Acute severe asthma is challenging for the clinician with respect to recognition and appropriate management. Currently, asthma accounts for between 1.7% and 2.0% of all ICU admissions [1]. Near-fatal asthma (NFA) is defined as acute asthma associated with a respiratory arrest or arterial carbon dioxide tension greater than 50 mm Hg, with or without altered consciousness [2]. There are two phenotypes of near-fatal asthma. The most common is responsible for 80–85% of all fatal events. It is characterized by eosinophilic inflammation associated with gradual deterioration over days or weeks occurring in patients with severe, poorly controlled asthma, and is slow to respond to therapy. The second phenotype, with neutrophilic inflammation, has both a rapid onset and response to therapy [3].
by Dr Anthony Holley and Dr Robert Boots

Assessment and monitoring
A history of intensive care admission is a well documented indicator of subsequent near fatal asthma. In a study of asthma patients admitted with a near fatal episode, two thirds of subsequent severe attacks or deaths occurred within one year of the previous life-threating admission [4].

The immediate assessment of patients with asthma should include the degree of respiratory distress (ability to speak, respiratory rate, use of accessory muscles, air entry), degree of hypoxia (cyanosis, pulse oximetry, level of consciousness) and cardiovascular stability (arrhythmias, blood pressure). Accessory muscle use, wheeze, paradox and tachypnoea may diminish with patient fatigue [5]. It should be noted that the clinical examination may be misleading. Asthmatics with poor perception of the severity of their asthma may appear deceptively well, despite significant decrements in lung function [6].

While the assessment relies on clinical signs, additional information may be obtained from chest radiography or blood gas analysis, but neither should delay the initiation of appropriate therapy. An episode of acute asthma is characterized by hyperinflation of the lungs on chest radiography. Abnormalities in pulmonary function tests include markedly decreased FEV1 or peak expiratory flow rate. Blood gas analyses may demonstrate respiratory alkalosis, hypoxaemia and hypocarbia. Asthmatic episodes are generally not characterized by marked arterial desaturations until late in the episode. Normocarbia should be considered as impending respiratory failure requiring aggressive treatment [7].

Patients who fail to respond to therapy (PEFR improved by less than 10–20%) or with persistent hypercapnia, tachypnoea (respiratory rate > 30), altered mental status, arrhythmias or significant comorbidities should be referred to the ICU [3]. The wide range of potential complications needs to be considered when managing severe asthma.

Therapy
The goals of therapy are the maintenance of oxygenation, relief of airflow obstruction, reduction of airway oedema and mucus plugging, while supporting ventilation as clinically indicated.

Oxygen
In asthma hypoxaemia results from ventilation/perfusion mismatching and is usually modest. Treatment should be based on achieving target oxygen saturations > 92%, rather than giving predetermined concentrations of inspired oxygen. Inspired oxygen must be humidified to prevent the bronchoconstrictive effect of dry gas.

b2 Agonists
Short-acting, rapid onset inhaled β2-agonists are the drugs of choice for treating acute asthma, salbutamol being the most frequently used. In acute severe asthma, salbutamol may be administered either by nebulisation or repeated activations of a metered dosed inhaler (MDI) via a large volume spacer. However, data comparing the two modes of drug delivery in severe asthma exacerbations are lacking. If the prior use of an MDI has been inadequate, nebulised aerosolisation may be advantageous [8].
 
β2-agonists may be delivered by bolus (intermittent) versus continuous nebulisation, the latter being distinctly different from ‘back-to-back’ nebulisation. The continuous method involves the use of adapted systems to deliver larger quantities of the same bronchodilator agent over a number of hours (e.g. salbutamol at a rate of 10–20 mg/h). A systematic review of randomised controlled trials of acute asthma in adults failed to identify any significant differences in lung function or hospital admission rates between the continuous and intermittent methods [9]. Intravenous β2-agonists have been described as rescue therapy for use in patients unresponsive to inhaled bronchodilator and systemic corticosteroid therapy, or when the inhaled route is not practical [10].

Adrenaline
Adrenaline has been administered both by nebulisation and intravenously. There are theoretical advantages to the use of intravenous adrenaline in acute severe asthma, as opposed to using pure β2 agonists. The alpha effect of adrenaline may be beneficial in decreasing airway oedema, while the beta effect provides for bronchodilation. With respect to adrenaline infusions, their use would be reasonable as a rescue therapy in critical asthma, particularly if associated with hypotension not secondary to dynamic hyperinflation [11].

Ipratopium bromide
Anticholinergics agents block muscarinic receptors in airway smooth muscles, inhibit vagal cholinergic tone and result in bronchodilatation. Ipratropium bromide has a mild additional bronchodilating effect when added to ß agonists that may only be significant in severe asthma [12]. The combination of ipratropium bromide with a β2-agonist has been shown to be superior to a β2 agonist alone [13].

Corticosteroids
Corticosteroids have been shown to improve asthma symptoms by reducing airway inflammation, airway reactivity, airway secretions and restoring the integrity of the airways. Additional to their anti-inflammatory effect, steroids increase both the number and sensitivity of β-receptors on the bronchial smooth muscle [14,15]. Since the benefits of corticosteroid treatment are not usually seen until  6–24 h after administration, therapy should be instituted early. Oral and intravenous routes of corticosteroid administration are equally efficacious [16]. There is some suggestion that for patients with severe symptoms, intravenous corticosteroid therapy may have an early effect (within 1 to 6 hours) by reversing β2-receptor down regulation seen in chronic β2-agonist use [17].

Aminophylline
The use of intravenous aminophylline as a routine agent in the treatment of acute asthmatic patients has declined in the past few years. A Cochrane review [18] failed to show any evidence of benefit of aminophylline, especially in severe asthma,  and is associated with more adverse effects. Whether aminophylline has a place as an additional therapy after treatment with established medications remains uncertain.

Magnesium sulphate
Magnesium may be effective in acute asthma through relaxation of smooth muscle and inhibition of smooth-muscle contraction. Magnesium is involved in acetylcholine and histamine release from cholinergic nerve terminals and mast cells, respectively. The ability of magnesium to block the calcium-ion influx into the bronchial smooth muscle may have therapeutic benefit in severe acute asthma [19]. Magnesium is safe, inexpensive and has shown benefit in the severe asthmatic subgroup and therefore its use in this setting would seem appropriate [20].

8. Heliox
Helium/oxygen mixtures have the potential to decrease airway resistance secondary to their lower density with respect to air (80% helium/20% oxygen mixture has a density approximately one third that of air). It decreases the work of breathing in situations of increased airway resistance. Heliox may improve pulmonary function in more severe asthmatics, is safe, well tolerated but at this point rquires further validation of benefit [21].

Anaesthetic volatiles
Patients with severe bronchospasm requiring mechanical ventilation and not responding to conventional bronchodilator therapy may benefit from an inhaled volatile anaesthetic agent with bronchodilating properties such as
enflurane or isoflurane [22-26].

Antibiotics
There is no benefit to the routine use of antibiotics unless bacterial infection is likely [27].

Ventilation
Despite appropriate therapy, there continues to be a small group of patients who deteriorate or those who present in extremis and require mechanical ventilation. The rate of intubation in patients with acute severe asthma is low at 3-8 % [28].

Non invasive ventilation
Surprisingly only a few reports have described the use of non invasive ventilation (NIV) in patients with acute severe asthma. A Cochrane review performed in 2005 concluded that there are promising results in favour of the use of NIV in severe acute asthma. However, the regular use of NIV in status asthmaticus still remains controversial in the absence of large randomised controlled trials [29].

Invasive ventilation
Deteriorating consciousness, severe exhaustion and cardiopulmonary arrest are absolute indications for intubation and mechanical ventilation. Severe hypercapnia, acidosis and fatigue may not warrant immediate intubation, but rather aggressive and continuous bronchodilator therapy. Intubation and mechanical ventilation in the asthmatic should not be embarked upon lightly. The optimal means of intubation is usually direct laryngoscopy, following rapid sequence induction. The best agents to use are those most familiar to the operator. Induction may effectively be achieved with propofol or thiopentone, however careful dosage adjustment is required for potential haemodynamic compromise. The asthmatic patient is often volume depleted, with induction resulting in both loss of sympathomimetic tone and drug induced vasodilation. Additional to this, the development of intrinsic PEEP with an inappropriate ventilation strategy, may rapidly result in catastrophic circulatory collapse. In this regard ketamine with its sympathomimetic and bronchodilating properties has been advocated by many as the induction agent of choice [30]. The usual dose of ketamine for intubation is 1-2 mg/Kg given intravenously over two minutes. Suxamethonium may be used safely to achieve rapid paralysis for intubation, but the known complications need to be considered. Following induction, maintaince with fentanyl and midazolam is appropriate.

On-going paralysis may initially be required to facilitate ventilation, however because of the significant risk of critical care neuromyopathy, (especially given the combination with steroids) neuromuscular blockade should be withdrawn as soon as possible [31].

Ventilation strategy
The mode of ventilation may be a crucial factor for successful outcome of near-fatal asthma. Mechanical ventilation is difficult because of the combination of severe restrictive and obstructive defects. The obstructive defect may result in dynamic hyperinflation. This may then lead to barotrauma, volutrauma or catastrophic haemodynamic compromise secondary to impairment of venous return [7]. It is the practice of the authors to initially hand-bag asthmatic patients following intubation. This allows for an assessment of severity of bronchospasm and for a slow rate of 4-5 breaths per minute and avoids dynamic hyperinflation [32]. Once the situation is considered stable an attempt to mechanically ventilate the patient is made. Regardless of the mode of ventilation selected, mechanical ventilation in near-fatal cases should aim to maintain adequate oxygenation, minimize dynamic hyperinflation, avoid barotrauma and allow some degree of permissive hypercapnia until bronchodilators and steroids improve airflow. Outcome is improved in mechanically ventilated asthmatics by limiting airway pressure using a low respiratory rate and tidal volume while permitting a moderate degree of hypercarbia and respiratory acidosis [33].

Conclusion
Acute severe asthma remains a significant clinical problem, which requires early identification to facilitate appropriate therapeutic interventions. An understanding of the available agents and potential pitfalls in the management of near fatal asthma is mandatory for the emergency physician.

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The authors
Anthony Holley BSc. MBBCh. DipPaeds. DipDHM. FACEM. FJFICM
Staff Intensivist
and Robert Boots, M.D.

Department of
Intensive Care Medicine,
Royal Brisbane & Women’s Hospital
Herston QLD 4029
Australia