The first step in managing a severe asthma exacerbation with respiratory distress and hypoxia is rapid bronchodilation using nebulized salbutamol (a beta-2 agonist) plus ipratropium (an anticholinergic). This combination provides immediate airway smooth muscle relaxation and reduces bronchospasm effectively, improving airflow and oxygenation. Oral corticosteroids are important but have a delayed onset, so they are secondary to rapid bronchodilation. IV aminophylline and antibiotics are not first-line in acute exacerbations without signs of infection or inadequate response to initial therapies. Immediate reversal of bronchospasm is critical to prevent respiratory failure.

Reference: Harrison's Principles of Internal Medicine, J. Larry Jameson, 20th Edition.