Asthma affects about 300 million people globally and over 400,000 deaths annually [1,2]. Approximately 12 million people in the United States each year experience an acute exacerbation of their asthma. Acute asthma should be differentiated from poor asthma control. In acute asthma, patients will exhibit increasing shortness of breath, chest tightness, coughing, and/or wheezing. In contrast, poor asthma control typically presents with a diurnal variability in airflow and is a characteristic that is usually not seen during an acute exacerbation [3]. Various clinical signs and symptoms may assist the clinician in determining the severity of acute asthma. For example, audible wheezing is usually a sign of moderate asthma, whereas no wheezing can be a sign of severe airflow obstruction. Major risk factors for near-fatal and fatal asthma should be recognized, and their presence makes early recognition and treatment of an asthma exacerbation essential. The history should include a review of comorbidities; adherence and proper use of medications, particularly proper technique in use of metered-dose inhalers; previous episodes of near-fatal asthma; and whether the patient has experienced multiple emergency room visits or hospitalizations, particularly those requiring admission to an intensive care unit, involving respiratory failure, intubation and mechanical ventilation [3,10]. Patient education is important to ensure that the patient understands that asthma is mostly a chronic disease and necessitates the avoidance of allergens, prevention of infections, adherence with routine vaccinations, management of comorbid conditions and adherence to treatment regimens. An individual management plan should include how to recognize an impending exacerbation and provide an incremental therapy regimen to be implemented according to the degree of severity and when to seek medical care. Additionally, social factors and psychiatric disorders need to be appropriately treated because each can affect access to care, adherence, and lead to other comorbid conditions [3,23]. This article is a structured review of the available literature regarding the diagnosis and management of acute asthma. Show Key words: Asthma flare; Acute asthma; Asthma attack; Wheezing; Acute asthma diagnosis; Acute asthma management Abbreviations EPR-3 - The Expert Panel Report 3 Introduction Asthma exacerbations are avoidable with appropriate, regular therapy and patient education. Despite this, asthma affects about 300 million people globally and over 400,000 deaths annually [1, 2]. In the United States alone, approximately 12 million people each year experience an acute exacerbation of their asthma [3,4]. The World Health Organization has reported 180,000 deaths from acute asthma exacerbations in 2013 [5,6]. Additionally, the financial impact of acute asthma exacerbations on patients and society is significant with total expenditures estimated to be $56 billion per year in the United States [7,8]. This manuscript is about acute asthma, its diagnosis, prognosis, and treatment. Various clinical symptoms and signs may assist the clinician in determining the severity of acute asthma (Figure 1) [3]. To prevent severe exacerbations of asthma, the goals for the physician managing subjects with asthma include: 1. Recognition of patients who are at a greater risk for near-fatal or fatal asthma. 2. Education of the patient to recognize deterioration in their disease. 3. Provision of an individual action plan for the patient to manage the exacerbation and to know when to seek professional help. This has been associated with improved health outcomes and a reduction in hospital admissions [5,9]. 4. Management of comorbidities, for example, rhinitis, sinusitis, obesity, gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), chronic obstructive respiratory disease (COPD), vocal cord dysfunction (VCD) and atopic dermatitis [8-12]. Physical Examination Clinical estimates of severity based on an interview and a physical examination can result in an inaccurate estimation of disease severity; audible wheezing is usually a sign of moderate asthma, whereas no wheezing can be a sign of severe airflow obstruction. Symptoms of severe asthma include chest tightness, cough (with or without sputum), sensation of air hunger, inability to lie flat, insomnia and severe fatigue. The signs of severe asthma include use of accessory muscles of respiration, hyperinflation of the chest, tachypnea, tachycardia, diaphoresis, obtundation, apprehensive appearance, wheezing, inability to complete sentences and difficulty in lying down. Altered mental status, with or without cyanosis, is an ominous sign and immediate emergency care and hospitalization are required. A detailed examination should include examining for signs and symptoms of pneumonia, pneumothorax or a pneumomediastinum, the latter of which can be investigated by palpation for subcutaneous crepitations, particularly in the supraclavicular areas of the chest wall. Special attention should be paid to the patient's blood pressure, pulse and respiratory rate. Tachycardia and tachypnea may be suggestive of a moderate to severe exacerbation, while bradycardia may indicate impending respiratory arrest. Pulsus paradoxus is often present and may correlate with the severity of exacerbation (Figure 1) [3,10,15]. Differential Diagnosis of Acute Asthma The differential diagnosis of acute asthma includes COPD, VCD, bronchitis, bronchiectasis, epiglottitis, foreign body, extra-or intra-thoracic tracheal obstruction, cardiogenic pulmonary edema, non-cardiogenic pulmonary edema, pneumonia, pulmonary embolus, chemical pneumonitis, and hyperventilation syndrome [10]. Acute Asthma Triggers Risk factors for asthma exacerbations can be identified from the clinical history. The patient interview should include questions about recent events including [3,15]:
Allergen or pollutant exposure Predictors of Fatal or Near Fatal Asthma Major risk factors for near-fatal and fatal asthma are recognized, and their presence makes early recognition and treatment of an asthma exacerbation essential. The history should include a review of previous episodes of near-fatal asthma and whether the patient has experienced multiple emergency room visits or hospitalizations, particularly those requiring admission to an intensive care unit, involving respiratory failure, intubation and mechanical ventilation. A history of allergic asthma and other known or suspected allergic symptoms should be obtained. For example, Nelson et al. identified a trigger for severe asthma is allergy to the mold Alternaria and several dust mite species [16]. Subjects with Alternaria sensitization are found to be 5 times more likely to exhibit increased wheezing, airway responsiveness and bronchodilator use [7]. Adherence with medical treatments should be reviewed; poor adherence with prescribed therapies is a major risk factor. Inadequate therapy may include excessive use of ß2-agonists, concomitant use of ß-blockers, and failure to prescribe or use inhaled corticosteroids (ICS) as a primary therapy. Recent withdrawal of oral corticosteroids (OCS) suggests that the patient is at greater risk for a severe exacerbation. Lack of a written asthma action plan is another risk factor. Limited access of the patient to appropriate health care and lack of education about appropriate management strategies are additional risk factors. Socioeconomic factors associated with severe asthma exacerbations include the non-adherent adolescent or elderly asthmatics living in inner city environments. Certain ethnic groups within a population may have a higher incidence of severe asthma, such as Americans of African or Spanish inheritance. Comorbidities, such as chronic lung, psychiatric, and cardiovascular diseases are other risk factors [15,17]. Physiological and Laboratory Parameters Serial measurements of lung function facilitate quantification of the severity of airflow obstruction and response to therapy. A peak expiratory flow (PEF) rate provides a simple, quick, and cost-effective assessment of the severity of airflow obstruction. Patients can be supplied with an inexpensive PEF meter and taught to perform measurements at home to detect deterioration of their asthma. An individual management plan will be based upon the personal best PEF value. Predetermined PEF values can be set at which time the patient is alerted to the degree of severity of symptoms and can institute appropriate therapy and/or consult their physician (Figure 2). In non-acute settings, assessment of PEF and spirometry before and after administration of a bronchodilator can indicate the likely degree of improvement in lung function which can be achieved by adequate therapy. PEF values of 50-79% of predicted or personal best signify the need for immediate treatment with an inhaled short acting beta agonist (SABA). Values below 50% of personal best indicate the need for immediate medical care. Values below 35% of personal best indicate a possible severe life-threatening episode. This treatment should be administered with a SABA via nebulizer or metered dose inhaler (MDI). SABA dose, response, and further management is depicted in Figure 2 [3, 17-20]. The forced expiratory volume in one second (FEV1) is measured by spirometry to assess the volume of air exhaled over one second and is the most sensitive test for airflow obstruction. The FEV1 is less variable than PEF and is independent of effort once a moderate effort has been made by the patient. Post bronchodilator reversibility should be assessed and an increase in FEV1 > 12% and > 200 ml is diagnostic of asthma [3]. Fractional exhaled nitric oxide (FeNO) testing is a measure of lower airway eosinophilic inflammation that is assessed through an exhaled breath into a device. The Expert Panel 4 (EPR-4) does not recommend the use of FeNO alone to assess asthma control or the severity of an acute asthma exacerbation. However, testing may be helpful in asthma management when used in conjunction with spirometry and the patient’s clinical history [21,22]. Most patients do not require laboratory testing for the diagnosis of acute asthma. If laboratory studies are obtained, they must not delay asthma treatment. Laboratory studies may assist in detecting other comorbid conditions that complicate asthma treatment, such as infection, cardiovascular disease, or diabetes. A measurement of brain natriuretic peptide (BNP) and a 2-D transthoracic echocardiogram aid in the diagnosis of congestive heart failure. For patients taking diuretics who have co-morbid cardiovascular disease, serum electrolytes may be useful as frequent SABA administration can cause transient decreases in serum potassium, magnesium, and phosphate. A baseline electrocardiogram and monitoring of cardiac rhythm are appropriate in patients older than 50 years of age and in those with comorbid cardiovascular disease or COPD. A complete blood cell count (CBC) may be useful in patients with fever or purulent sputum; however, modest leukocytosis is common in asthmatics, and patients using corticosteroids may have a corticosteroid-induced neutrophil leukocytosis. Serum theophylline levels are essential for patients taking theophylline due to its narrow therapeutic window [17]. Chest radiographs are not usually necessary for the diagnosis of acute asthma if the examination of the chest reveals no abnormal findings other than the expected clinical signs and symptoms associated with an acute exacerbation. If a complication is suspected, such as pneumonia, pneumothorax, pneumomediastinum, congestive heart failure, or atelectasis secondary to mucous plugging, a chest X-ray should be obtained [17]. Arterial blood gas (ABG) analysis should be considered in patients who are critically ill and have oxygen saturations of < 92% or an FEV1 < 30% who do not respond to intensive conventional treatment. Proper interpretation of the pH, PaO2, and PaCO2 may help further assess the severity of an acute exacerbation of asthma (Figure 1). For example, a breathless asthmatic presenting with a PaCO2 > 45 mmHg indicates a life-threatening attack and the need for transfer to a medical intensive care unit for further care. Less than 10% of asthmatic patients presenting to the emergency department have arterial oxygen values < 50 mmHg and carbon dioxide levels > 45 mmHg [20,23]. Lactic acidosis is common in severe acute asthma. However, elevated lactic acid levels are also associated with high doses of inhaled ß2-agonist treatment [24]. Venous blood gases (VBG) have been evaluated as a substitute for arterial measurements since venous blood is easier to obtain. However, The Expert Panel Report 3 (EPR-3) does not recommend substituting venous PCO2 (PvCO2) for ABG. Arteriovenous correlation for PCO2 is poor, and therefore PvCO2 cannot be relied upon as an absolute representation of PaCO2. However, a normal PvCO2 has a good negative predictive value for a normal PaCO2. Therefore, it may be used as a screening test to exclude hypercapnic respiratory distress [17,25]. Figure 1. Acute asthma severity: clinical signs and symptoms. Originally published as Figure 5-3 in the Expert Panel Report 3. Definition of abbreviations: PaO2 = arterial oxygen pressure; PCO2 = partial pressure of carbon dioxide; PEF = peak expiratory flow  Figure 2. Management of Asthma Exacerbations: Home Treatment Predicted. Originally published as Figure 5-4 in the Expert Panel Report 3. Treatment Treatment is based not only on assessment of lung function parameters but on clinical findings and the efficacy of previous treatment. A seasonal exacerbation of asthma in a pollen-sensitive patient is more easily treatable than an exacerbation triggered by a viral infection. A patient who is over-using short acting ß2-agonists may be refractory to nebulized ß2-agonists and will usually require a SCS. Physician knowledge of an individual patient will suggest whether a SCS is required or whether an exacerbation can be managed on high doses of ICS [17,26]. There are various national and international guidelines available for the diagnosis and management of acute asthma. In particular, the EPR-3 guidelines are referenced in this manuscript as it is centered upon a systematic review of the published scientific literature and provides the best evidence for clinical practice guidelines. EPR-3 recommended treatment choices in order of introduction in the acute setting are listed below and depicted in Figure 3. Treatment options and their recommended doses are listed in Figure 4. The 2020 EPR-4 provides focused updates to the Asthma Management Guidelines. However, the EPR-4 does not include any new recommendations for the evaluation and management of acute asthma [21]. Primary treatment choices include:
Some patients may not respond to primary treatment and show signs of worsening asthma. Other treatments are sometimes used in these patients and may include:
Figure 3. Acute Asthma Management: Emergency Department and Hospital-Based Care. Originally published as Figure 5-6 in the Expert Panel Report 3. FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; MDI = metered dose inhaler; PCO2 = partial pressure of carbon dioxide; PEF = peak expiratory flow; SABA = short-acting beta2-agonist; SaO2 = oxygen saturation Short-acting β2-agonists EPR-3 guidelines recommend the use of only selective SABAs in high doses (i.e. albuterol, levalbuterol) due to the risk of cardiotoxicity, especially in elderly asthmatic patients. Initial treatment should begin with albuterol, either administered by MDI with a spacer device or mask (children < 4 years of age) or nebulizer. Treatment should be continued until the patient has stabilized or a decision to hospitalize is made. Studies show that the use of either MDI or nebulizer for delivery of inhaled SABAs produces similar outcomes. Nebulizer treatment may be preferred in patients who are unable to cooperate using an MDI because of the severity of acute asthma, age or agitation. Additionally, continuous nebulization should be considered in very severe asthma based on evidence of reduced admissions and improved pulmonary function [17, 27-29]. Levalbuterol (R-albuterol) nebulizer solution can be given in a similar fashion. Notably, levalbuterol administered at one-half the mg dose of albuterol is found to deliver comparable efficacy and safety. However, the efficacy of continuous nebulization has not been evaluated. Continuous administration of albuterol via large volume nebulizers may be more efficacious when compared to intermittent administration in patients with severe asthma [17]. For patients unable or unwilling to use an MDI/spacer or nebulizer, epinephrine may be utilized, injected subcutaneously or intramuscularly, as long as the patient is carefully monitored for signs of adrenergic toxicity. At this time, there is no proven advantage of use of epinephrine over SABA. If there is no immediate response to epinephrine, treatment should be discontinued, and the patient hospitalized [17]. Ipratropium Bromide Ipratropium bromide is a quaternary derivative of atropine sulfate available as a nebulizer solution. It provides competitive inhibition of acetylcholine at the muscarinic cholinergic receptor, thus relaxing smooth muscle in large central airways. It is not a first-line therapy but can be added in severe asthma particularly when albuterol is not optimally beneficial. It can be given with albuterol or levalbuterol and may be used for up to 3 hours in the initial management of acute asthma. There is increasing support for adding ipratropium bromide to β2-agonist therapy in more severe asthma exacerbations in children. Studies indicate that combined therapy reduces the risk of hospital admission by 25% [17, 29,30]. Corticosteroids Treatment in the ambulatory setting: High-dose ICS may be initiated in selected patients. Evidence suggests equivalence in treatment of mild asthma exacerbations with OCS. However, due to limited data, high-dose ICS should be reserved for patients with mild asthma and those who refuse or cannot tolerate OCS, e.g., have brittle diabetes or experience major side effects from SCS. Guidelines recommend at least quadrupling the recommended dose of ICS. For example, a top recommended maintenance dose of fluticasone can be increased from 220 µg, 2 puffs 2x/day to 220 µg, 4 puffs 4x/day for exacerbations. Beclomethasone can be increased from 160 mcg, 2 puffs, 2x/day to 160 mcg, 4 puffs, 4x/day [3, 31]. Treatment should be started before the patient becomes too ill to manage their disease at home. Inhaled therapy reduces the risk of unwanted side effects associated with SCS treatment e.g., insomnia, increased appetite, hyperactivity, psychosis, and effects on bone metabolism and other organ systems. ICS are less likely to be effective in patients with upper respiratory tract infections or those who are over-utilizing ß2-agonists. In mild asthma exacerbations, the use of formoterol/budesonide combination as maintenance or reliever therapy has demonstrated improved exacerbation control long term and reduced need for OCS. In comparison to short-acting bronchodilators, formoterol provides rapid-onset bronchodilation and prolonged duration of action. In contrast, salmeterol is not as beneficial in providing immediate bronchodilation due to its slow onset of action. Combining formoterol with budesonide provides extra ICS that may be helpful in corticosteroid-responsive inflammation [32,33]. Inhaler technique should be assessed periodically as part of routine asthma care as incorrect technique is common and may contribute to uncontrolled asthma. Poor inhaler technique reduces drug delivery and has been associated with poor disease control [34]. OCS, with instructions for its use, should be prescribed as a backup treatment regimen for patients with severe asthma and the patient and/or family understand when to start it. They should also have immediate access to a physician and/or other healthcare professional until the asthma exacerbation is resolved [35-37]. When an ICS is prescribed for mild asthma and is not effective, OCS are indicated, regardless of their potential side effects. Glucocorticoid-induced psychosis, hypertension, and other side effects should be concomitantly treated until the OCS is tapered and no longer necessary for treatment. Short courses of OCS are effective to establish control of flare-ups of asthma or during a period of gradual deterioration of asthma not responding to increased doses of an ICS. Treatment should be continued until the patient is well or achieves a PEF of 80% of personal predicted best. Improvement may be seen between 5 to 14 days, although patients whose asthma is corticosteroid-resistant may take several weeks to respond. It is not necessary to taper OCS after three weeks or less of treatment, but when used for longer than 3 weeks, it is advisable to taper the medication over one to two weeks to decrease withdrawal side effects such as fatigue, myalgias, nausea/vomiting, abdominal pain, decreased appetite and joint pain [17,37]. Treatment in the acute setting: There are no substantial data to indicate that SCS are immediately helpful in the acute asthma setting because the onset of action does not occur for hours after administration. However, SCS are the best medications available to reduce airway inflammation and should be used immediately until the attack has abated as evidenced based on their clinical response or by the PEF and FEV1 returning to near baseline levels [17]. Intramuscular (IM) or intravenous (IV) corticosteroids may be used in the initial treatment of acute asthma; however, there is no evidence that these routes have a more rapid onset of action or are more effective than is oral administration [17]. Treatment after discharge from the hospital: After discharge from the hospital, approximately 10-20% of patients treated for acute asthma will relapse within 2 weeks. This may be due to unresolved inflammation associated with asthma. Therefore, close follow-up is necessary. As a result, EPR-3 encourages treatment with OCS following emergency room discharge. ICS therapy should be resumed, or short/long term ICS therapy initiated to reduce the chances of a relapse. When the patient’s asthma is stable, the ICS should be incrementally reduced to maintain an asymptomatic state and a PEF at a personal best level. A combination of long acting β2-agonist and an ICS can be considered to achieve the lowest ICS dose possible [17,38-40]. Magnesium Sulfate Magnesium sulfate has both immediate bronchodilator and mild anti-inflammatory effects. IV magnesium is a safe and effective treatment and may be considered in patients presenting with severe life-threatening asthma exacerbations (FEV1 < 25% predicted) and those who remain in the severe category after 1 hour of intensive conventional treatment [3,17]. In these cases, a single infusion of magnesium sulfate 2 grams may be administered to the patient over 20 minutes [15] Heliox – Driven Albuterol The role of heliox - driven albuterol in the treatment of acute exacerbations is controversial. Despite these uncertainties, heliox – driven albuterol may be considered in both children and adults who exhibit severe life-threatening exacerbations and those who remain in the severe category after one hour of intensive conventional therapy [17,41]. Hospitalization Failure to respond to treatment necessitates hospitalization. The patient’s fluid status should be assessed and oral or intravenous hydration therapy administered as indicated. Hydration in young infants and children may be essential as these patients are at increased risk for dehydration due to poor oral intake and an increased respiratory rate. Oxygen may be administered at 2 to 4 L/min via a nasal cannula or mask, whichever is better tolerated to maintain a SaO2 > 90%. In pregnant patients and those with underlying cardiac disease, a SaO2 > 95% is recommended. The patient should be monitored continuously with pulse oximetry and telemetry. Blood gases should be obtained until the patient is stable. The patient should be treated with continuous metered-dose albuterol or nebulized albuterol or levalbuterol, with or without ipratropium bromide, and a corticosteroid. Viral respiratory tract infections are more common in acute asthma exacerbation and therefore antibiotics should be reserved for patients who present with evidence of a co-existing bacterial infection, i.e., pneumonia, bronchitis, and sinusitis. EPR-3 does not recommend the use of methylxanthines, mucolytics, sedation or chest physiotherapy for treatment of acute asthma [3, 17]. Impending respiratory failure The use of non-invasive positive pressure ventilation (NPPV) in the treatment of severe acute asthma can be tried in patients who are at increased risk of respiratory failure, can safely cooperate with NPPV treatment, and do not require emergent intubation [17]. A review article by the Cochrane Reviews Group carried out a search of randomized controlled trials of adults with severe acute asthma that presented to the emergency department or were admitted to the hospital. Studies in the article were included if the intervention was usual medical care for the management of severe acute asthma plus NPPV compared to usual medical care alone. All six studies that were reviewed concluded that NPPV may be beneficial. The results did not show a clear benefit for NPPV use for its primary outcomes, i.e. mortality rate and tracheal intubation. However, NPPV use did show favorable outcomes in many secondary objectives, such as number of hospital admissions, length of ICU stay, length of hospital stay, and improvement in lung function parameters (PEF, FVC, FEV1, and FEF25-75). Study quality of the evidence was an issue in this review as all six studies included had at least one identifiable source of unclear or high risk of bias. As only six studies were reviewed by the Cochrane Reviews Group, no guidelines or implications for current practice can be made. Randomized controlled trials with a large sample size, good methodological design, and minimizing the risk of bias are needed to answer the question of the use of NPPV in acute asthma [42]. The EPR-3 recommends that intubation should not be delayed in a patient once it is deemed necessary. Patients that present with apnea or coma should be intubated immediately. Persistent or increasing hypercapnia, exhaustion, and mental status changes strongly suggest the need for mechanical ventilation. Intubation is difficult in patients with acute asthma and should be performed, where possible, by a physician who has extensive experience in airway management. Ventilator management by a physician expert is important because ventilation of patients with severe acute asthma is complicated. Two important issues to consider at the time of intubation include intravascular volume, which must be maintained or replaced, because hypotension commonly accompanies the introduction of positive pressure ventilation. In addition, high ventilator pressures should be avoided where possible, due to their associated risks of barotrauma. “Permissive hypercapnia” or “controlled hypoventilation” is the preferred ventilator strategy because this provides adequate oxygenation and ventilation without the risks of barotrauma associated with high ventilator pressures. SABA should be continued in ventilated patients, although no randomized controlled trials provide evidence to support its use. Conclusion Asthma affects approximately 300 million people in the world and over 400,000 deaths annually. The World Health Organization recognizes asthma as a major global health issue affecting all age groups in all countries. All patients presenting with an asthma exacerbation should be triaged and evaluated immediately. Treatment should be based on recognition of a moderate, severe, or life-threatening exacerbation. Clinicians should recognize the symptoms, signs, and risk factors (including comorbidities) for severe and life-threatening exacerbations. Primary treatment includes oxygen administration, SABA, and SCS. If the patient cannot tolerate SCS, high dose ICS may be initiated in selected patients. For patients that do not respond to primary treatment and show worsening signs of ventilation, secondary treatment options may be utilized. These include epinephrine, magnesium sulfate, heliox – driven albuterol, intubation and mechanical ventilation, and noninvasive positive pressure ventilation. At the time of discharge, referral to an asthma specialist and education on self-management of asthma may reduce the frequency of ED visits. Likewise, inhaler technique for all prescribed medications should be reviewed and reinforced for proper and correct technique. Patients should be referred for a follow-up appointment with an asthma specialist within 1-4 weeks. What are the most common abnormal arterial blood gas findings in the asthmatic patient?Arterial blood gas (ABG) measurement provides important information in acute asthma. This test may reveal dangerous levels of hypoxemia or hypercarbia secondary to hypoventilation and, hence, respiratory acidosis. However, the typical finding in the early stages of an acute episode is respiratory alkalosis.
How Does asthma affect arterial blood gas?In a study, asymptomatic patients with asthma had significantly lower partial pressure of carbon dioxide (PCO2) in arterial blood and end-tidal PCO2 (PETCO2) values compared to normal subjects, with no difference in the ventilatory pattern [6].
Is an asthma attack respiratory acidosis or alkalosis?Any lung disease that leads to shortness of breath can also cause respiratory alkalosis (such as pulmonary embolism and asthma).
Does PCO2 increase during asthma attack?During an asthma exacerbation there is air trapping and ventilation/perfusion mismatch, resulting in hypoxemia. Initially compensation occurs and hyperventilation causes the PCO2 to decrease. When further air trapping leads to decreased lung compliance and increased work of breathing, the PCO2 will begin to increase.
|
