Case 7.2 – Severe Asthma

Acute severe asthma is a medical emergency that requires prompt recognition and treatment. The following features indicate severe asthma:

Clinical Features:

• Peak Expiratory Flow (PEF): 33-50% of predicted or best
• Respiratory Rate: ≥25 breaths per minute
• Heart Rate: ≥110 beats per minute
• Speech: Inability to complete sentences in one breath

Life-Threatening Features (require immediate ICU assessment):

• PEF: \<33% of predicted or best
• SpO₂: \<92% on room air
• Silent chest, cyanosis, or feeble respiratory effort
• Bradycardia, dysrhythmia, or hypotension
• Exhaustion, confusion, or reduced consciousness

Near-Fatal Asthma:

• Raised PaCO₂ and/or requiring mechanical ventilation with raised inflation pressures

Note: The absence of any of these features does not exclude a diagnosis of severe asthma. Clinical judgment is essential.

Management of acute severe asthma requires immediate intervention with a structured approach:

Immediate Management (First Hour):

1. Oxygen Therapy:

• High-flow oxygen via face mask to maintain SpO₂ 94-98%
• Do not withhold oxygen for fear of hypercapnia

2. Bronchodilators:

• β₂-agonist: Salbutamol 5mg via oxygen-driven nebuliser, repeat every 15-20 minutes or consider continuous nebulisation
• Anticholinergic: Ipratropium bromide 0.5mg mixed with salbutamol nebulisers (repeat 4-6 hourly)

3. Corticosteroids:

• Prednisolone 40-50mg PO immediately
• Or hydrocortisone 100mg IV if unable to take oral medication
• Continue for at least 5 days

4. Monitoring:

• Continuous SpO₂ monitoring
• Peak flow before and after treatment
• Heart rate, respiratory rate, blood pressure
• Arterial blood gas if SpO₂ \<92% or other features of life-threatening asthma

Second-Line Treatments (if not responding):

• Magnesium Sulphate: 1.2-2g IV infusion over 20 minutes
• Aminophylline: Loading dose 5mg/kg IV over 20 minutes (if not on oral theophylline), then infusion
• ICU referral: For consideration of intubation and mechanical ventilation

Subsequent Management:

• Continue high-dose inhaled bronchodilators via nebuliser or spacer
• Continue oral prednisolone
• Monitor PEF and clinical features closely
• Chest X-ray to exclude pneumothorax, pneumonia, or other complications

Criteria for Hospital Admission:

• Any feature of life-threatening asthma
• PEF \<75% of predicted or best after initial treatment
• Previous near-fatal asthma or brittle asthma
• Presentation at night
• Pregnancy
• Recent hospital admission or ED attendance

Mechanical ventilation is indicated in acute severe asthma when medical management fails and the patient develops life-threatening features. The decision to intubate should be made early by experienced clinicians.

Absolute Indications:

• Respiratory arrest
• Cardiac arrest
• Severe hypoxemia: Despite maximal oxygen therapy
• Reduced level of consciousness: Drowsiness, confusion, or coma
• Respiratory exhaustion: Unable to maintain respiratory effort

Relative Indications:

• Rising PaCO₂: Especially with acidosis (pH <7.2)
• Hypoxemia: PaO₂ <8 kPa (60 mmHg) despite high-flow oxygen
• Deteriorating PEF: Despite aggressive treatment
• Physical exhaustion: Patient unable to speak or becoming drowsy
• Haemodynamic instability: Hypotension or arrhythmias

Important Considerations:

• A normal or rising PaCO₂ in acute asthma is a concerning sign and may indicate impending respiratory failure
• Intubation and mechanical ventilation in severe asthma is difficult and carries significant risks including:
  • Barotrauma and pneumothorax
  • Hypotension due to dynamic hyperinflation
  • Difficulty achieving adequate ventilation due to high airway resistance
• Use of non-invasive ventilation (NIV) is generally not recommended in acute severe asthma
• Senior anaesthetic and intensive care input should be sought early

Ventilation Strategy:

• Use low tidal volumes (6-8 ml/kg)
• Allow permissive hypercapnia
• Prolonged expiratory time to prevent air trapping
• Monitor for complications including pneumothorax
• Continue aggressive medical therapy including bronchodilators and steroids

Long-acting β₂-agonists (LABAs) play an important role in the management of chronic asthma, but should never be used as monotherapy.

Evidence for Efficacy:

• Symptom Control: Multiple randomized controlled trials have shown that LABAs improve asthma symptoms, reduce nocturnal awakenings, and decrease the need for rescue bronchodilator use
• Lung Function: LABAs produce significant improvements in FEV₁ and peak expiratory flow compared to placebo
• Exacerbation Reduction: When combined with inhaled corticosteroids (ICS), LABAs reduce the frequency of asthma exacerbations
• Quality of Life: Improvement in asthma-related quality of life scores

Types of LABAs:

• Salmeterol: Duration of action ~12 hours, twice daily dosing
• Formoterol: Duration of action ~12 hours, twice daily dosing, faster onset of action than salmeterol
• Vilanterol: Duration of action ~24 hours, once daily dosing

Combination Therapy:

• LABAs should ALWAYS be prescribed in combination with ICS, never as monotherapy
• Combination ICS/LABA inhalers are preferred to ensure adherence
• Examples: Seretide (fluticasone/salmeterol), Symbicort (budesonide/formoterol), Relvar (fluticasone furoate/vilanterol)

Safety Concerns:

• Early studies raised concerns about increased asthma-related deaths with LABA monotherapy
• These concerns led to black box warnings in some countries
• Subsequent evidence shows that when combined with ICS, LABAs are safe and reduce exacerbations
• The key principle is: Never prescribe LABAs without ICS

Place in Therapy (Step-wise Approach):

• Step 3: Add LABA to low-moderate dose ICS if not controlled on ICS alone
• If no response to LABA after 4 weeks, consider stopping and increasing ICS dose or adding leukotriene receptor antagonist
• If good response but still not controlled, continue LABA and increase ICS dose

MART Therapy (Maintenance and Reliever Therapy):

• Budesonide/formoterol can be used as both maintenance and reliever therapy
• Evidence shows this approach reduces exacerbations and improves symptom control
• Allows for flexible dosing in response to symptoms

Each of these medications works through different mechanisms to produce bronchodilation in acute asthma:

1. Salbutamol (Short-Acting β₂-Agonist):

• Mechanism: Selective β₂-adrenoceptor agonist
• Site of Action: β₂-adrenoceptors on bronchial smooth muscle
• Cellular Action:
  • Binding to β₂-receptors activates adenylyl cyclase
  • Increases intracellular cyclic AMP (cAMP)
  • Increased cAMP activates protein kinase A
  • Results in phosphorylation of proteins that regulate smooth muscle contraction
  • Causes smooth muscle relaxation and bronchodilation
• Additional Effects:
  • Inhibits release of bronchoconstrictor mediators from mast cells
  • Increases mucociliary clearance
  • Reduces microvascular permeability
• Onset: 5 minutes when inhaled
• Duration: 4-6 hours
• Side Effects: Tachycardia, tremor, hypokalaemia (via β₂-receptor stimulation)

2. Ipratropium Bromide (Anticholinergic):

• Mechanism: Muscarinic receptor antagonist (M₁, M₂, and M₃ receptors)
• Site of Action: Muscarinic receptors on bronchial smooth muscle
• Cellular Action:
  • Blocks acetylcholine binding to muscarinic receptors
  • Prevents vagally-mediated bronchoconstriction
  • Blocks the pathway: vagal stimulation → acetylcholine release → M₃ receptor activation → smooth muscle contraction
  • Reduces intracellular calcium, leading to bronchial smooth muscle relaxation
• Additional Effects:
  • Reduces mucus secretion
  • Particularly effective for bronchospasm triggered by irritants or cold air
• Onset: 10-15 minutes when inhaled
• Duration: 3-4 hours
• Side Effects: Dry mouth, metallic taste (quaternary ammonium compound, minimal systemic absorption)
• Synergy: Works synergistically with β₂-agonists as they target different pathways

3. Magnesium Sulphate:

• Mechanism: Multiple mechanisms producing bronchodilation
• Primary Mechanisms:
  • Calcium Channel Antagonism: Competes with calcium for entry into smooth muscle cells through voltage-gated calcium channels
  • Reduced intracellular calcium decreases smooth muscle contraction
  • Results in bronchial smooth muscle relaxation
• Secondary Mechanisms:
  • Inhibits acetylcholine release from nerve terminals
  • Reduces histamine release from mast cells
  • Stabilizes mast cell membranes
  • May enhance the action of β₂-agonists
  • Anti-inflammatory effects by reducing pro-inflammatory cytokines
• Dosing: 1.2-2g IV infusion over 20 minutes
• Evidence: Most effective in severe asthma exacerbations (PEF \<30% predicted)
• Side Effects: Flushing, sensation of warmth, hypotension (usually mild), rarely respiratory depression with high doses
• Monitoring: Blood pressure during infusion, check magnesium levels if renal impairment

Comparative Summary:

• First-line: Salbutamol (most rapid and potent bronchodilator)
• Adjunct: Ipratropium (added to salbutamol in severe cases, different mechanism)
• Second-line: Magnesium (reserved for severe/life-threatening asthma not responding to first-line treatment)