Management of acute exacerbations in emergency care primarily depends on nebulizers. Although jet nebulizers (JN) have been traditionally used, vibrating mesh nebulizers (VMN) are now being implemented.

A study compares aerosols generated by VMN with NIV and pulmonary deposition and distribution across regions of interest with administration of radiolabeled aerosol with jet nebulizer (JN) during NIV.

Methods

A crossover single dose study involving 9 stable subjects with moderate to severe COPD randomly allocated to receive aerosol administration by the VMN and the jet nebulizer operating with oxygen at 8 lpm during NIV. Radiolabeled bronchodilators (fill volume of 3 mL: 0.5 mL salbutamol 2.5 mg + 0.125 mL ipratropium 0.25 mg and physiologic saline up to 3 mL) were delivered until sputtering during NIV (pressures of 12 cmH2O and 5 cmH2O - inspiratory and expiratory, respectively) using an oro-nasal facemask. Radioactivity counts were performed using a gamma camera and regions of interest (ROIs) were delimited. Aerosol mass balance based on counts from the lungs, upper airways, stomach, nebulizer, circuit, inspiratory and expiratory filters, and mask were determined and expressed as a percentage of the total.

Results

Both inhaled and lung doses were greater with VMN (22.78 ± 3.38% and 12.05 ± 2.96%, respectively) than JN (12.51 ± 6.31% and 3.14 ± 1.71%; p = 0.008). Residual drug volume was lower in VMN than in JN (3.08 ± 1.3% versus 46.44 ± 5.83%, p = 0.001). Peripheral deposition of radioaerosol was significantly lower with JN than VMN.

Intragroup analysis of radioaerosol pulmonary index for ROI across vertical and horizontal gradients is shown in Table below

When analyzing intergroup deposition in different ROI across vertical and horizontal gradients, we found that NIV + VMN group had higher counts in comparison to NV + VMN group, as shown in Table below.

The percentage of inhaled mass was significantly higher in NIV + VMN group when compared to NIV + JN group (19.90 ± 3.18% versus 7.03 ± 2.97%, p = 0.008). VMN presented a lower residual volume (3.20 ± 1.33% versus 48.53 ± 6.40%, p = 0.008) and more radioaerosol deposited in the face mask and upper airways, in comparison to jet nebulizer during NIV. The JN demonstrated greater deposition in the expiratory filter than the VMN device. No differences were found regarding to mass balance found in the stomach, circuit and inspiratory filter for either group. Table represent the mass balance obtained in each compartment from both groups and mass balance of aerosol across pulmonary, extrathoracic and device compartments.

Conclusion

This study found more than 3-fold aerosolized particles from the total dose of 3 mL of solution charged into the VMN in comparison to JN. Further randomized controlled trials are necessary to evaluate clinical response to the increased level of aerosol deposition obtained from VMN and its impact to relieve respiratory discomfort and dynamic hyperinflation in COPD, as well as to develop recommendations for the use of this resource.

Reference

[1] Global Initiative for Chronic Obstructive Lung disease (GOLD), Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease, (2013) available from: http://www.goldcopd.org/ , Accessed date: 3 April 2013.

[2] P. Haidl, S. Heindl, K. Siemon, M. Bernacka, R.M. Cloes, Inhalation device requirements for patients' inhalation maneuvers, Respir. Med. 118 (2016) 65–75.

[3] D. Hochrainer, H. Hӧlz, C. Kreher, L. Scaffidi, M. Spallek, H. Wachtel, Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and pressurized metered dose inhalers, J. Aerosol Med. 18 (3) (2005 Fall) 173–282.

[4] V.G. Press, V.M. Arora, L.M. Shah, S.I. Lewis, K. Ivy, J. Charbeneau, et al., Misuse of respiratory inhalers in hospitalized patients with asthma or COPD, J. Gen. Intern.Med. 26 (6) (2011 Jun) 635–642.

[5] W. Vincken, P.R. Dekhuijzen, P. Barners, The ADMIT series – Issues in inhalation therapy. 4) How to choose inhalers devices for the treatment of COPD, Prim. Care Respir. J. 19 (1) (2010 Mar) 10–20.

[6] C. Leach, G.L. Colice, A. Luskin, Particle size of inhaler corticosteroids: Does it matter? Allergy Clin. Immunol. 124 (6 Suppl) (2009 Dec) S88–S93.

Budesonide is a medication used to manage and treat inflammatory diseases, mainly affecting the airways and gastrointestinal tract. It is in the corticosteroid class of medications. Clinicians are accustomed to adding budesonide suspension for inhalation to normal saline for nebulization. It is worth studying whether the particle size and zeta potential of the diluted budesonide suspension will affect the physical properties of the drug solution and whether it will affect the clinical efficacy.

A study analyzes the in vitro characteristics of inhaled budesonide suspension with different concentration gradient particle size and zeta potential, and compares the clinical efficacy, for providing the rational use of inhaled suspension in clinics with evidence-based medical evidence．

METHODS

According to the dilution times of budesonide suspension in clinical practice, the undiluted group, 1-fold dilution group, 2-fold dilution group, and 4-fold dilution group of budesonide suspension were set( n = 20). The changes of suspension particle size, zeta potential, and clinical efficacy of the four groups were compared．

RESULTS

The particle size of budesonide suspension with different concentration gradients changed significantly. There was a significant difference( P＜0．000 1) between the undiluted group ( 4 075±60) nm and the 1-fold dilution group ( 1 557±132) nm, and there was a significant difference ( P＜0．01) between the double dilution group ( 1 557±132) nm and the 2-fold dilution group ( 1 067±233) nm. At the same time, there was no significant difference between the 2-fold dilution group and the 4-fold dilution group. With the increase in dilution ratio, the zeta potential of budesonide suspension became extremely unstable, and the clinical efficacy gradually decreased．

Changes in particle size of budesonide suspensions at different concentration gradients

Changes in the Potential of Budesonide Suspensions at Different Concentration Gradients

CONCLUSION

The difference in concentration gradient can significantly affect the particle size and zeta potential of budesonide suspension, which may cause the decrease in titer.In order to ensure clinical efficacy, the diluted solvent of budesonide suspension for inhalation should not exceed 1 time of the original solution.

Reference

[1] Feng Q，Xiao H，Zheng C，et al．Immunosuppressive triangle depletion through the combination punches strategy for enhanced immunotherapy．Applied Materials Today，2022，26: 1013-1015．

[2] Chen C M，Chang C H，Chao C H，et al．Biophysical and chemical stability of surfactant /budesonide and the pulmonary distribution following intra-tracheal administration［J］．Drug Delivery，2019，26( 1) :604-611．

[3]Wang H M．Analysis of ultrasonic atomized inhalation of antibiotics in infant pneumonia treatment.［J］．Pak J Pharm Sci，2018，31:1653-1657．

Pediatric bronchopneumonia is a common clinical respiratory disease in pediatrics and is the leading cause of death in children<5 years of age. The clinical course of bronchopneumonia is influenced by a number of factors, including the patient's age, condition, immunity, and various medical interventions. In addition to infection control, anti-inflammatory measures such as cough suppression and sputum reduction should not be neglected. At present, the clinical treatment of pediatric bronchopneumonia is mainly the application of anti-infective drugs for antibacterial and antiviral therapy, but the simple application of anti-infective drug therapy is not ideal.

Ambroxol hydrochloride is an expectorant, on the one hand, it can dilute sputum, strengthen the ciliary function of columnar epithelial cells, which is conducive to sputum discharge; on the other hand, it can promote the synthesis and secretion of alveolar surface-active substances, and reduce the surface tension; in addition, it has an antioxidant effect as well as reduces the release of inflammatory mediators, attenuates bronchial hyperresponsiveness and reduces inflammatory reactions in lung tissues. Other studies have shown that Ambroxol hydrochloride increases the concentration of antimicrobial drugs in the airways, enhances their anti-infective capacity, and strengthens the ability of macrophages to phagocytose and kill bacteria. Therefore, Ambroxol Hydrochloride is widely used in the clinical treatment of respiratory diseases to stop cough and expectorant, especially nebulized inhalation can directly enter the lesion to play a rapid role. Budesonide is a new type of adrenocorticotropic hormone, with high glucocorticoid receptor binding capacity, strong anti-inflammatory effect, and a small dose can achieve significant therapeutic effect.

The application of budesonide in the treatment of pneumonia is mainly related to the following effects:

1.inhibition of the synthesis and release of inflammatory cytokines and inflammatory mediators.

2. Repairing the airway and inhibiting airway hyperreactivity.

3. Inhibiting the release of mucus glycoproteins in the airways and secretion from the airway epithelial mucosa. 

The systemic adverse effects of glucocorticoids limit the clinical use of these drugs. However, nebulized inhalation budesonide dose is small, the drug is mainly absorbed by the lungs, high deposition rate in the lungs, long retention time, strong local anti-inflammatory effect, and strong first-pass metabolism of budesonide swallowed through the mouth (90%), so there are fewer adverse reactions at therapeutic doses, and the safety is higher.

A study showed that budesonide combined with aminobromosol hydrochloride nebulized inhalation treatment of pediatric bronchopneumonia was superior to nebulized inhalation of aminobromosol hydrochloride alone, both in terms of the degree of symptom elimination and the duration of symptoms. Therefore, budesonide combined with ambroxol hydrochloride nebulized inhalation is effective in improving the symptoms of pediatric bronchopneumonia, and is worthy of clinical recommendation.

Invasive mechanically assisted ventilation is a common treatment for intensive care unit (ICU) patients. Because of a variety of factors, including an aging population, the number of patients who receive mechanical ventilation is increasing. Each year, one-third of patients require mechanical ventilation (MV) for more than 48 h, and many patients require aerosol therapy during the MV. Aerosol therapy is a safe and convenient method of treatment and commonly used in patients with invasive MV in the ICU, especially for patients with asthma and chronic obstructive pulmonary disease. The three most commonly used aerosolizing drugs are bronchodilators, corticosteroids, and antibiotics. However, the effect of aerosolized inhalation is reduced due to the establishment of an artificial airway in a tracheal intubated patient.  In patients with artificial airways, aerosol transmission was only one-sixth of what it was in patients without artificial airways. Over the past 25 years, with the development of aerosol equipment and operation technology, the aerosol delivery to invasive MV patients has almost been matched and even exceeded that reported in patients with nonartificial airways.

Many factors may affect the efficacious delivery of aerosols to the lungs. These factors are associated with patients, drugs, devices, artificial airways, ventilator settings, and ventilator circuits. The position of nebulizers placed by ICU nurses is another important factor. In clinical practice, the most common nebulizer position was between the tracheal tube and the Y-piece (41~46%) or after Y-piece (39~41%), respectively. Many in vitro tests showed that, when the nebulizer was placed after Y-piece or between the ventilator inlet and heated humidifier, drug delivery to the lungs was the largest.

A study indicated that when the nebulizer was placed 80 cm away from the Y-piece, the salbutamol concentrations were the highest in both serum and urine, whilst the lowest drug concentration was found when the nebulizer was located between the tracheal tube and Y-piece.

                                            Different positions of the nebulizer

Most patients with invasive MV will receive aerosol therapy every day, and ICU nurses play a crucial role during the implementation of this therapy. However, some studies showed marked discrepancies in the nebulizer operation between trial and clinical practice paradigms. This was particularly true when it came to the optimal nebulizer position. Thus, targeted atomization education or training is necessary for all ICU nurses. Increasing the awareness of ICU nurses to different nebulizer positions will likely affect aerosol delivery and help determine which position is best for patients. Moreover, standards or guidelines for aerosol therapy should focus on standardizing the atomization operation and developing measures to deal with potential hazards. Furthermore, targeted atomization educational programs should be implemented through departments or hospital education and academic conferences. Finally, future atomization studies should attempt to mirror clinical practice settings and be easy to operate. Even though the study data shows that changing the ventilator parameters during the atomization operation may be more effective, this may be very difficult to implement in clinical practice.

Reference

[1] Tobin M., Manthous C. Mechanical ventilation. American Journal of Respiratory and Critical Care Medicine.

[2] Luyt C. E., Hékimian G., Bréchot N., Chastre J. Aerosol therapy for pneumonia in the intensive care unit. Clinics in Chest Medicine.

[3] Pleasants R. A., Hess D. R. Aerosol delivery devices for obstructive lung diseases. Respiratory Care.

[4] Wen M., Zheng F. M., Li G. X., Xu J. Q. Observation on the airway effect of nebulizer at different positions for patients undergoing mechanical ventilation. Chinese General Nursing. 

Mechanically ventilated patients should be in a sitting or semi-sitting position during nebulization inhalation therapy. Domestic and foreign research and expert consensus recommend this position. When in a sitting or semi-sitting position, the patient's diaphragm moves downward and the chest cavity expands, which can increase the amount of bronchial gas exchange and improve the effect of nebulization therapy. For mechanically ventilated patients, the healthy side should be in a lying position and the head of the bed should be raised to 30~50° during nebulization therapy, which is conducive to the deposition of nebulized drugs. In addition, raising the head of the bed by 45° can reduce the incidence of ventilator-associated pneumonia (VAP) in mechanically ventilated patients.

Any obstruction in the ventilator circuit or tracheal tube, whether due to the accumulation of condensed water, tubing bends or kinks, may cause the aerosol to hit the narrow part of the tubing; the angle of the airway outlet will also affect the flow characteristics of the aerosol and increase the possibility of impact, resulting in aerosol waste and affecting the efficiency of atomization. It can be seen that before the ventilator atomization inhalation treatment, it is important to organize the ventilator pipeline and clean the condensed water.

The retention of airway secretions in patients will increase airway resistance, resulting in uneven distribution of aerosol in the airway and reduced drug deposition rate, thus affecting the effect of atomization treatment. Therefore, before atomization inhalation treatment, the sputum blocking the artificial airway should be fully aspirated.

In order to reduce the need to disconnect the ventilator circuit and avoid the escape of aerosols to contaminate the environment, it is recommended that mechanically ventilated patients use a closed suction device during aerosol inhalation therapy. The use of a closed suction device can reduce the risk of medical staff being exposed to contaminated condensed water and airway secretions. Compared with an open suction device, a closed suction device can prevent the occurrence of VAP, shorten the length of ICU stay, and reduce the rate of respiratory microbial colonization. Therefore, there is no need to remove the closed suction device during ventilator aerosol inhalation therapy.

Reference

[1] DHAND R.How should aerosols be delivered during invasive mechanical ventilation?［J］.Respir Care，2017，62（10）：1343-1367.

[2] WILLIAMS J P，ARI A，SHANMUGAM R，et al.The effect of different closed suction catheter designs and pmdiadapters on aerosol delivery in simulated adult mechanical ventilation with and without exhaled humidity ［J］.Respir Care，2018，63（9）：1154-1161.

[3] HESS D.The ventilator circuit ［ED/OL］. （2021 -10 -14）［2021-10-15］

Aerosol inhalation is used to treat respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis and pneumonia[1].It has the advantages of simple operation, high local drug concentration and few side effects,and is therefore very popular among clinicians and patients.However,not all drugs are suitable for nebulization inhalation.

The most commonly used nebulization preparations includeβ2 receptor agonists and steroids. The main nebulization products on the domestic and foreign markets include salbutamol, ipratropium bromide, budesonide, isoproterenol, etc.[2]. Ambroxol is an expectorant widely used in clinical practice. It has the effect of dissolving sticky sputum and making sputum easier to cough up. Because ambroxol has a rapid and effective effect, good tolerance, and can be used for a long time, it is considered to be an ideal expectorant[3].

The method of administration in its instructions and relevant pharmacopoeias is oral or intravenous administration. No nebulizer inhalation has been launched on the market so far. However, many domestic clinicians use ambroxol injection for nebulization inhalation to treat respiratory diseases.

There is currently a lack of systematic evaluation of relevant evidence on its effectiveness and safety. This study systematically evaluated the effect of ambroxol injection nebulization inhalation in the treatment of pneumonia, and analyzed the application value of ambroxol nebulization inhalation in the treatment of respiratory diseases in combination with clinical practice.

Reference: 

1. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest, 2005; 127(1): 335-371.

2. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol, 2003; 56(6):600-612.

3. Yang HD, Xu B. Mechanism and clinical application of ambroxol. Chinese Journal of Hospital Pharmacy, 2002; 22(1): 44.

Objective： To assess the effectiveness and safety of an aerosol inhalation of ambroxol in accessory treatment of pneumonia.

Methods： Biomedical databases, including MEDLINE, EMbase, The Cochrane Central Register of Controlled Trials (CENTRAL), CBM-disk and CNKI were searched. Randomized controlled trials (RCTs) and quasi-RCTs that compare aerosol inhalation of ambroxol with placebo or other aerosol inhalation regimens were collected. A critical quality assessment and Meta-analysis were performed for included studies.

Results： Thirteen RCTs were included and all of them were carried out in China. None of the trials described the method of randomization, allocation concealment, blind, and follow-up. With Juni scales, 13 trials scored C degree. Compared with the control group, aerosol inhalation of ambroxol improved total improvement rate and symptoms, and shortened hospital stay. Although statistical difference was not found in some comparisons, all trials showed beneficial tendency. We didn't find any RCTs describing the safety of ambroxol aerosol inhalation.

Conclusion： Because of the low quality of RCTs on ambroxol aerosol inhalation for pneumonia, no reliable conclusion can be drawn from our Meta-analysis. Well-designed RCTs and economic evaluation are urgently needed to evaluate the value and safety of aerosol inhalation of ambroxol in treating pneumonia.