Acute viral infections affecting the lower respiratory tract are experienced by 11-12% of children in the first year of life, 6% of children aged 1 to 2 years, and 3.5% of children over 2 years of age [1, 2]. Among infants under 12 months of age suffering from acute respiratory viral infection, the bronchi and bronchioles are involved in the inflammatory process in a third of cases, of which broncho-obstructive syndrome develops in a third of cases. Viral lower respiratory tract infections account for 17% of hospitalizations in early childhood [3]. The mortality rate for viral bronchiolitis and bronchitis does not exceed 0.3-1.0%, and children with concomitant diseases die, in particular premature infants, suffering from bronchopulmonary dysplasia or congenital heart defects [4].
Acute bronchiolitis (AB) is a widespread inflammation of the small bronchi and bronchioles against the background of a viral infection in a young child, which manifests itself in the form of bronchial obstruction syndrome with respiratory failure and hypoxemia, with auscultatory phenomena in the lungs such as diffuse crepitus and wheezing [5, 6]. It is the signs of severe respiratory failure and the predominance of crepitus in the auscultatory picture that distinguish bronchiolitis from obstructive bronchitis [7]. In severe cases of bronchiolitis in a child, the respiratory rate reaches 70 per minute or more, there may be “moaning” or “groaning” breathing with “bloating” of the wings of the nose and strong retractions of the yielding places of the chest and hypochondrium, with episodes of apnea, which is accompanied by cyanosis, lethargy , reduction in nutrition volume [8]. The nature of OB in 90% of cases is viral, and most often its etiological factor is respiratory syncytial virus (RS) [9].
Etiotropic treatment: state of the issue and prospects
There is no effective etiotropic treatment for OB yet [10]. The use of inhaled ribavirin for RS viral bronchiolitis is not justified, although some researchers have reported a decrease in the duration of hospitalization and the frequency of repeated episodes of broncho-obstructive syndrome in patients receiving ribavirin [11]. For the prevention (but not for treatment) of acute RS viral bronchiolitis in children at risk of severe RS virus infection, palivizumab, which is a drug of monoclonal antibodies to the F protein of the RS virus, has been used for more than 10 years [12]. Another monoclonal antibody drug, motavizumab, which has a higher affinity for the F protein of the RS virus, seemed promising in the treatment of RS viral bronchiolitis. However, the licensing of motavizumab was temporarily suspended because its use in clinical trials was accompanied by a high incidence of hypersensitivity reactions [12].
Other areas of development of antiviral drugs for the treatment of viral bronchiolitis include small interfering RNA, which reduces the expression of viral RNA and, accordingly, reduces the production of viral protein, as well as drugs that inhibit RNA polymerase [12].
The goals of OB therapy are to maintain adequate fluid balance, normal oxygenation, and improve respiratory function. In the absence of evidence of bacterial superinfection, antibiotics should not be prescribed for bronchiolitis [13].
Journal "Child's Health" 1 (69) 2021
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Maintaining adequate fluid balance during bronchiolitis
Children suffering from bronchiolitis often develop dehydration. Firstly, this is due to a decrease in the amount of food and fluid consumed due to lethargy, shortness of breath, and difficulty in nasal breathing. Secondly, dehydration occurs due to additional fluid losses associated with tachypnea, fever, and sometimes vomiting due to coughing [14]. To restore water and electrolyte balance, oral rehydration with saline solutions is performed [15]. Breastfeeding should not be stopped. Since a baby with shortness of breath and nasal congestion gets tired quickly during sucking, feeding should be frequent and divided. To reduce shortness of breath and reduce the risk of aspiration of food, a semi-vertical position of the child during feeding is recommended; the head end of the crib should be raised by 30-45 °. In severe cases, rehydration is carried out through a tube or parenterally [15]. Since RS viral infection can lead to the syndrome of inappropriate secretion of antidiuretic hormone, and also due to the risk of developing pulmonary edema, the volume of intravenous infusions should be limited and administered to 2/3 of the calculated fluid requirement [15].
Ensuring normal oxygenation during bronchiolitis
Supplemental oxygen is prescribed when blood oxygenation decreases, which is monitored by the level of hemoglobin oxygen saturation (SpO2) [16]. It should be remembered that SpO2 threshold values depend on the clinical indicators of the child’s condition. To decide whether oxygen therapy is necessary, it is important to assess the presence and severity of shortness of breath. For an initially healthy child without shortness of breath, fever and normal appetite, it is recommended to administer additional oxygen when SpO2 drops below 90%. Since the affinity of hemoglobin for oxygen decreases during acidosis and fever, a significantly higher partial pressure of oxygen in the alveoli and arterial blood is required to achieve the same SpO2 values. Therefore, in these cases, oxygen therapy should be started already at SpO2≤94% [5].
Improving respiratory function in bronchiolitis
In foreign clinics, to facilitate the passage of the gas mixture through narrowed respiratory tracts, heliox, which is a mixture of helium and oxygen, is used. Ease of breathing is achieved due to the fact that the density of helium is lower than that of air. The use of heliox improves clinical indicators of disease severity, but does not affect the frequency of tracheal intubation and mechanical ventilation [17].
Respiratory support includes continuous positive airway pressure (CPAP) to prevent dynamic airway collapse and improve gas exchange. The CPAP method is indispensable for severe respiratory failure, when an increase in the oxygen fraction in inspired air of 50% is required, as well as for children with apnea. In rare cases, tracheal intubation and artificial ventilation (ALV) are required. Sometimes surfactant is administered during mechanical ventilation [15]. To improve ventilation of the posterior-lower sections of the lungs, it is recommended to position the child on his stomach, which is used in a 24-hour hospital setting [15].
To facilitate nasal breathing, the nasopharynx is sanitized with saline solutions and an electric aspirator. The effect of local vasoconstrictors for children in the first months of life has not been proven [5]. Steam inhalations are ineffective for bronchiolitis [18]. There is also no convincing data in favor of the effectiveness of chest drainage massage for bronchiolitis [19].
Bronchodilator therapy for bronchiolitis
The mechanism of bronchial obstruction in bronchiolitis is associated with swelling of the mucous membrane of the bronchi and bronchioles, accumulation of mucous secretions and cellular debris in the lumen of the respiratory tract, and, to a lesser extent, with bronchospasm. The small caliber of the bronchi and bronchioles makes children especially vulnerable to the development of bronchial obstruction, because swelling of the mucous membrane of the small airways in a child by just 1 mm causes an increase in air flow resistance by more than 50%. The valve mechanism of bronchial obstruction leads to air retention in the lungs. In those segments of the lungs where the obstruction of the bronchioles or bronchi is complete, atelectasis is formed [20].
For bronchiolitis, three classes of inhaled bronchodilators are used - β2-adrenomimetics (salbutamol, fenoterol), anticholinergic drugs (ipratropium bromide) and α-, β-adrenergic agonists (epinephrine); β2-adrenergic agonists temporarily improve the well-being of children suffering from bronchiolitis by dilating the bronchi and bronchioles and thus reducing shortness of breath and cough [5, 21]. The use of these drugs does not shorten the duration of the disease and, when taken on an outpatient basis, does not reduce the frequency of hospitalization, but significantly improves the quality of life of patients [21]. In this regard, their use should not be abandoned, despite the contradictory information about their effectiveness: it must be remembered that the effectiveness criteria in different studies are different. The starting bronchodilator is usually salbutamol, which is a highly selective β2-adrenergic receptor agonist and is used at a dose of 0.15 mg/kg 3-4 times a day (up to one year of age - no more than 1.25 mg per inhalation) [21].
Anticholinergic drugs (ipratropium bromide) have shown effectiveness only in selected patients [22, 23]. The action of ipratropium bromide is based on the blockade of M-cholinergic receptors of the tracheobronchial tree, due to which it dilates mainly large and medium bronchi and reduces the secretion of bronchial mucus [24]. According to an analysis from the standpoint of evidence-based medicine, no particular advantages of using combination drugs (for example, the combination of fenoterol + ipratropium) have been identified, although in our country it is combination drugs that are used more often [25].
Bronchodilator therapy should be carried out under the close supervision of a physician. Not all children respond to bronchodilators. If there is no effect after using several doses of a bronchodilator, it is not advisable to continue its use [5]. It is also necessary to take into account possible side effects when using bronchodilators, most often these are hyperexcitability, tremor, sleep disturbance. Often these negative reactions may not appear immediately, but on the 3-4th day of treatment. Preference should be given to inhaled forms of bronchodilators [5].
Inhaled epinephrine (Adrenaline) theoretically has advantages over β2-adrenomimetics and anticholinergic drugs due to its additional α-adrenomimetic effect, which leads to a decrease in mucus secretion and a decrease in edema of the airway mucosa - the main mechanism of bronchial obstruction in bronchiolitis [26]. The advantage of Adrenaline over salbutamol and placebo for children with bronchiolitis has been confirmed in clinical studies [26]. When used on an outpatient basis, epinephrine significantly reduces the risk of hospitalization, although it does not affect the length of the patient’s hospital stay [26].
Glucocorticosteroids for bronchiolitis
Convincing data in favor of therapy with inhaled or systemic glucocorticosteroids (GCS) for bronchiolitis have not been obtained. GCS do not reduce the length of hospitalization and do not provide significant clinical improvement in the condition of patients with bronchiolitis [27]. An exception is the results of Schuh et al., who demonstrated the effectiveness of high doses of oral dexamethasone (1 mg/kg) administered early in the disease to children suffering from moderate to severe bronchiolitis [28].
A number of studies have examined the combination of bronchodilators and corticosteroids, either inhaled or systemic [29]. The largest study was conducted in a Canadian emergency department using a combination of inhaled epinephrine and oral dexamethasone for 6 days, which resulted in a 9.3% lower risk of hospitalization by day 7 of treatment among children receiving the study drug combination [ thirty]. Inhaled corticosteroids may be useful when used in conjunction with bronchodilators in case of repeated episodes of broncho-obstructive syndrome, atopic predisposition in a child and suspected bronchial asthma [29].
Hypertonic solution for bronchiolitis
Of interest is the use of hypertonic sodium chloride solution in inhalation therapy of bronchiolitis in children [31]. The use of hypertonic saline in the treatment of viral bronchiolitis in hospitalized children was first reported in 2003 [32]. Previously, it was used by patients with cystic fibrosis and mucociliary dysfunction [33, 34]. The mechanism of action of hypertonic saline solution is associated with a decrease in edema of the mucous membrane and submucosal layer of the bronchi and bronchioles due to the absorption of fluid along the osmotic gradient, which leads to an increase in the lumen of the airways [32]. In addition, a hypertonic solution hydrates the mucus layer in the respiratory tract, which reduces viscosity and improves the rheological properties of mucus secretions [35]. Hypertonic saline stimulates cilia movement by releasing prostaglandin E2 [36]. It can also provoke coughing and sputum production, which helps reduce bronchial obstruction.
The effectiveness of using a hypertonic solution for bronchiolitis has been confirmed in a number of clinical studies. Inhalation of a 3% sodium chloride solution reduces the length of a child’s hospital stay and improves clinical indicators of the severity of the disease [36]. Saline solution at a concentration of 3% is safe. When using more concentrated solutions of sodium chloride, in particular 7%, the risk of bronchospasm and paradoxical suppression of the motor activity of the ciliated epithelium increases [37]. Moreover, even a 3% saline solution is usually used in combination with bronchodilators, which prevents the potential development of bronchospasm. Nebulizer therapy regimens with hypertonic saline usually involve a single inhalation volume of 2-3 ml (instead of saline when used in combination with a bronchodilator with a frequency of 3-4 times. When used without a bronchodilator, inhalation with a hypertonic saline can be done every 2 hours [36]. Hypertonic the solution is equally effective when applied using a compressor and an ultrasonic nebulizer [38].
Other drugs for bronchiolitis
Evidence-based guidelines recommend that DNase [39] and montelukast [40] should not be used for bronchiolitis.
Comparative analysis of the effectiveness of various inhalation therapy regimens for children with bronchiolitis: own data
Despite the fact that the problem of OB in children is not new, the treatment of this condition still causes controversy among researchers in scientific fields and doubts among doctors at the bedside. Disagreements in solving everyday clinical problems regarding the choice of the optimal method of treatment for children with OB were the impetus for research work that was carried out in the Department of Diagnostics and Rehabilitation Treatment of the Scientific Center for Children's Health of the Russian Academy of Medical Sciences in 2009-2011.
We want to present the experience of using two bronchodilator drugs for bronchiolitis - salbutamol and the combination of fenoterol with ipratropium bromide, and also demonstrate the advantages of replacing saline with hypertonic saline in combination with a bronchodilator drug.
Bronchodilator therapy for patients with stable chronic obstructive pulmonary disease
TO
The cornerstone in the treatment of patients with chronic obstructive pulmonary disease (COPD) is therapy aimed at reducing bronchial obstruction. For this purpose, short- and long-acting b2-agonists, anticholinergic drugs, and methylxanthines are used. The position on the leading role of bronchodilator therapy in the complex treatment of patients with COPD is enshrined in both national and international consensus recommendations [1].
However, the criteria for choosing first-line bronchodilators in the clinical situation under discussion remain very uncertain.
, and often contradictory (given the fact that b2-agonists are usually as effective in COPD as anticholinergic drugs). Thus, experts from the European Respiratory Society (ERS) recommend either b2-agonists or anticholinergic drugs without clear criteria for choosing between them [2]. On the contrary, the recommendations of the American Thoracic Society (ATS), the French Pulmonological Society give preference to anticholinergic drugs (as the drugs of choice in patients with persistent symptoms), while b2-agonists are proposed to be used “on demand” in patients with paroxysmal dyspnea [3,4] . Finally, according to experts from the British Thoracic Society (BTS), b2-agonists should be prescribed initially, and anticholinergic drugs should only be used if sympathomimetics are insufficiently effective or if it is necessary to “strengthen” bronchodilator therapy [5].
Until relatively recently (1970–80s), the assumption about the possibility of using bronchodilators for COPD seemed, at least, controversial. Indeed, for many years, COPD was defined as a disease whose key pathophysiological feature was “fixed” or “irreversible” bronchial obstruction, developing as a result of inflammatory-degenerative changes in the airways and lung tissue. The irreversibility of bronchial obstruction has traditionally been considered as a reference point in the algorithm for the differential diagnosis of COPD and bronchial asthma (BA).
The belief in the irreversibility of bronchial obstruction was seriously shaken in the mid-70s of the twentieth century by the results of studies assessing the clinical effectiveness of the anticholinergic drug ipratropium bromide in patients with COPD.
Anticholinergics
First of all, it is obviously worth recalling that anticholinergic drugs (Atropa belladonna, Datura stramonium, etc.) have been used to treat respiratory diseases for several millennia. The anticholinergic effect of belladonna alkaloids, including atropine (daturine), isolated in 1833, was proven at the beginning of the 19th century. Since the mid-19th century, atropine has become the “gold standard” in the treatment of asthma. By the way, it was subsequently found that the effect of smoking cigarettes or inhaling the smoke of burning powder from belladonna leaves was comparable in severity of bronchodilation to modern bronchodilators [6].
However, over time, the use of atropine as a bronchodilator in the treatment of asthma has decreased markedly. On the one hand, this was explained by a significant number of adverse events (dry mouth, mydriasis, etc.), especially with systemic use of the drug. On the other hand, more effective and safe bronchodilator drugs appeared - sympathomimetics (1920s) and, with certain reservations, methylxanthines (1930s).
The renaissance of cholinergic blockers (anticholinergic drugs) occurred in the 1970s, when it was possible to prove the important role of the parasympathetic nervous system in the control of bronchial patency in asthma, as well as to isolate and classify muscarinic receptors (Table 1) [7,8].
As a result of numerous studies, by 1975 a fundamentally new drug was developed -
ipratropium bromide
. During clinical trials of the new drug, it turned out that its bronchodilator effect in asthma is small and is mainly additive to that of b2-agonists. At the same time, an unexpected but pleasant “surprise” was the clear bronchodilator effect of the drug in patients with COPD. Thus, perhaps for the first time, it was possible to demonstrate the reversibility of bronchial obstruction in this category of patients [8].
As a result of further research, two pathophysiological components of bronchial obstruction in COPD were finally established - reversible and irreversible.
Progressive pulmonary emphysema and the so-called small bronchi disease form an irreversible or “emphysematous” component of bronchial obstruction
. These structural changes, naturally, cannot be the point of application of drug therapy.
In turn, the reversible component of bronchial obstruction
develops as a result of processes described by the term “inflammatory remodeling of the bronchial wall” (edema, deposition of proteoglycan in the submucosa and adventitia of the bronchial wall, hypertrophy of the mucous glands and hyperplasia of goblet cells, an increase in the microvascular network of the bronchi, hypertrophy and hyperplasia of bronchial smooth muscle cells).
In this case, inflammatory swelling of the mucous membrane of the respiratory tract and excessive formation of viscous secretions, which significantly worsen the patency of the bronchi, become of particular importance. These processes are controlled by the parasympathetic nervous system, the tone of which is naturally increased in COPD. Stimulation of the vagus nerve branches by inflammatory mediators (eg, bradykinin) leads to the release of acetylcholine, which activates the corresponding muscarinic receptors in the airways (Table 1) [8]. Stimulation of M3 receptors has the greatest pathophysiological “consequences”: contraction of smooth muscle cells, hypersecretion of submucosal glands and goblet cells, swelling of the bronchial mucosa. Parasympathicotonia also causes a certain basal bronchomotor tone, as well as its slight variability.
Anticholinergic drugs (anticholinergic drugs or M-anticholinergics), which are competitive antagonists of acetylcholine, block muscarinic receptors and thereby eliminate the known effects of parasympathicotonia on postsynaptic smooth muscle receptors and mucus-forming elements of the bronchi. M1 receptors are localized in the parasympathetic ganglia and control the process of neurotransmission, and M2 receptors, located at the endings of postganglionic nerve fibers, are autoreceptors and control the release of acetylcholine into the synaptic cleft. In this regard, pharmacological blockade of M2 receptors leads to the release of significant amounts of acetylcholine and a possible worsening of bronchial obstruction.
The pathophysiological “contribution” of contraction of smooth muscles of the respiratory tract to the formation of bronchial obstruction in COPD turned out to be less certain. In the works of MS Dunnil et al., A. Nagai et al. [9,10] it has been shown that in COPD hyperplasia of airway smooth muscle occurs, although less pronounced than in asthma. in vitro studies
a clear relaxation of smooth muscle cells was found, the same in both asthmatics and those without asthma [11]. At the same time, when prescribing bronchodilators to patients with COPD, only restriction (“limiting”) of the shortening of bronchial smooth muscles occurs. This once again proves that bronchoconstriction itself has limited significance in the formation of bronchial obstruction in COPD.
Important for explaining the role and place of anticholinergic blockers in the treatment of COPD (and the disease mainly affects people in older age groups) is the fact that the sensitivity of muscarinic receptors does not decrease with age.
All of the above explains the current recognition of anticholinergic drugs as the drugs of choice in the treatment of COPD. Drugs in this group can be prescribed “on demand”, i.e. to relieve acute respiratory symptoms. However, their use on a regular basis is more justified, since anticholinergic drugs, acting on the reversible component of chronic bronchial obstruction, slow down the rate of progression of ventilation disorders and improve the quality of life of patients.
The most well-known and currently widely used inhaled anticholinergic drug is ipratropium bromide (IB).
. The drug is well tolerated, effective and safe with long-term use, does not cause the development of tachyphylaxis, and has no cardiotoxic effects. At the same time, it is important to recall once again that the sensitivity of M-cholinergic receptors does not decrease with age. That is why existing recommendations for the management of patients with COPD define approaches to prescribing IB as follows: treat “... as long as the symptoms of the disease continue to cause inconvenience to the patient” [3].
At the same time, information security is not free from known shortcomings. First of all, it has a short duration of action (4–6 hours), which results in the need for repeated inhalations (4 times a day), and the drug does not allow adequate control of possible deterioration of bronchial obstruction at night or in the early morning hours. In addition, like atropine, IB is not a selective anticholinergic blocker and dissociates equally quickly from all three types of muscarinic receptors. In this case, blockade of M2 receptors, as mentioned above, can lead to paradoxical bronchoconstriction [7].
A representative of a new generation of anticholinergic drugs is tiotropium bromide (TB)
.
The peculiarities of the chemical structure of TB explain the uniqueness of its interaction with muscarinic receptors, namely, its unique kinetic selectivity, i.e. differences in the rate of dissociation with the corresponding receptors (Table 2), as well as an increased duration of action [12,13]. In the course of the studies, in particular, it was shown that long-term bronchodilation (~ 24 hours), recorded after a single inhalation of TB, persists even after long-term use for 12 months [14,15,16].
Long-term TB therapy (for 12 months) is accompanied by optimization of bronchial obstruction, regression of respiratory symptoms, and improvement in the quality of life of patients [17]. At the same time, it was possible to demonstrate the therapeutic superiority of TB over IB in the long-term treatment of patients with COPD [18]. An important advantage of inhaled anticholinergic drugs is the minimal frequency and severity of adverse events. The most relevant of them is that dry mouth, as a rule, does not lead to discontinuation of medications [15,17,18].
b2-agonists
Along with anticholinergic drugs, b2-agonists, short-acting and long-acting, are also widely used for COPD.
The action of b2-agonists (stimulants of b2-adrenergic receptors) is mediated through an increase in the intracellular concentration of cAMP, which leads to a variety of biological and therapeutic effects (including relaxation of the smooth muscles of the respiratory tract and improvement of bronchial patency). The question of the therapeutic comparability of b2-agonists and anticholinergic drugs in COPD has been discussed for a long time, and the choice between these groups of drugs was (and is) often made empirically. However, it is currently proposed to choose one or another direction of bronchodilator therapy, taking into account the individual sensitivity of the patient (based on the results of the inhalation test).
Short-acting b2 agonists
can be used “on demand”, i.e. to relieve symptoms and on a regular basis. According to the results of a meta-analysis conducted by P. Sestini et al. [19], regular use of short-acting b2-agonists for 1–8 weeks leads to a slight increase in FEV1 (~ 0.14 L) and also reduces the severity of shortness of breath compared to placebo. However, the data do not provide clear evidence of a therapeutic superiority of regular use of inhaled b2-agonists compared with their on-demand use.
A retrospective analysis of studies devoted to the optimization of bronchodilator therapy for patients with COPD showed that the least number of exacerbations of the disease is observed with combination treatment (salbutamol + IB) compared with monotherapy with a b2-agonist or anticholinergic blocker [20].
The emergence of long-acting b2-agonists
(salmeterol, formoterol) has renewed the debate about the advantages of sympathomimetics over anticholinergic drugs. However, the results of the first controlled studies assessing the effectiveness of short-term administration (4–16 weeks) of the long-acting β2-agonist salmeterol in patients with stable COPD indicated a modest superiority of the bronchodilator over placebo (the increase in FEV1 was ~ 0.1 L) [21].
More recent studies have shown that long-term use of salmeterol is accompanied by a more pronounced bronchodilator effect [22], minimization of clinical symptoms [23], improvement in the quality of life of patients with COPD [24], and prolongation of the time interval from the moment the drug is prescribed to the development of the first exacerbation of the disease [ 25].
At the same time, in comparative studies - salmeterol vs
.
IB [26] and
formoterol vs. IB [27] – comparable therapeutic efficacy (regression of shortness of breath, increase in FEV1) of both directions of therapy was demonstrated.
Despite the limited pathogenetic contribution of bronchoconstriction to obstruction of the airways in patients with COPD and, accordingly, the insignificant effect of b2-agonists on the tone of bronchial smooth muscle cells, their use in the clinical situation under discussion has become almost textbook. Almost all researchers note a significant improvement in the condition of patients, regression of symptoms (especially in the morning), a decrease in the number of severe exacerbations and hospitalizations, which often do not correlate with the dynamics of FEV1.
In this regard, it should be noted that b2-agonists, in addition to their bronchodilator effect, also have other sanogenetic effects. The explanation for the latter should be sought primarily in the widespread localization of b2-adrenergic receptors not only in the smooth muscle cells of the bronchi, but also in skeletal muscles, myocardium, vascular wall, etc. And hence the multiplicity of therapeutic effects of b2-agonists: stimulation of the beating of the cilia of the ciliated epithelium of the bronchial mucosa and improvement of mucociliary clearance; increasing the strength and endurance of the respiratory muscles, incl. and diaphragm; increased myocardial contractility, decreased vascular resistance, decreased hemodynamic load on the heart and, as a consequence, increased physical performance [28].
Methylxanthines
For several decades, methylxanthines (theophylline, etc.) have been used in the treatment of asthma. Bronchodilator effect of theophylline (TF)
is carried out through inhibition of phosphodiesterase (blockade of phosphodiesterase receptors, mainly types III and IV) with a subsequent increase in the intracellular content of cAMP and relaxation of the smooth muscles of the respiratory tract. Recently, it has become known that type IV phosphodiesterase receptors are also localized on the surface of “inflammatory cells” (eosinophils, neutrophils, etc.), which explains the immunomodulatory and anti-inflammatory effects of TF.
The bronchodilator effect of TF is clearly manifested in the treatment of patients with COPD. Thus, in particular, short-term administration (6–12 weeks) of long-acting theophylline is accompanied by improved symptomatic control of the disease, especially in the morning, and an increase in FEV1 [29,30].
When discussing the possibilities of using TF in patients with COPD, one cannot ignore its extrapulmonary effects:
improvement of peripheral ventilation; reducing the development of “air traps”; improvement of diaphragm function, especially with hyperinflation of the lung; improvement (restoration) of mucociliary clearance; dilation of the arteries of the pulmonary circulation, decreased pressure in the pulmonary artery and hemodynamic “unloading” of the right heart, increased physical performance.
However, despite these and other evidence of the “therapeutic attractiveness” of TF, the role and place of the drug in the treatment of COPD has not yet been fully determined. This is partly due to the fact that TF metabolism is subject to significant changes. Thus, in smokers, people suffering from chronic alcoholism, patients taking rifampicin or anticonvulsants, the clearance of TF is accelerated, which means that when using a standard dosage regimen, the plasma concentration of the drug may not reach the therapeutic level. On the contrary, with age, in the presence of arterial hypoxemia (PaO2 < 45 mm Hg), respiratory acidosis, in patients with congestive heart failure, cirrhosis of the liver, carrying a viral infection, taking macrolides (primarily clarithromycin and erythromycin), fluoroquinolones, cimetidine (but not ranitidine), there is a slowdown in the clearance of TF, which means that even with a standard dosage regimen there is a risk of toxic concentrations of the drug appearing in the blood plasma.
However, the predictability of the effects on the plasma concentration of TF makes it possible to either avoid them or change the dose (while monitoring the concentration of the drug in the blood). It was also shown that when TF and salmeterol were used together, the amount of adverse events was comparable to the frequency of adverse events with monotherapy with each of them [31].
The second no less serious circumstance limiting the widespread use of TF is its small therapeutic latitude (proximity of therapeutic and toxic concentrations), which requires determining the concentration of the drug in the blood plasma. It has been established that the optimal concentration of TF in blood plasma is 8–15 mg/l. An increase in concentration to 16–20 mg/l is accompanied by a more pronounced bronchodilator effect, but at the same time it is fraught with a large number of adverse events, especially in patients of older age groups [32]. Meanwhile, recent studies have shown that the anti-inflammatory effect of TF is more pronounced when low drug concentrations are reached (5–10 mg/l) [33].
Currently, TF is usually classified as a second-line drug.
(i.e. after anticholinergics and b2-agonists), a kind of reserve for those patients in whom other areas of bronchodilator therapy do not adequately control the symptoms of the disease. It is also possible to prescribe TF to those patients who cannot use inhalation delivery devices.
Combined bronchodilator therapy
The combination of an inhaled b2-agonist (short-acting or long-acting) and an anticholinergic blocker is accompanied by an improvement in bronchial obstruction to a greater extent than when prescribing any of these drugs as monotherapy [34–37]. It is possible to optimize the ventilation function of the lungs to an even greater extent with the simultaneous use of b2-agonists, anticholinergic blockers and TF [38]. However, according to popular opinion, combination therapy should be used, as a rule, only if it is impossible to achieve an optimal therapeutic effect when prescribing any one class of bronchodilators.
In accordance with modern recommendations for the management of patients with COPD, in cases of inadequate control of the disease, combination therapy should be resorted to: Combivent
(IB + salbutamol) or
Berodual
(IB + fenoterol). The use of combination drugs promotes better compliance and significantly reduces the cost of treatment compared to using each drug separately.
Inhaled glucocorticoids
Currently, inhaled glucocorticoids (IGCs) deserve special attention in the treatment of COPD, taking into account the possible modification of bronchial patency when prescribed. Based on the recognition of the leading role of inflammation in the pathogenesis of bronchial obstruction in COPD ( "Chronic obstructive pulmonary disease is a disease characterized by partially irreversible airflow limitation. Airflow limitation, as a rule, has a steadily progressive nature and is caused by an abnormal inflammatory response of the lung tissue to irritation by various pathogens particles and gases" [1]
), it would be realistic to assume that the administration of anti-inflammatory drugs would lead to improved symptomatic and functional control of the disease.
Despite the fact that chronic inflammation plays a major role in the origin of COPD and asthma, the specific cellular and molecular mechanisms of inflammation in these diseases are different. Thus, in BA, the cytogram of inflammation of the bronchial mucosa is represented predominantly by eosinophilic leukocytes and CD4+ lymphocytes, and in cases of COPD, the dominant inflammatory cells are neutrophils, macrophages and CD8+ lymphocytes [39]. Hence the significant differences in response to treatment in asthma and COPD. Eosinophil cell inflammation is effectively controlled by glucocorticoids. On the contrary, these drugs have virtually no effect on the severity of neutrophil cell inflammation and the production of known inflammatory mediators and proteases by neutrophils. Moreover, in relation to eosinophilic and neutrophilic leukocytes, glucocorticoids demonstrate exactly the opposite effects - apoptosis of eosinophils and prolongation of neutrophil life.
All this explains the inconsistency of the results obtained during short-term use of IGCs in patients with COPD (including the dynamics of FEV1). Hence the well-known discrepancies in the interpretation of the role and place of IGK. Thus, according to the results of studies conducted in France, practitioners prescribe IGCs to patients with COPD in 76% of cases [40], which is comparable to the frequency of their prescription in the UK [3,41]. At the same time, the testimony that argued for this “therapeutic maximalism” was confirmed only in 10–30% of cases [1,5,40].
In turn, large-scale multicenter controlled studies (Copenhagen City Lung Study, EUROSCOP, ISOLDE, Lung Health Study II), aimed at assessing the clinical and functional effectiveness of long-term use of IGCs, yielded unexpected results (Table 3) [42]. Thus, it was shown that during the first 6 months, FEV1 values in COPD patients taking IGCs increased slightly, but by the end of the third year, bronchial patency indicators were comparable to those in groups of patients receiving placebo. However, it was found that long-term use of IGCs is accompanied by a reduction in the number of severe and moderate exacerbations of COPD by 25%
[43].
Currently, it is considered advisable to use IGCs only in patients with symptomatic COPD and positive results of the “inhalation test” ( The inhalation test is the administration of IGCs for 6 weeks - 3 months, and it is considered positive when FEV1 increases by 200 ml or more or by 15% or more compared to baseline values. In this case, FEV1 is determined 30-45 minutes after inhalation of the corresponding bronchodilator(s). It should be emphasized that monotherapy with IGCs in patients with COPD is unacceptable, and these drugs are prescribed in conjunction with bronchodilator therapy [1] .
), as well as with severe disturbances of bronchial obstruction (FEV1<50%) and repeated exacerbations of the disease, requiring the prescription of antibiotics and/or systemic glucocorticoids.
Long-term use of systemic glucocorticoids (> 2 weeks) in patients with stable COPD is not recommended due to the high risk of adverse events.
In conclusion, when characterizing bronchodilator therapy for patients with stable COPD, it is advisable to refer to the well-known provisions of the GOLD initiative [1]:
- Bronchodilators are central to the symptomatic treatment of COPD.
- Inhalation therapy is preferred.
- The choice of drug between b2-agonists, anticholinergics, theophylline, or a combination of these drugs depends on the availability and individual response to treatment in the form of relief of symptoms and absence of side effects.
- Bronchodilators are prescribed as needed or regularly to prevent or reduce the severity of symptoms.
- Long-acting bronchodilators are more suitable for regular use.
- Combination bronchodilators may increase effectiveness and reduce the risk of side effects compared with increasing the dose of a single drug.
- Currently, none of the areas of bronchodilator therapy is able to interrupt the progressive decline in bronchial patency (we can, obviously, only slow down the rate of this progression, when rational bronchodilator therapy “accompanies” the elimination of known risk factors for COPD).
- Unlike bronchial asthma, as adequate control of which is achieved in most patients it is possible to minimize therapy (“step down”), with COPD, taking into account the progressive course of the disease, over time we can only talk about intensifying treatment (“step up”) - picture 1.
Rice.
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Material and methods
The study included 52 children under 12 months of age who were hospitalized for OB no later than 72 hours from the onset of broncho-obstructive syndrome. Exclusion criteria were chronic lung and heart diseases, diagnosed bronchial asthma, as well as the extremely serious condition of the child, requiring transfer of the patient to the intensive care unit.
To assess the degree of respiratory disorders, indicators such as respiratory rate (RR), hemoglobin oxygen saturation (SpO2) and a scale of respiratory disorders (RDAI - Respiratory Distress Assessment Instrument), showing the degree of bronchial obstruction, were used (Table 1).
. Respiratory Disorders Inventory (RDAI).
By randomization, patients were divided into three groups (Fig. 1), which subsequently received various inhalation therapies 3 times a day at 8-hour intervals.
. Distribution of children into treatment groups.
Patients underwent aspiration of nasal mucosa and, if indicated, oxygen therapy and intravenous rehydration. If necessary, additional inhalations of a bronchodilator were performed or systemic corticosteroids were administered, and such cases were necessarily recorded. Dynamic indicators of the child's condition were assessed upon admission, 60 minutes after inhalation, then daily in the morning before and 60 minutes after inhalation. Additional criteria for the effectiveness of therapy were the duration of oxygen therapy and the duration of hospitalization. The “duration of hospitalization” was taken to be the period of time from admission to the hospital until the moment when the child met the following criteria: normal appetite, respiratory distress scale score less than 4 points, SpO2 ≥95% when breathing room air, remaining at this level for at least 4 hours. Adverse effects that could be related to the therapy were also assessed: tachycardia, tremor, hyperexcitability, sleep disturbance, increased cough, pallor, hypertension and vomiting.
Mucolytic and bronchodilator drugs in the treatment of bronchial obstruction during ARVI in children
In children with acute respiratory viral infections, the lower respiratory tract is often involved in the pathological process with the development of obstructive syndrome. The use of the combined drug Ascoril expectorant (bromhexine + salbutamol + guaifenesin), due to its combined bronchodilator and mucolytic action, leads to a rapid regression of the symptoms of the disease, preventing its transition to a more severe long-term course, and subsequently reduces the need for antibiotics. The clinical effectiveness and high safety profile of Ascoril expectorant allow us to recommend it as the drug of choice in children over 2 years of age with mild to moderate bronchial obstruction due to ARVI.
Rice. 1. Dynamics of symptoms of night cough in children during therapy with a combination drug (bromhexine + salbutamol + guaifenesin), compared with monotherapy with a mucolytic (bromhexine)
Rice. 2. Dynamics of symptoms of daytime cough in children during therapy with a combination drug (bromhexine + salbutamol + guaifenesin), compared with monotherapy with a mucolytic (bromhexine)
Rice. 3. The effectiveness of therapy with a combination drug (bromhexine + salbutamol + guaifenesin) in comparison with monotherapy with a mucolytic (bromhexine) according to the total symptom score, M ± m
Acute respiratory viral infections (ARVI) account for more than half of all acute infectious diseases in children, and during periods of epidemics the share of ARVI increases to 80–90%. The highest incidence rates of ARVI are observed in preschool children. Young children suffer from acute respiratory viral infections on average 3–4 times a year, while 30–40% of children in this age category suffer at least 6–8 acute respiratory viral infections per year. Children who begin to attend preschool institutions suffer from acute respiratory viral infections 1.5 times more often in the first year than their peers at home. The frequency of ARVI decreases with age, so schoolchildren suffer on average 2-3 ARVI per year.
ARVI is registered throughout the year, but the greatest number of diseases occurs from early autumn to late spring.
In children with respiratory diseases, especially at an early age, the lower respiratory tract is often involved in the pathological process with the development of obstructive syndrome (OS). There are several phenotypes of bronchial obstruction that have both clinical and prognostic significance. Transient obstruction is observed in children only in the first three years of life, persistent obstruction is observed mainly in the first 6 years of life. OS can develop in children after three years of life (late onset). In this case, atopic and non-atopic phenotypes of obstructive syndrome are distinguished, that is, OS in combination with and without atopy. Information obtained from long-term observation shows that in children with transient obstruction, pulmonary function is altered from birth, even before the first episode of obstruction. On the contrary, children with persistent obstruction and a high risk of developing bronchial asthma (BA) have normal lung function at birth, and obstructive disorders develop by the age of 4–6 years. Probably one of the significant factors predisposing to virus-induced obstructive symptoms in the first years of life is a decrease in airway lumen due to impaired fetal development in the antenatal period.
Obstructive pulmonary disease in preterm infants is usually associated with a combination of pulmonary immaturity, oxygen therapy, and ventilatory support. This primarily concerns children with low birth weight and severe neonatal respiratory disease. However, even in premature infants with an initial absence of diseases of the neonatal period, when examined at a later age, reduced respiratory function is diagnosed. It has been suggested that in prematurity, infants may be prone to an obstructive pattern. Testing of healthy premature babies in the second year of life shows that their lung function does not normalize during the period of greatest lung growth. The mechanism of persistent decline in pulmonary function in children born prematurely is not determined. This process may be the result of a narrower airway lumen and decreased elasticity of the lung tissue, which secondarily leads to changes in the alveolarization of the lung parenchyma.
Early respiratory viral infections may be a more important risk factor for bronchial obstruction than atopy. In the autumn-winter period, severe cases of bronchiolitis in children of the first two years of life are often caused by respiratory syncytial virus (RSV) and are of a typical seasonal nature. It has been established that severe bronchiolitis in 30–40% of cases is combined with the likelihood of developing asthma. RSV, when combined with human bocavirus, causes a more severe course of the disease.
The second most common etiological factor for bronchiolitis is rhinovirus (RV). In moderate to severe cases, it increases the risk of developing asthma. It should be noted: many other viral infections - influenza, parainfluenza, coronavirus infection, enterovirus, adenovirus, as well as infections caused by human metapneumovirus and bocavirus - affecting small bronchi and bronchioles, occur with the clinic of bronchiolitis. In newborns at risk of atopy, it has been shown that moderate/severe obstruction in RV disease is a more significant risk factor not only for the development of repeated episodes of obstruction by 3 years, but also the development of asthma by 6 years. Data from a number of studies have shown that the leading risk factors for recurrent bronchial obstruction after acute bronchiolitis were RV infection and a family history of asthma. Children with RV infection who received oral corticosteroid therapy were significantly less likely to develop subsequent recurrent obstruction. A study of the balance between Th1 and Th2 types of immune response showed that in children with atopy, peripheral mononuclear cells incubated with the RV virus produce interleukin-10 (IL-10), while in patients without atopy - gamma interferon and IL -12. The reduced ability of blood mononuclear cells to produce interferon gamma and IL-12 reduces viral clearance and may lead to asthma exacerbation by promoting Th2 inflammation and a deficiency of the Th1 antiviral immune response. It is currently debated whether recurrent airway infection leads to damage and thus to asthma or whether children are predisposed to asthma because they have altered interferon levels or a different cytokine response.
For a better understanding of postnatal processes, information about the antenatal period of development is important. Branching of the respiratory tract occurs in the first half of pregnancy, therefore, the characteristics of the antenatal period can affect their caliber. The ADAM33 gene plays an important role in antenatal lung development, especially in the morphogenesis of airway branching at 3–5 years of age. This gene also determines the size of the airways.
A combination of atopy in the mother with deterioration of pulmonary function in newborns has been noted, but the mechanism of this process has not been studied. Children born to mothers with preeclampsia, hypertension, and diabetes have an increased risk of developing early transient, persistent, and later obstruction. Prescription of antibiotics during labor can cause both early transient and persistent obstruction.
Maternal smoking has a direct negative effect on fetal lung development, as it leads to a decrease in IL-4 and interferon gamma and increases the proliferation of mononuclear cells in umbilical cord blood on house dust. Other studies of cord blood cells show that maternal smoking is associated with increased IL-13 and decreased interferon-gamma mRNA response after stimulation, as well as TNF-alpha production. Epidemiological studies have confirmed that maternal smoking and atopy are combined with subsequent bronchiolitis in children in the first year of life. Thus, maternal smoking significantly affects the nature of the immune response in newborns, as well as the anatomical features of the structure of the lower respiratory tract (underdevelopment of the alveoli).
RSV bronchiolitis is combined with an increase in the expression of Th2-pattern cytokines or a decrease in Th1. This makes the hypothesis that RSV causes asthma attractive. Bronchial hyperreactivity after bronchiolitis persists for a long time, this may explain the predisposition to bronchial obstruction in later life. However, the discovery of specific RSV IgE in children with bronchiolitis suggests that the result of early RSV infection in some patients may be a Th2-type immune response that predisposes these children to the development of asthma.
Genetic studies have established that polymorphism of the IL-8, IL-10 genes and toll-like receptor (TLR) genes is combined with the severity of RSV infection. It is assumed that the development of asthma in a normal child is not caused by RSV itself, but by previous exposure to unfavorable genetic and antenatal factors against the background of RSV bronchiolitis. This allows us to consider bronchiolitis as a marker of these problems, and not the cause of subsequent disorders. The addition of viral infections in such children will occur with complications and more severe manifestations of airway obstruction, which requires urgent and adequate treatment.
There is a hypothesis that early exposure to viral infections may prevent the onset of AD in later life. A connection has been established between the beginning of a child’s attendance at an organized institution at an early age and more frequent obstruction, while asthma in such children by the age of 6 develops less often than in “home” children. It is known that most asthma exacerbations are combined with viral infections. At an early age, diagnosing asthma is a difficult task due to the variability and nonspecificity of clinical manifestations, as well as the difficulties of performing functional diagnostics. In children of preschool and school age, there is an interaction between exposure to allergens, sensitization to them and viral infections.
The nonatopic phenotype of bronchial obstruction creates the greatest difficulties in diagnosing the disease. It is known that severe adenoviral infection can lead to long-term bronchial obstruction in a previously healthy child. Respiratory viruses (RV, RSV, metapneumovirus, influenza virus) affect the epithelium of the lower respiratory tract and provoke a local immunological reaction, as well as a protective antiviral response with the production of interferons, chemotaxis and activation of NK cells. The airway epithelium is a key component in respiratory disorders. Respiratory viruses damage the ciliated epithelium of the mucous membrane of the respiratory tract, increase its permeability to allergens and toxic substances, increase the sensitivity of the receptors of the submucosal layer of the bronchi, which causes their hyperreactivity and the occurrence of obstructive manifestations in children. The bronchial epithelium produces secretions containing nonspecific and specific anti-infective defense factors and responds to signals from immune cells that are involved in the initiation and maturation of the innate and adaptive immune response, including the inflammatory response to pathogens, the Th2-type immune response, structural changes in the airways and angiogenesis.
However, regardless of the predisposing factors, repeated episodes of respiratory diseases accompanied by bronchial obstruction form and/or aggravate bronchial hyperreactivity, which may likely contribute to the development of recurrent and chronic forms of bronchitis or the risk of asthma. The search for optimal diagnostic and treatment technologies that allow timely correction of bronchial obstruction is an important task for a pediatrician and pulmonologist.
Given the variety and severity of clinical symptoms, in the treatment of children with respiratory viral infections, drugs are used that act on various components of the pathological process. Mucoactive agents (ambroxol, acetylcysteine, carbocysteine) occupy a significant place in the treatment of cough during ARVI. They help to liquefy sputum, increase the secretion of its liquid part, stimulate the work of the ciliated epithelium, and promote the production of surfactant. The main direction of action of drugs in this group is to optimize the rheological properties of respiratory tract secretions, which can have a positive effect on the restoration of impaired mucociliary clearance.
The basis of complex drug therapy for bronchial obstruction during respiratory infections are bronchodilators. For mild manifestations of bronchial obstruction and the presence of difficult to separate sputum against the background of ARVI, the administration of combination drugs containing mucolytics and bronchodilators is effective. The combined drug Uskoril provides bronchodilator and expectorant effects, reduces the duration of cough, makes it productive, which helps to enhance mucociliary transport.
The components of the drug Ascoril - bromhexine + salbutamol + guaifenesin - have a bronchodilator, mucolytic and expectorant effect. Salbutamol, as a fast-acting beta-2 agonist, has a bronchodilator effect. Bromhexine hydrochloride with its active metabolite ambroxol has a pronounced mucolytic and expectorant effect due to the depolymerization and destruction of mucoproteins and mucopolysaccharides of sputum. It also stimulates the activity of secretory cells of the bronchial mucosa. Guaifenesin stimulates the secretion of the liquid part of bronchial mucus, reduces the surface tension and adhesive properties of sputum, reduces anxiety, reduces psychogenic and autonomic symptoms, and improves sleep. Menthol (racementhol) has a mild antispasmodic effect and has weak antiseptic properties. According to our data, the use of Ascoril expectorant in children aged 2 to 10 years with mild or moderate obstructive syndrome during ARVI has a pronounced positive effect on the course of the disease, both as assessed by doctors and according to the results of a parent survey. Acute respiratory diseases in the observed children occurred with a cough due to the involvement of various parts of the respiratory system in the inflammatory process (laryngotracheitis, bronchitis). In children under 6 years of age, Ascoril expectorant was prescribed 5 ml (1 teaspoon) 3 times a day, for children from 6 to 10 years old - 5–10 ml (1–2 teaspoons) 3 times a day. The best results of treatment were observed when it was started early - from the first day of the disease. The duration of therapy was 7–10 days, depending on the dynamics of symptom regression. The validity of the use of short-acting beta-2 agonists (salbutamol) as part of Ascoril is due to the presence of bronchial obstruction disorders in more than 60% of children according to bronchophonography. Oscillations in the high-frequency part of the spectrum (more than 5000 Hz), as well as deviations in the spirogram in the form of mild and moderate manifestations of bronchial obstruction were observed in more than 50% of children. Obvious clinical signs of bronchial obstruction were characterized by short-term episodes of shortness of breath, bouts of unproductive cough, and a small amount of wheezing in the lungs in only 15% of children. In patients receiving a combination drug (bromhexine + salbutamol + guaifenesin), compared with the control group of children receiving only a mucolytic (bromhexine), earlier positive dynamics were observed. By the 2–3rd day of treatment, the cough became wet, there was an improvement in sputum discharge; by the 6–7th day of treatment, the symptoms disappeared in most children (p
The presence of a short-acting bronchodilator in the drug, as well as the complementary effect of mucolytic, sedative, anti-inflammatory components, determined the pronounced clinical effectiveness and led to the disappearance of cough symptoms 3-4 days earlier than in patients in the comparison group (p
A decrease in the severity of cough symptoms was accompanied by improved sleep, increased activity in children, and normalization of their emotional state. The total score of clinical symptoms during treatment showed that the effectiveness of therapy with Ascoril expectorant was statistically significant (p
Three children (4%) of the Ascoril therapy group were given an antibacterial component due to the lack of effectiveness of treatment, but the need for its administration was significantly lower (2.5 times) than in the group of children receiving a mucolytic (in 3 children - 10%; p The positive dynamics of clinical symptoms was accompanied by a significant improvement in bronchophonography and spirography, which indicates the normalization of bronchial patency. One child had an allergic reaction to the drug in the form of a rash. The remaining children had no side effects or adverse reactions.
Thus, the combined drug Ascoril expectorant, providing a combined bronchodilator and mucolytic effect, potentiates the restoration of mucociliary clearance and leads to a more rapid regression of ARVI symptoms, preventing the transition of the disease to a more severe long-term course, and subsequently reduces the need for antibiotics. Clinical efficacy and high safety profile allow the use of Ascoril expectorant as the drug of choice in children over 2 years of age with mild to moderate bronchial obstruction due to ARVI.
When providing emergency care to children with severe broncho-obstructive syndrome, the basis of drug treatment is short-acting bronchodilators. Bronchodilators are necessary for obstructive bronchitis, bronchiolitis, threat of exacerbation or exacerbation of asthma. In pediatrics, to relieve acute bronchial obstruction disorders, various groups of bronchodilators are used: beta-2 agonists, anticholinergic drugs, methylxanthines.
The action of beta-2 agonists is based on stimulation of adrenergic receptors and is associated with activation of adenylate cyclase coupled to the receptor, which leads to an increase in the formation of c-AMP and stimulation of the calcium pump. As a result of a decrease in calcium concentration in myofibrils, dilatation of the bronchi occurs. When used inhaled, they provide a rapid (within 3–5 minutes) bronchodilator effect and help improve mucociliary transport. The method of drug administration depends on the age of the child and the severity of the disease: using metered-dose aerosol inhalers (MDIs), MDIs with a spacer, in the form of solutions for inhalation through a nebulizer and/or enterally.
To relieve bronchial obstruction in children, a combination of short-acting beta-2 agonists with cholinergic drugs is used. According to the international recommendations of the Global Initiative for Asthma (GINA, 2010) and the Russian national program “Bronchial asthma in children. Treatment strategy and prevention" (2008), a fixed combination of fenoterol and ipratropium bromide (Berodual®) is the first line of treatment for exacerbations in children from an early age. The components of the drug have different points of application and mechanisms of action. Due to the synergistic effect, the fixed combination drug uses a lower dose of the beta-2 agonist (fenoterol), which reduces the risk of side effects. Inhalations of Berodual solution through a nebulizer are carried out up to 3-4 times a day in a dosage appropriate to the child’s age (for 1 inhalation): newborns and infants - 1 drop/kg body weight; children from 1 to 6 years old – 10 drops; children over 6 years old – 10–20 drops. After inhalation, the child must be observed for 30–40 minutes.
For bronchial obstruction with severe symptoms of respiratory failure, inhaled corticosteroids (budesonide) are prescribed. The use of budesonide suspension (Pulmicort®) for nebulizer therapy in children has been well studied. Currently, more than 15 randomized controlled clinical studies of the effectiveness and safety of this drug have been published involving children aged 3 months to 18 years with varying degrees of severity of bronchial obstruction. Thus, an open study of the effectiveness of the Pulmicort® suspension was conducted at the emergency stage in Yekaterinburg and Nizhny Novgorod. The drug was used in children with moderate exacerbations of asthma at home in doses of 0.25–0.5 mg, which led to the normalization of the patients’ condition and made it possible to avoid hospitalization in all cases. In Nizhny Novgorod, doses of the drug 0.125–0.25 mg were used 2 times a day for 2 weeks in children with exacerbations, which made it possible to relieve all symptoms by the beginning of the second week of therapy. In young children at the children's clinical hospital of the First Moscow State Medical University named after. THEM. Sechenov used combination therapy (Pulmicort + Berodual + ambroxol). This combination had a faster positive effect than inhalation with Berodual solution alone or Berodual + ambroxol.
When treating exacerbations of asthma or relieving obstruction due to lower respiratory tract infections, the initial dose of Pulmicort® suspension is 0.5–1 mg 2 times a day for children from 6 months. Studies have also shown the effectiveness of administering the suspension once a day.
Currently, Pulmicort® suspension is the only inhaled glucocorticosteroid intended for use via a nebulizer, registered for the treatment of stenosing laryngotracheitis. For stenosing laryngotracheitis, Pulmicort inhalations are used to treat acute symptoms of croup at a dose of 1 mg 2 times every 30 minutes.
If inhaled steroids are ineffective or inhalations are impossible, systemic steroids (orally or parenterally) are prescribed. Indications for the use of systemic steroids for acute obstruction are:
- insufficient effect of bronchodilators (beta-2 agonists or anticholinergics);
- severe and life-threatening conditions;
- history of steroid use to relieve exacerbations.
The therapeutic effect of systemic steroids for severe obstruction lasts for 8–12 hours.
It should be remembered that these drugs have a delayed onset of action (4-6 hours), so if indicated, they should be administered as early as possible. The lowest dose that provides control of the symptoms of the disease is used (1 mg/kg body weight per day when administered orally). The duration of the course usually does not exceed 3–5 days. When conducting a short course of systemic steroids, they can be discontinued at once; a gradual dose reduction is not required. Since ARVI can provoke exacerbations in patients with asthma, the practicing physician must know the algorithm for relieving asthma exacerbations. In cases of mild exacerbation, therapy is started with inhaled short-acting beta-2 agonist using a pMDI with a spacer. If necessary, inhalations are repeated every 20–30 minutes for an hour. In young children, it is advisable to use a combined bronchodilator (beta-2 agonist and ipratropium bromide), and use a nebulizer as a delivery device. If there is no trend towards a decrease in the clinical symptoms of obstruction, the severity of the exacerbation should be reconsidered.
For moderate exacerbation of asthma, the administration of inhaled steroids (Pulmicort® suspension) in combination with bronchodilators through a nebulizer is indicated.
Severe exacerbation of asthma is an indication for hospitalization. At the outpatient stage, emergency care begins according to the previously stated principles. It should be remembered that inhaled bronchodilator therapy is carried out simultaneously with the administration of systemic steroids and oxygen therapy.
In young children with obstruction due to ARVI, a combination of an inhaled bronchodilator, a mucolytic, and an inhaled glucocorticosteroid is effective. The inclusion of mucoactive agents that have a multifactorial effect in the drug complex is advisable from 2–3 days. The drug of choice for inhalation therapy via a nebulizer is ambroxol. Mineral water should not be used for inhalation through a nebulizer. All bottled mineral waters (Essentuki, Narzan, etc.) are intended for the treatment of diseases of the gastrointestinal tract and kidneys and are not indicated for inhalation therapy, especially using a nebulizer.
Thus, only an integrated approach to the treatment of obstructive syndrome in ARVI, taking into account the clinical situation and the age of the child, can ensure high therapeutic effectiveness and have a positive impact on the patient’s quality of life.
For mild manifestations of bronchial obstruction and the presence of difficult to separate sputum against the background of ARVI, the administration of combination drugs containing mucolytics and bronchodilators is effective. The combined drug Ascoril provides bronchodilator and expectorant effects, reduces the duration of cough, makes it productive, which helps to enhance mucociliary transport.
