An Overview Of The Background, Causes, Diagnosis, Pathophysiology, Screening Methods Of Asthma And Review Of Case Studies On Asthma

Abstract

Asthma was considered common global respiratory condition before the COVID-19 pandemic in 2019 according to a recent study. The causes, diagnosis, pathophysiology, screening methods of anti-asthmatic drugs and review of case studies related to this common airway disease will help in developing new medications. This review is concise presentation of the causes, diagnosis, pathophysiology, screening methods of anti-asthmatic drugs and review of case studies related to Asthma.

Keywords

Introduction

• Airway inflammation

Mast cells are activated by cytokines and other mediators, which leads to the production of inflammatory chemicals like leukotrienes. These chemicals cause the airways to become inflamed and attract more immune cells, which worsens the inflammation [4]. 

• Airflow obstruction

The airway smooth muscle contracts, which narrows the airway lumen. This can be caused by a number of factors, including: 

• Edema: The airway wall thickens due to edema. 
• Mucus plugging: Mucus can plug the airways. 
• Airway remodeling: Repeated asthma attacks can cause irreversible changes to the airways, such as increased thickness of the smooth muscle in the airways[4]. 

• Airway hyperresponsiveness

The airways become more responsive to stimuli, which can lead to an exaggerated bronchoconstrictor response. This can be caused by increased histamine from mast cells, increased airway smooth muscle mass, and other factors[4]. 

Asthma can be caused by a range of environmental and genetic factors, including: premature birth and low birth weight and exposure to tobacco smoke [4].

Diagnosis of Asthma

Spirometry

Spirometry is a pulmonary function test that measure the volume of air an individual inhales or exhales as a function of time. Spirometry measures how much and how quickly air can be expelled following a deep breath. Flow or the rate at which volume is changing as a function of time can also be measured with spirometry [5].

Peak flow meter:

Peak expiratory flow measurement (peak flow) is a simple measure of the maximal flow rate that can be achieved during forceful expiration following full inspiration. Patients can learn the technique quickly, and the equipment necessary is affordable and widely available [5].

Screening Methods of Asthma

Invivo Models

1. Histamine and Acetylcholine induced Bronchoconstriction in Guinea Pigs (histamine Chamber test):

This is the traditional model of airway obstruction, in which inhalation of histamine or other spasmogens can induce symptoms having resemblance with bronchial asthma in guinea pigs.

Histamine and acetylcholine when inhaled causes hypoxia and leads to convulsion in guinea pigs. Histamine causes very strong smooth muscle contraction, hypotension and dilation of capillaries in cardiovascular system. In this model histamine (0.25%) and acetylcholine (10%) is to be given as aerosol under a constant pressure 40 mmHg from the inbuilt nebulizer of the histamine chamber. An outstanding effect of histamine and acetylcholine leads to severe bronchoconstriction in the guinea pigs that causes asphyxia (oxygen deprivation condition) and convulsive dyspnoea. The time required for the appearance of Proconvulsive Dyspnoea (PCD) is noted. Then, animals are removed from histamine chamber and returned to their home cage. Twenty-four hours later these animals are treated with vehicle, test drug or standard (Chlorpheniramine maleate (for histamine) or Atropine (for acetylcholine)) (2 mg/kg, oral) and animals are subjected again to the histamine chamber to repeat the exposure to histamine or acetylcholine aerosol. The onset latency of PCD is noted after 1 h of drug treatment up to 24 hr [6].

2. Milk-induced leukocytosis and eosinophilia:

Parenteral administration of milk can increase in Total Leukocyte Count (TLC)/eosinophil count, and this leads to release in inflammatory mediators like cytokines and histamine and promote the inflammation while eosinophils acts as an inflammatory cell and secrete mediators like Eosinophil Cationic Protein (ECP), Tumour Necrosis Factor (TNF) and Prostaglandin (PG), which results in bronchoconstriction and promotion of respiratory tract inflammation (Osama and Joshi, 1984). Therefore, this model can be used for screening antiasthma tic Test drug that can inhibit the milk-induced leukocytosis and eosinophilia (Bhargava and Singh, 1981) [6].

Exvivo Models

1. Spasmogen induced contraction on isolated guinea pig tracheal chain and guinea pig ileum preparation:

For evaluation of bronchodilatary activity of the test drugs, isolated guinea pig tracheal chain and guinea pig deum preparation can be used in vitro for induction of contraction using various spasmogens involved in asthma like histamine, acetylchlone , Leukotnene , Ca- ionophore or carbachol. Dose dependent ability of these drugs to induce relaxation in the presence of these spasmogens is evaluated by the model given below:

1. Isolated Guniea Pig tracheal chain preparation:

Guniea pigs are euthanized with an overdose of pentobarbital (100 mg/kg. i.p.). The trachea is rapidly dissected free of surrounding tissues and placed in Petri dish containing oxygenated

Kreb's solution (NaCl -114.0 mM; CaCl?-2.5 nm; KCI-4.7 mM; glucose-11.7 mM; NaHCO3-25 M MgCl, -1.2 mM; KH,PO, -1.2 mM). Trachea is sectioned into 12 rings of about same width and connected with each other using short loops of Antiasthmatics silk thread. Tracheal chains are then suspended in organ tubes filled with 20 ml of Kreb's solution under a uniform tension of 500 mg. The solution is bubbled continuously with 95% O, and 5% CO? at 37± 10°C. The tissues are allowed to equilibrate to the Kreb's solution for a period of 30 minutes. Thereafter, contractions are recorded by installing carbachol (2 x10 g/ml) or histamine (10 g/ml) in the tissue bath using student physiograph using isotonic transducer. Then the same procedure is repeated by adding the test compound in the tissue bath either before the spasmogens or after the maximum response of the spasmogens to record the relaxing effect [6].

1. Isolated guinea pig ileum preparation (Magnus, 1904):

In this model, rather than a respiratory organ, guinea pig ileum is used because spasmogens involved in asthma also contracts the guinea pig ileum. Guinea pigs are first euthanized with an overdose of pentobarbital (100 mg/kg. i.p.) and ileum is quickly dissected out into pieces and suspended in organ bath containing 20 ml of Tyrode's solution (NaCl -137.0 mM: CaCl?-1.8 nm; KCl -2.7 mM; NaHCO3-11.9 nM; MgCl2 -1 mM; NaH2PO4 -0.4 mM) and is maintained at 37 ± 10°C under basal tension of 500 mg. The bathing solution is bubbled continuously with 95% O? and 5% CO? at 37 +10°C. The tissues are allowed to be equilibrated to the Tyrode's solution for a period of 30 minutes. Thereafter, contractions are recorded by installing carbachol (2 x 10 g/ml) or histamine (10 g/ ml) in the tissue bath using student physiograph using isotonic transducer. Then the same procedure is repeated by adding the test compound 10 to 10 g/ml at 5- or 10-min intervals in the tissue bath either before the spasmogens or after the maximum response of the spasmogens to record the relaxing effect. % inhibition of spasmogens induced contraction by test compound is measured. The inhibition of contraction produced by spasmogens is considered as antiasthamatic effect [6].

2. Bronchial perfusion of isolated lung

In this method a perfusion fluid is introduced in trachea to run down through the bronchi and allowed to pass through alveoli. The induction of bronchoconstriction using spasmogens leads to the reduction in the flow rate of perfusion fluid. Thus, bronchial perfusion of the isolated lung provides a simple method for evaluating the effect of bronchodilator or anti-asthmatic activities of test agents on bronchiolar muscle, which on bronchodilatation increases the rate of flow. This method is commonly employed to evaluate sympathomimetic drugs [6].

Review of salbutamol induced lactic acidosis case studies 

1. Salbutamol-induced lactic acidosis in status asthmaticus survivor

A 40-year-old man who had poor-controlled asthma, presented with progressive dyspnea with coryza symptom for 6 days. He was intubated and admitted into medical intensive care unit due to deteriorated respiratory symptom. Severe asthmatic attack was diagnosed and approximate 1.5 canisters of salbutamol inhaler was administrated within 24 h of admission. Initial severe acidosis consisted of acute respiratory acidosis from ventilation-perfusion mismatch and acute metabolic acidosis resulting from bronchospasm and hypoxia-related lactic acidosis, respectively. The lactate level was normalized in 6 h after hypoxemia and ventilation correction. Given the lactate level re-elevated into a peak of 4.6 mmol/L without signs of tissue hypoxia nor other possible etiologies, the salbutamol toxicity was suspected and the inhaler was discontinued that contributed to rapid lactate clearance. The patient was safely discharged on the 6th day of admission [7].

2. Salbutamol- Induced Severe Lactic Acidosis In Acute Asthma

A 42-year-old patient was admitted to emergency department with respiratory distress and wheezing. He informed us like he had, a runny nose, shortness of breathe, wheezing for last 3 days .he used increased doses of inhaled salbutamol at home, so that he have tightness in chest and trouble in breathing. The patient experiencing asthma since childhood, and his medical history was also marked by a similar episode a year ago. His pulse rate was 130 beats/min, respiratory rate 45 breaths/min, oxygen saturation 91% on room and blood pressure was 140/75?mmHg. His examination report is like he had wheezing symptoms sometimes. The remaining physical examination was normal. The patient received supplement oxygen with seven doses of nebulized salbutamol (35?mg in total: 5?mg every 20?min) and ipratropium 250?µg as well as intravenous methyl prednisolone 120?mg, deep venous thrombosis, and stress ulcer prophylaxis. After 2?h, the patient became less responsive to the medical treatment, so a bolus dose of sulfate magnesium 2?g was administered without any clinical improvement: oxygen saturation was     87% on high-flow oxygen with worsening of dyspnea, limited inspiratory flow, and we noticed decreased wheeze. As conclusion nebulized salbutamol with oxygen supply has increased efficiency than inhaled salbutamol as single dose for patient [8].

3. Conundrum in an asthma exacerbation

A 66-year-old man, an asthmatic, presented with symptoms suggestive of an acute exacerbation of asthma. His arterial blood gas revealed type 1 respiratory failure (PaO2 <8>

DISCISSION AND CONCLUSION

The indoor and outdoor allergens were learnt from the review and it was concluded that avoidance of allergens could be effective way of tackling Asthma [2,3]. The spirometer and Peak flow meter were found to be the most common devices used to diagnose Asthma. Apart from measuring the airflow spirometer can be used to measure change in respiratory rate with respect to time. Peak flow meter was patient friendly as they can learn the technique quickly, and the equipment necessary is affordable and widely available [5]. The invivo models Isolated Guniea Pig tracheal chain preparation, Isolated guinea pig ileum preparation and Bronchial perfusion of isolated lung were studied. The Bronchial perfusion of isolated lung is commonly employed method for screening anti-asthmatic drugs as the method is simple and effective [6]. Salbutamol-induced lactic acidosis is a rare presentation that could manifest in specific clinical context as acute asthmatic attack treatment. An increase of glycolysis pathway leading to pyruvate escalation is the mechanism of hyperlactatemia in ?2-adrenergic agonist drug.

Salbutamol-induced lactic acidosis should be considered in an asthma exacerbation:

1. if there are no signs of shock or hypoperfusion;
2. if the lactate rises rapidly after salbutamol therapy;
3. if the lactate level rise is associated with an objective improvement in hypoxaemia and peak flow (or forced expiratory volume in 1?s (FEV1)).

Treatment of salbutamol-induced lactic acidosis is to reduce the salbutamol frequency. Peak flow or FEV1 measurement by a peak flow metre or a bedside spirometer is an essential bedside tool that should be used to monitor response to treatment in an asthma exacerbation. The re-elevation of serum lactate in status asthmaticus patient who had been administrated with the vast amount of ?2-adrenergic agonist should be considered for salbutamol-induced lactic acidosis and promptly discontinued especially when there were no common potentials [7,8,9].

REFERENCES

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