agents were recommended for nebu-lized therapy by the Society of Infectious Diseases Phar-macists for treatment or prevention of bronchopulmonaryinfection.(10) Among these antimicrobial agents, only to-bramycin has been well evaluated and used for cysticfibrosis, hospital-acquired pneumonia, and non-cystic fi-brosis bronchiectasis. However, in the present survey, wefound that gentamicin was used nearly 10 times more thantobramycin, although the efficacy and safety of gentamicinhave not been evaluated.

In addition, an appropriate aerosol delivery device is alsocritical for successful therapy. The features (advantages anddisadvantages) of various types of nebulizer devices shouldbe recognized.(11,12) In the survey, we found that jet nebu-lizers were used in 53.3% of hospitals, whereas ultrasonicnebulizers were used in 47.7% of hospitals, which wasconsistent with the literature we searched. Nevertheless, byconsidering the potential heating activity that could damagesome medicines, including proteins or corticosteroids, it wasrecommended that jet nebulizers were superior to ultrasonicnebulizers.

Safety issues of nebulized therapy should always be ofconcern. In the present survey, palpitation, tremor, nausea orvomiting, and allergic reaction to the drugs encountered bypatients with nebulized therapy were reported. These ad-verse events can be caused by either the medicine (i.e., b2-agonist) or the nebulized breathing maneuver. Recognizingthe potential adverse events will help to avoid or reducesuch unhappy experiences. Cross infection reported by 2.4%

of responders is another important adverse effect that shouldbe emphasized and avoided. A filter to capture aerosol ex-halation during nebulized therapy was not being used inmost parts of China due to economic conditions or un-awareness, which may be one of the potential causes ofcross infection. The cleaning of the devices is also veryimportant to avoid cross infections.

Continuous medical education and training are essentialfor better management of nebulizer therapy. Even in tertiaryhospitals, 75.4% of responders requested more training ofnebulized therapy, which would be helpful for their futureclinical practice. Consensus statements of aerosol inhalationtherapy for chronic pulmonary diseases in adults(13) andpediatrics(14) are recommended in China.

It is essential to emphasize that inhalation therapy bypMDIs and DPIs should always be recommended as thefirst-line inhalation therapy, if these devices are used prop-erly. Plaza et al. also addressed the importance of effectiveeducational strategies for the improvement of prescribers’knowledge of inhalers and inhalation techniques, especiallyfor the use of MDIs and DPIs.(15)

This study was the first national questionnaire survey onthe application of nebulized therapy in China. A fewweaknesses are worth mentioning. Firstly, the study siteswere not randomly selected. Hospitals that had not con-ducted nebulized therapy might not provide a response tothe survey and, hence, led to an underestimation of theunavailability of nebulized therapy, especially in commu-nity hospitals. Secondly, the departments in which the re-sponders served were not evenly distributed; thus, moreresponders from respiratory departments could lead to anoverestimation of the use of nebulized therapy. Thirdly,most responders were chief and attending doctors; lesstrained doctors might not master the nebulized techniquewell. In spite of these limitations, the data in the presentstudy still provided a strong evidence of how nebulizedtherapy is being used in China.

Table 3. Most Commonly Prescribed Medicines In Different Levels Of Hospitals

Tertiary (n = 4,812) Secondary (n = 1,088) Primary (n = 549)

SABASalbutamol 68.3% (3,288) 64.5% (702) 19.9% (109)Terbutaline 20.8% (999) 12.7% (138) 5.6% (31)

SAMAIpratropium 48.1% (2,313) 40.3% (439) 8.9% (49)

GCSBudesonide 61.6% (2,966) 54.8% (596) 17.1% (94)Dexamethasone 6.0% (291) 7.8% (85) 5.1% (28)

MucolyticsAmbroxol 11.9% (575) 9.5% (103) 2.9% (16)

AntibioticsGentamicin 3.7% (177) 3.4% (37) 4.9% (27)Tobramycin 0.4% (20) 0.2% (2) 0.5% (3)

Combination therapySABA +GCS 43.5% (2,093) 36.9% (401) 10.6% (58)SABA + SAMA 14.1% (677) 16.4% (178) 2.4% (13)SABA + SAMA +GCS 18.1% (869) 11.7% (127) 2.2% (12)SAMA +GCS 11.1% (535) 0.9% (108) 2.9% (16)

GCS, corticosteroids; SABA, short-acting b2-agonist; SAMA, short-acting muscarinic antagonists.

390 ZHU ET AL.

Conclusions

The present national survey is the first to report theclinical application of nebulized therapy in China. It isnecessary to be aware of the medicines, devices, indications,adverse events, as well as preparations of nebulized therapy.All levels of doctors were in need of continuous medicaleducation and technical training of nebulized therapy, inparticular, those serving in community hospitals.

Acknowledgments

This study was supported by the Development Plan ofChangjiang Scholars and Innovative Research Team(ITR0961) and The National Key Technology R&D Pro-gram of the 12th National Five-Year Development Plan(2012BAI05B00). All authors would like to acknowledge allresponders and sites for their great contribution regardingdata collection.

Zheng Zhu and Jinping Zheng drafted the manuscript.Jinping Zheng, Yanqing Xie, and Yi Gao steered studydesign and data collection. Zheng Zhu and Mei Jiang per-formed statistical analysis. Zhongping Wu and LipingZhong collected survey forms.

Author Disclosure Statement

The authors declare that there are no conflicts of interest.They also disclose no financial support for this survey.

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Received on April 11, 2013in final form, October 31, 2013

Reviewed by:David Geller

Myrna Dolovich

Address correspondence to:Dr. Jinping Zheng

State Key Laboratory of Respiratory DiseaseNational Clinical Research Center

for Respiratory DiseaseFirst Affiliated Hospital of Guangzhou Medical University

151 Yanjiang RoadGuangzhou 510120

China

E-mail: jpzhenggy@163.com

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