Asthma Pathophysiology Overview

Asthma

• Asthma is a common chronic inflammatory disease affecting the airways, characterized by reversible airflow obstruction, exacerbations, and remissions.
• It is the most common chronic pediatric disease, with a global prevalence of 11-13%.
• In the USA, asthma affects 9.5% of all children.
• Only 8% of hospitalized children with asthma require the ICU.

### Asthma Pathophysiology

• Asthma pathophysiology involves acute and chronic inflammation and airway hyperresponsiveness.
• Bronchial smooth muscle constriction, airway edema, and mucous plugging are the classic pathophysiologic triad in asthma.
• Mast cell activation, denuded airway epithelia, inflammatory cell migration, collagen deposition, and fibrosis below the basement membrane are histological findings.
• Mast cells release mediators like histamine, prostaglandins, and leukotrienes causing bronchoconstriction.
• T-lymphocyte release of cytokines like IL 4, 5, 8, and 13 amplify the inflammatory response.
• B cells produce excessive IgE, stimulating mast cells to release leukotrienes.
• This process leads to excess mucus production, epithelial cell destruction, airway plugging, and airway surface denuding.

### Asthma Triggers

• Airway irritants like cigarette smoke, inhaled particulates, respiratory tract viruses, psychologic stress, and cold air can trigger asthma attacks.
• Increased mucus production with large amounts of cellular debris and increased viscosity contributes to airway obstruction.
• Inflammation-mediated airway edema, mucus hypersecretion, airway plugging, and bronchospasm lead to severe airway obstruction in severe asthma attacks.

### Asthma Exacerbations

• Genetics, environmental exposures, and viruses play key roles in acute exacerbations.
• Acute exacerbations are characterized by a rapid increase in airway resistance, reactive airways, and minimal response to medications.
• Respiratory insufficiency can develop leading to respiratory failure or even death.
• Asthma symptoms include tachypnea, wheezing, persistent coughing, nocturnal coughing, chest pain, chest tightness, dyspnea, and emesis.

### Physical Examination and Assessment

• Physical examination findings include wheezing, diminished breath sounds, prolonged expiratory phase, pulsus paradoxus, accessory muscle use, nasal flaring, and abdominal breathing.
• Pulsus paradoxus of >20 mm Hg indicates severe disease.
• Mental status changes like irritability, restlessness, lethargy, and confusion may be signs of respiratory failure and necessitate immediate attention.
• A clinical asthma score can help identify near-fatal asthma.
• Scores of >5 on the Wood asthma score indicate respiratory failure.

### Imaging and Diagnostic Studies

• Chest X-ray should be performed in severely ill asthmatics. Patients with a focal pulmonary asculatory finding or suspected airleak (i.e. pneumothorax, pneumomediastinum) should also undergo imaging.
• Arterial blood gas monitoring is not routinely necessary in all patients.
• Patients early in their asthma exacerbation often present with hypoxia and hypocarbia.
• A PaCO2 >40 torr in a severe exacerbation implies developing respiratory muscle fatigue.

### Laboratory Tests

• Electrolytes and blood counts in acute severe asthma may reflect dehydration and acidosis.
• Patients may be hypokalemic secondary to beta-agonist treatments.
• Myoglobin may be elevated in near-fatal asthma.
• Troponin may be elevated in critical asthma due to sustained diastolic hypotension and decreased coronary perfusion.

### Management of Severe Asthma

• Treatment of severe, acute status asthmaticus can be divided into validated and non-validated therapies.
• Validated mainstay therapies include oxygen, hydration, beta-agonists, steroids, anticholinergics, and mechanical ventilation for respiratory failure.
• Non-validated therapies include magnesium sulfate, bicarbonate, mucolytic drugs, chest physiotherapy, heliox, antibiotics, high-frequency oscillatory ventilation, and inhaled anesthetics.

### Oxygen Therapy

• Hypoxemia in status asthmaticus results from ventilation-perfusion mismatch due to bronchial obstruction.
• Bronchodilators can exacerbate hypoxemia by abolishing regional pulmonary hypoxic vasoconstriction.
• Early, humidified oxygen in acute severe asthma management is supported by clinical experience.
• Various oxygen delivery methods should be used to maintain oxygen saturation greater than 92%.

### Emergency Department Management of Acute Asthma

• For mild asthma attacks, one or more treatments with inhaled B2-agonists and a 3-5 day course of oral steroids may suffice.
• For moderate or severe asthma attacks, patients require more aggressive treatment with supplemental oxygen delivery immediately, with SPO2 maintenance above 92%.

### Nebulized B-2 Agonists

• Nebulized B-2 agonists are commonly used as first-line treatment after oxygen.
• Albuterol is administered at a dose of 0.15 mg/kg up to 5 mg, repeated every 10-20 minutes.
• Systemic corticosteroids (oral prednisone, IV methylprednisolone, or IM dexamethasone) should be administered.

### Anticholinergic Agents

• Nebulized anticholinergic agents (ipratropium bromide) can be added to intermittent albuterol administration.
• Magnesium sulfate can be given IV and has been shown to reduce ICU admissions.

### PICU Admission

• Patients remaining in respiratory distress after receiving aggressive therapy for more than an hour or who are deteriorating during emergency department treatment may require PICU admission.

### Hydration

• Most asthmatics are dehydrated on presentation.
• Fluid replacement and maintenance are crucial to correct dehydration and minimize thickening of secretions.

### Beta-Agonist Therapy

• Beta-agonists are a first-line treatment in status asthmatics, causing bronchial smooth muscle relaxation, increased diaphragmatic contractility, enhanced mucociliary clearance, and inhibition of bronchospastic mediators.
• Albuterol and terbutaline are generally preferred due to their beta-2 receptor selectivity, minimizing cardiac effects.
• Severe asthmatics are generally given intermittent high-flow nebulized albuterol at a dose of 0.05-0.15 mg/Kg to a maximum of 5 mg every 6-2 hours, depending on clinical status and response.
• Continuous nebulized albuterol may be superior for severe asthmatics.
• IV beta-agonist therapy (terbutaline) should be considered if the patient is unresponsive to continuous albuterol.

### Levalbuterol

• Levalbuterol is the pure (R)-albuterol isomer.
• It is as effective as albuterol but significantly more expensive.

### Epinephrine

• Epinephrine is an adrenergic drug with alpha, beta-1, and beta-2 effects.
• It is generally reserved for bronchospasm associated with anaphylaxis.

### Isoproterenol

• Isoproterenol is a potent beta-1 and beta-2 agonist.
• Isoproterenol use has been supplanted by terbutaline.
• Salmeterol is a long-acting beta-agonist, not indicated in the acute setting and associated with patient death.

### Steroid Therapy

• Steroids are mandatory first-line treatment in status asthmaticus.
• Steroids inhibit pro-inflammatory gene expression, with anti-inflammatory effects occurring between 6-12 hours after administration.
• Steroids reverse the downregulation of the beta-2 receptor after prolonged beta-agonist use.
• Oral and parental steroids are acceptable.

### Anticholinergic Agents

• The most commonly used anticholinergic agent is ipratropium bromide.
• It may be administered with albuterol nebulization and given as often as every 2 hours during continuous albuterol administration.
• Anticholinergic agents have synergistic effects with beta-agonists.

### Magnesium Therapy

• Magnesium inhibits calcium uptake, relaxes bronchial smooth muscle, and inhibits acetylcholine release.
• Magnesium sulfate infusion can cause side effects, including hypotension, facial flushing, muscle weakness, and absent reflexes.
• At the recommended dose of 25-50 mg/Kg, magnesium sulfate is relatively safe in the pediatric population.

### Heliox

• Heliox is a mixture of 30% oxygen and 70% helium.
• The lower density of helium reduces the Reynolds number, facilitating aerosol delivery to distal lung units and reducing work of breathing.
• The patient's oxygen requirement is a limiting factor as at least 60% helium is necessary for optimal effect.
• Heliox is a safe therapy with no known published adverse effects.
• It is considered an unproven therapy and should be used only in patients not responding to conventional therapy.

### Intravenous Isoproterenol

• Intravenous isoproterenol was previously the last resort prior to intubation in a patient with impending or established respiratory failure.
• It is a potent beta-1 and beta-2 agonist with a short duration of action, requiring continuous drip administration.
• Side effects include myocardial ischemia, cardiac dysrhythmias, and hyperglycemia.
• Isoproterenol has been largely supplanted by terbutaline and albuterol.

### Aminophylline

• Aminophylline was a mainstay of therapy for years, producing bronchodilation through various mechanisms.
• Side effects are common and worsen with levels greater than 20 mcg/dL.
• Aminophylline use should be restricted to children who respond poorly or fail to improve on maximal beta-agonist therapy.

### Ketamine

• Ketamine is a dissociative anesthetic with bronchodilator effects.
• It is often used during intubation in near-fatal asthmatic patients.
• Ketamine increases sialorrhea and bronchial secretions.
• Typically, the increased heart rate limits the use of ketamine over time.
• Ketamine infusion has not shown benefit to standard therapy in non-intubated patients in the emergency department.

### Noninvasive Ventilation

• Noninvasive ventilation may benefit patients with respiratory muscle fatigue.
• BiPAP can relieve anxiety and allow standard therapy to relieve symptoms.

### Intubation and Mechanical Ventilation

• Mechanical ventilation in an asthmatic is rare and used only when other treatments have failed.
• It carries a high risk of air trapping and the development of airleak syndrome.

### Sedation and Paralysis

• Patients should be sedated heavily and many are paralyzed prior to intubation.
• Benzodiazepines (midazolam) should be used due to their anxiolytic properties.
• Most opioids should be avoided as they produce additional histamine release.

Fentanyl

• Fentanyl is an analgesic agent that can be used in doses of 1-5 mcg/Kg.
• Fentanyl has less histamine release compared to other analgesics in the same class.

Induction

• Succinylcholine (2mg/Kg) can be used for induction.
• An NG tube is recommended during succinylcholine induction due to the high likelihood of vomiting.

Neuromuscular Blockade

• Cisatricurium is used to maintain neuromuscular blockade.
• The maintenance infusion rate for cisatricurium is 0.2-0.3 mg/Kg/hr.
• Cisatricurium is less likely to cause prolonged paresis in asthmatic patients compared to other non-depolarizing neuromuscular blocking agents, because it does not have a steroid based chemical structure.

Sedation

• IV Ketamine (1-2mg/Kg) can be used as a sedative and induction agent.
• Ketamine is preferred as it also has bronchodilator effects.

Mechanical Ventilation

• The goal of mechanical ventilation is to reverse hypoxemia, maintain acceptable pH, and avoid iatrogenic hyperinflation.
• Iatrogenic hyperinflation can lead to reduced cardiac output and air-leak syndrome.
• Achieving normal PaCO2 is not a primary objective.
• Pressure-regulated volume control (PRVC) mode is recommended.
• PRVC mode allows decelerating inspiratory gas flow, assured tidal volumes, and minimized peak airway pressures.
• Longitudinal comparison of peak inspiratory pressure (PIP) to plateau pressure (Pplat) can indicate airway resistance and response to therapy.
• Increasing PIP-to-Pplat ratio indicates increasing airway resistance.
• Decreasing PIP-to-Pplat ratio indicates response to therapy.
• Typical settings in a paralyzed patient during mechanical ventilation: PRVC mode, tidal volume 4-8 mL/Kg, and peak pressure to be monitored.