Inhalation therapy is a common method for treating respiratory diseases, including aerosol inhalation, aerosol inhalation via aerosol cans, dry powder inhalation, and nebulizer inhalation, with nebulizer inhalation having the most definite efficacy and the broadest indications. However, information on the dosing regimens and drug combinations for nebulized inhalation therapy is very limited. Recently, the American Society of Health-System Pharmacists published a guideline on the combination of commonly used nebulized inhalation drugs, which provides various recommendations on the drugs available for nebulized inhalation and their combinations in a table format for clinicians to understand and master. Based on this guideline, the expert group on nebulized inhalation treatment for chronic airway diseases in adults has formulated a consensus on nebulized inhalation drug treatment based on the current situation of nebulized inhalation treatment for respiratory diseases in China, and at the same time proposed a recommended nebulized treatment plan according to different diseases.
I. Nebulization inhalation methods
1.Nebulization method and device
Inhalation therapy can be divided into wet chemotherapy and nebulization therapy: wet chemotherapy evaporates water or solution into water vapor or aerosol consisting of 0.05-50 μg droplets through a wetting device to increase the humidity of the inhaled gas, moisten the airway mucosa, dilute the sputum, and maintain the effective contouring ability of mucus cilia movement. Nebulized therapy method applies specially designed aerosol generating device to form liquid droplets or solid particles of aerosol of water and medicine, which are inhaled and deposited in the respiratory tract and alveolar target organs for the purpose of treating diseases and improving symptoms, while nebulized inhalation also has a certain effect of wetting the airway.
When a physician decides to use nebulized inhalation therapy, he or she must also decide which inhalation device to use. Currently, the main nebulizer inhalation devices are small volume nebulizers (SVN), such as jet nebulizers (jet nebulizers) and ultrasonic nebulizers (USN), both of which have advantages and disadvantages.
Jet nebulization is the most commonly used nebulization method, oxygen can be used as the jet nebulization gas source, but must pay attention to the pressure and flow rate used. Comparatively speaking, the pressure and flow rate of the gas source generated by compressed air pumps are more constant, and the homogeneity of the treatment effect is more comparable and more suitable for comparing clinical efficacy. Ultrasonic nebulization may be detrimental to some drugs such as protein or peptide-containing compounds due to the violent shock of ultrasound that warms the liquid in the nebulization vessel. Ultrasonic nebulization is also less effective than jet nebulization for suspensions (e.g., glucocorticoid solutions). In addition, in some patients prone to CO2 retention (e.g., COPD with respiratory failure), high-flow oxygen nebulization inhalation can exacerbate CO2 retention while rapidly increasing PaO2. On the other hand, nebulized inhalation of bronchodilators in patients with bronchial asthma may cause a short-term decrease in arterial partial pressure of oxygen due to a change in V/Q ratio, and it may be beneficial to premedicate these patients with adequate oxygen or apply oxygen nebulized inhalation. For nebulized inhalation therapy, if continuous application or wetting of the inhaled gas is required, high volume USN can be used.
2. The choice of nebulizer inhalation device for patients with tracheal intubation and mechanical ventilation.
Patients with tracheal intubation often need nebulized inhalation bronchodilators to treat bronchospasm. However, tracheal intubation can affect the entry of aerosols into the lower airway, and a higher dose is generally required to achieve the same efficacy. The SVN is often used in patients with tracheal intubation and is placed on the Y-tube of the ventilator or on a compound connector of the line, between the ventilator and the Y-tube. The nebulizer can be driven by compressed air or continuous oxygen flow. Studies have shown that only 3% of the aerosol settles in the lungs when SVN is applied to mechanically ventilated patients. However, if the nebulizer is connected to the ventilator tubing with a compound connector and is open only during inspiration, the amount of deposition in the lungs can be significantly increased.
Commonly used nebulizer inhalation drugs in clinical practice
At present, nebulized inhalation drugs are commonly used in hospitals, including glucocorticoids, β2 agonists, anticholinergic drugs, mucolytics, antibacterial drugs, etc.
1. Glucocorticoid
Inhaled glucocorticoids are the most effective anti-inflammatory drugs for the treatment of bronchial asthma. A large number of studies have confirmed that they can effectively relieve asthma symptoms, improve quality of life, improve lung function, control airway inflammation, reduce the number of acute attacks and reduce mortality. In addition, regular treatment with inhaled glucocorticoids is also suitable for patients with severe COPD with frequent acute exacerbations.
(1) Budesonide: Nebulized inhalation form is available in China.
Formulation: Budesonide Suspension for Inhalation
Nebulized solution: 0.5 mg/2 mL; 1 mg/2 mL.
Dosage and Administration: 1~2 mg once, 2 times a day. Budesonide suspension for inhalation should be administered via a suitable nebulizer. Depending on the nebulizer, the actual dose inhaled by the patient is 40% to 60% of the labeled amount. The nebulization time and output depend on the flow rate, the volume of the nebulizer, and the volume of the drug solution. For most nebulizers, the appropriate volume is 2 to 4 mL.
Adverse effects: hoarseness, ulcers, pharyngeal pain and discomfort, tongue and mouth irritation, dry mouth, cough and oral candidiasis. If oropharyngeal candidiasis is detected, treat with an appropriate antifungal agent and continue budesonide. The incidence of Candida infection can be minimized by having the patient rinse his or her mouth after each inhalation. Budesonide is usually well tolerated by patients. Most adverse reactions are mild and localized. The systemic effects and oropharyngeal complications associated with budesonide are dose-dependent. Clinical manifestations of steroid overdose have been observed in 50% of patients taking budesonide at 1.6 mg daily or higher doses for prolonged use alone.
Note: 1) Nebulized inhalation of budesonide alone does not provide rapid relief of airflow limitation. Therefore, budesonide should not be used alone for the treatment of AECOPD, but in combination with bronchodilators and other drugs. Budesonide nebulizer inhalation may mask the symptoms of some existing infections and may induce new infections when used. Use with caution in patients with active or quiescent tuberculosis or fungal, bacterial or viral infections of the respiratory system.
(2) Fluticasone propionate: The nebulized inhalation form is not yet available in China.
(3) Dexamethasone: A synthetic water-soluble adrenal glucocorticoid hormone, which must be transformed by the liver after entering the body to act systemically. Dexamethasone has no lipophilic group in its structure and is more water-soluble, so it is difficult to bind to glucocorticoid receptors through cell membranes and exert therapeutic effects. Because dexamethasone inhaled by nebulization binds less to airway mucosal tissue, resulting in low intrapulmonary deposition rate and short retention time in the airway, it is difficult to exert local anti-inflammatory effects by inhalation. In addition, it is not recommended because of its long biological half-life, easy accumulation in the body, and enhanced inhibition of the subthalamic-pituitary-adrenal axis.
2. Bronchodilators
Bronchodilators are necessary for the prevention or relief of symptoms in patients with asthma and COPD, and inhalation therapy is the preferred mode of administration. Repeated administration of inhaled rapid-acting bronchodilators is one of the most important therapeutic measures to relieve acute asthma attacks, and is also an effective treatment for AECOPD.
(1) Fast-acting β2 agonists (SABA): Salbutamol and terbutaline are commonly used. The former has a strong effect on relaxing airway smooth muscle, usually takes effect within 5 min and can be maintained for 4-6 h. It is the drug of choice for relieving acute asthma attacks and can also be used for exercising asthma. The latter has a slower onset of action than salbutamol, and its bronchodilatory effect is also relatively weak.
Preparation: Salbutamol Sulfate Solution for Inhalation.
Nebulizing solution: 5 mg/mL.
Dosage and Administration: Nebulized by nebulizer, not by injection or oral administration. Intermittent use may be repeated up to 4 times daily. Adults: 0.5 to 1.0 mL (2.5 to 5.0 mg salbutamol sulfate) per dose should be diluted to 2.0 to 2.5 mL with injectable saline. the diluted solution should be inhaled by the patient through an appropriate nebulizer until no more aerosol is produced. The spray can be maintained for approximately 10 min if the nebulizer and driver are properly matched. 2.0 mL (10 mg albuterol sulfate) can be used intermittently without dilution, for which 2.0 mL (10 mg albuterol sulfate) is placed in the nebulizer and the patient is allowed to inhale the nebulized solution until remission, which usually takes 3 to 5 min.
Preparation: Terbutaline Sulphate Solution for Nebulization.
Nebulization solution: 5.0 mg/2 mL.
Dosage and Administration: As initial treatment, inhaled bronchodilators should be administered on an as-needed basis, without regular dosing. Body weight >20 kg: 5.0 mg (1 vial, 2 mL)/time , up to 4 times in 24 h; body? Weight <20 kg: 2.5 mg (half vial, 1 mL)/time, up to 4 times in 24 h. If 1 whole vial is not used up at once, it can be kept in the nebulizer for 24 h.
Adverse reactions and precautions: ①There may be slight tremors in skeletal muscles, usually more pronounced in the hands, which are common adverse reactions to the use of β-adrenergic agonists, but muscle spasms are very rare. Occasionally, headache has been reported. (3) Peripheral vasodilation and mild compensatory heart rate acceleration may occur in some patients. ④Allergic reactions, including angioneurotic edema, urticaria, bronchospasm, hypotension, and deficiency, are very rare. ⑤ If bronchospasm occurs after inhalation or if existing symptoms worsen, stop nebulizer inhalation immediately, assess the patient’s condition and change to other treatment. (6) Inhalation of this drug may cause pain in the mouth and throat. (7) Use with caution during pregnancy. Consider using this drug only if the benefits to the pregnant woman outweigh the possible risks to the fetus. It may leach into the postpartum lotion of women who use it and should not be administered to women who are breastfeeding their infants unless the expected benefits outweigh the possible risks. (8) Usually should not be taken with non-selective beta-blocking drugs such as antidepressants.
(2) epinephrine, isoprenaline: non-selective beta agonists, adverse effects on the cardiovascular system, generally not recommended for the treatment of asthma and COPD, except for anaphylaxis.
(3) Short-acting anticholinergic drugs (SAMA for short): commonly used drugs such as ipratropium bromide, whose bronchodilatory effect is weaker than that of β2 agonists, and the onset of action is slower, but the duration is longer.
Preparation: Ipratropium Bromide Solution for Inhalation.
Nebulized solution: 500 μg/2 mL; 250 μg/2 mL.
Dosage and Administration: Ipratropium Bromide Solution for Inhalation should only be inhaled through a suitable nebulization device and should not be taken orally or injected. First prepare the nebulizer to add the nebulized inhalation solution. Squeeze the drug solution from the vial into the nebulizer dish. Install the nebulizer and use it as prescribed. A normal nebulizer inhaler can be used for inhalation of ipratropium bromide solution. In the presence of oxygen administration facilities, nebulized inhalation solution is best given under the condition of oxygen flow rate of 6-8 L per minute. The dosage should be adjusted according to individual patient needs; usually 500 μg/2 mL per inhalation for adults. adverse reactions and precautions: ① Common non-respiratory adverse reactions are headache, nausea and dry mouth. (2) Anticholinergic adverse reactions such as tachycardia, palpitations, ocular dysregulation, gastrointestinal motility disorders and urinary retention are rare and reversible, but the risk of urinary retention is increased in patients with existing urethral obstruction. (③Ocular adverse reactions include pupil dilation and increased intraocular pressure, so use with caution in patients with closed-angle glaucoma. ④As with other inhaled bronchodilators, it may sometimes cause coughing, local irritation, and in rare cases, bronchospasm from inhalation irritation. ⑤ Metabolic reactions such as rash, angioedema of the tongue, lips, and face, urticaria, laryngospasm, and allergic reactions have been reported. (6) It should be used with caution in patients with prostate enlargement or bladder cancer neck obstruction.
(4) Compound ipratropium bromide solution nebulized solution (2.5 mL): contains 0.5 mg of ipratropium bromide and 3.0 mg of salbutamol sulfate, along with β2 agonists and anticholinergic drugs, which have a superimposed effect on the bronchodilatory effect.
Formulation: ipratropium bromide solution for inhalation
Nebulized solution: 2.5 mL; contains ipratropium bromide 0.5 mg and salbutamol sulfate 3.0 mg (equivalent to salbutamol base 2.5 mg).
Dosage and Administration: Administered through a suitable nebulizer or intermittent positive pressure ventilator. For adults (including elderly) and adolescents over 12 years of age. Acute exacerbation: A therapeutic dose of 2.5 mL will provide relief in most cases. In severe cases where 2.5 mL does not provide symptomatic relief, a dose of 2 x 2.5 mL may be used. Maintenance treatment period: 2.5 mL of medication 3 to 4 times a day is sufficient.
Adverse effects and attention: the same as the above β agonist drugs and anticholinergic drugs.
3.Mucolytic agents
Although a small number of COPD patients may benefit from the use of mucolytic nebulized inhalation, the overall efficacy is not significant and therefore is not currently recommended as a routine drug for COPD. Inhalation administration has the potential to exacerbate airway hyperresponsiveness.
(1) Alpha-chymotrypsin: a peptidase with no evidence of therapeutic effect by inhalation in the small to medium airways, and no pharmacological data related to the combination, is prohibited for nebulization by ultrasound.
(2) Ambroxol hydrochloride: The product specification does not recommend the use of nebulized inhalation, but there have been many reports of clinical experience with nebulized treatment with static pulse formulations in China. At present, nebulized inhalation formulations are available abroad. In view of the fact that ultrasonic nebulization can heat the nebulized liquid until the protease is denatured, ultrasonic nebulization is not recommended for drug delivery.
4. Antibacterial drugs
It is advisable to avoid the local application of antimicrobial drugs, which are rarely absorbed in the local application of skin mucosa, cannot reach effective concentration at the site of infection, and are easy to cause allergic reactions or lead to the production of drug-resistant bacteria. To date, there is no preparation specifically for nebulized inhalation in China, and most clinical and research studies have used intravenous preparations instead. The intravenous preparation is not entirely suitable for nebulized drug delivery, and the intravenous preparation contains preservatives, such as phenol and sulfite, which can induce bronchial asthma.
(1) Gentamicin: it is more frequently used in China, but its efficacy and safety are still lacking sufficient evidence-based medical evidence.
(2) Amphotericin B: for aerosol inhalation, 5-10 mg for adults each time, dissolved into 0.2%-0.3% solution with sterilized water for injection; for ultrasonic nebulized inhalation, the concentration of this product is 0.01%-0.02%, 2-3 times daily inhalation, 5-10 mL each time. At present, except for tobramycin (Novartis: TOBI), which is approved by the FDA for nebulized inhalation treatment of cystic fibrosis disease [20], the safety of the other drugs has not been confirmed.
5. Others
(1) Theophylline: It is usually used as an intravenous push. It has some bronchodilatory effects, but is weaker than SABA, and no studies have confirmed its additional benefit as a beta2 agonist addition to therapy in adults with severe acute exacerbations of asthma. Theophylline remains one of the main drugs currently used in the treatment of acute exacerbations of COPD in China due to its low price and within a safe dose range. Theophylline has an irritating effect on the airway epithelium, so it is not clinically recommended for nebulized inhalation therapy.
(2) Chinese patent medicine injection: the clinical application of nebulized inhalation experience and research are insufficient, the reliability of efficacy and safety are yet to be verified, so it is not recommended.
Inhalation drugs and dose recommendations for common diseases
Airflow-restricted diseases are the preferred indications for nebulized inhalation therapy, especially for acute exacerbations of AECOPD and asthma. For non-acute exacerbations of asthma and COPD, quantitative aerosol (MDI) or dry powder inhaler (DPI) are recommended first. Some patients with more severe disease requiring larger doses of medication and those who cannot use inhalation devices properly, such as infants and children, may also be considered for administration by nebulized inhalation.
1. Studies have shown that SABA inhalation therapy should be given regularly during an acute asthma attack. Continuous nebulized inhalation of SABA followed by intermittent nebulized inhalation therapy as needed is recommended for patients hospitalized for an acute asthma attack, and when continuous nebulized inhalation is not available, intermittent nebulized inhalation therapy can be given directly.
Main symptoms Nebulization protocol dyspnea ● SABA Continuous nebulized inhalation for 1 h ● Glucocorticoids Symptoms cannot be relieved after 1 h Add SAMA
Compared with monotherapy, the combination of SABA and SAMA can better improve lung function and reduce hospitalization rate in acute exacerbations of severe asthma; however, it is controversial whether the combination of SABA and SAMA can achieve better clinical efficacy than SABA monotherapy in mild and moderate asthma exacerbations, and the combination may lead to overtreatment and economic waste; especially in hospitalized patients, the combination of SABA and SAMA has not been found to be effective. The combination of SABA and SAMA has not been found to be more clinically effective than SABA monotherapy, especially in hospitalized patients. Therefore, for acute attacks of mild to moderate asthma, SABA monotherapy inhalation therapy is preferred, and when the treatment effect is not good, the addition of SAMA combined with nebulizer inhalation therapy will be considered.
In acute asthma exacerbation, combined nebulized inhalation bronchodilator and glucocorticoid therapy can be used. Some studies have shown that concomitant inhalation of high-dose glucocorticoids has a better bronchodilatory effect compared with inhalation of salbutamol alone. Hospitalization rates were lower with the addition of inhaled glucocorticoids than with the addition of systemic glucocorticoids, especially in patients with severe acute exacerbations of asthma. Another study showed that nebulized inhaled glucocorticoids, such as fluticasone propionate, combined with nebulized inhaled bronchodilators in adult patients with acute asthma exacerbations treated in the emergency room improved peak expiratory flow (PEF) and dyspnea symptoms more rapidly than systemic prednisolone, and shortened the length of stay.
2. Recommended nebulized inhalation treatment plan for AECOPD
The Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (2011 Revision) published by GOLD states that a single inhaled short-acting β2 agonist or a combination of a short-acting β2 agonist and a short-acting anticholinergic drug is the preferred bronchodilator in acute exacerbations of COPD. These drugs improve symptoms and FEV1. There is no difference between using MDI and nebulized inhalation, but the latter may be more appropriate for more severe patients.
In patients with AECOPD with high sputum, inhaled SABA in combination with a mucolytic agent has a synergistic effect on sputum removal. The former (e.g. salbutamol) diastole the airways, allowing sputum to be easily expelled; the latter (e.g. amiloride) dissolves sputum, reduces its viscosity and promotes sputum excretion.
Nebulized inhaled glucocorticosteroids can treat AECOPD as effectively as oral hormones and can replace oral glucocorticosteroid therapy, but are relatively more expensive. Therefore, prednisolone therapy of 30-40 mg daily orally for 14 d is recommended as the preferred treatment for AECOPD [28].
3. drugs Recommended dose budesonide suspension AECOPD: 2-4 mg twice daily Acute asthma exacerbation: 1-2 mg twice daily Fluticasone suspension 0.5-2 mg twice daily [29] Salbutamol sulfate Intermittent therapy 2.5-10 mg four times daily Continuous therapy 5-10 mg diluted to 100 mL with saline and treated by aerosol using a nebulizer. Commonly administered at a rate of 1 to 2 mg/h Terbutaline sulfate On-demand weight > 20 kg: 5.0 mg/dose, up to 4 doses in 24 h weight < 20 kg: 2.5 mg/dose, up to 4 doses in 24 h ipratropium bromide 0.5 mg may be repeated 3 to 4 times daily until the patient's condition stabilizes in the acute phase, with the dosing interval determined by the response to treatment compound ipratropium bromide solution Nebulized solution ipratropium bromide 0.5 mg and salbutamol sulfate 3.0 mg 3 to 4 times a day
IV. Adverse reactions and precautions of nebulized inhalation therapy
1, complications and risks of nebulized inhalation therapy: (1) drug-related adverse reactions;; (2) bronchospasm; (3) intra-hospital infection; (4) airway burns; (5) ineffective airway hydration.
2. Precautions: (1) Disinfect the nebulizer regularly to avoid contamination and cross-infection, and advocate a nebulizer for each patient to avoid cross-infection. (2) Avoid the use of beta agonists in excessive doses, especially in the elderly, to avoid the occurrence of serious arrhythmias. (3) In a few patients, after nebulizer inhalation, instead of bronchodilation, bronchospasm is induced, which is the so-called “therapeutic paradox phenomenon”. The reasons may be: hypotonicity of drug solution, preservative-induced, low temperature of aerosol or allergy to drug solution. The cause should be sought and timely preventive and control measures should be taken. (4) Drugs with strong irritation to the respiratory tract should not be used for nebulized inhalation. Alkaline solutions, hypertonic saline, and distilled water can cause airway hyperreactivity and lead to bronchospasm and should be avoided for nebulized inhalation. Oily preparations should also not be administered by inhalation, as they can cause lipid pneumonia. (5) When using compressed air/oxygen-driven nebulizer inhalation therapy, a certain flow rate (6-8 L/min) and patency of the tubing should be maintained. (6) Ultrasonic nebulization has the effect of heating, which may destroy the composition of drugs, such as budesonide.
V. Precautions for drug compounding
The Compatibility Table provides a simple and quick reference for medical personnel on the compatibility of commonly used intravenous drugs, including glucocorticoids, antibacterial drugs and other drugs. The Stability of Trissel Mixing Components and Trissel’s two clinical pharmacy databases provide comprehensive data on a wide range of nebulized inhalation drugs, including compatibility and stability data for various drugs used in combination in the same nebulizer.
Compatibility of drugs
Note: The dark green shaded portion with the letter C indicates that there is evidence from clinical studies confirming the stability and compatibility of this pairing; the blue shaded portion with the letter R indicates that there is insufficient evidence to evaluate compatibility, but there are extensive clinical reports in this country; the red shaded portion with the letter X indicates that there is evidence confirming or suggesting that this pairing is incompatible or inappropriate; the yellow shaded portion with the letter NI indicates that there is insufficient There is sufficient evidence to evaluate compatibility, so this pairing should be avoided unless further evidence is obtained in the future
aThe manufacturer (AstraZeneca) of budesonide (Pulmicort) stated that cloudy turbidity occurs in mixtures of budesonide and cromoglicic acid (Intal), but this information was not included in the drug insert and was not confirmed by studies.
bThe manufacturer confirmed the cromoglicic acid (Intal, King Pharmaceuticals) with salbutamol (Ventolin, GlaxoSmithKline), fenoterol (Berotec, Boehringer Ingelheim), ipratropium (Alupent, Dey Laboratories), and terbutaline (Bricanyl, AstraZeneca) for Compatibility.
cThe drug insert for ipratropium bromide (Atrovent, Boehringer Ingelheim) states that ipratropium bromide should not be combined with cromoglicic acid because precipitation will occur. The cloudy haze reported immediately after mixing cromoglicic acid with ipratropium bromide is thought to be due to the action of an unknown excipient in cromoglicic acid; the manufacturer attributes the cloudy haze to the benzalkonium chloride in the formulation. However, ipratropium bromide has also been reported to remain chemically stable for 1 h when mixed with orally inhaled sodium cromoglycate solution in a nebulizer.
dAmbroxol hydrochloride (Mucosolvan, Boehringer Ingelheim) product insert does not recommend nebulized inhalation use.
eSalbutamol and ipratropium bromide are available in a combination solution for nebulized inhalation (Combivent, Boehringer Ingelheim), whose drug insert states not to mix this product with other drugs in the same nebulizer.