Acute severe asthma

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Chapter 31 Acute severe asthma

Acute severe asthma is a medical emergency associated with significant morbidity and mortality. The majority of adverse outcomes are attributed to underestimation of severity with delayed and/or inadequate treatment ¹^–³ and are potentially preventable.

The worldwide prevalence of asthma varies widely (2–37% in children),⁴ but it is now clear that the overall prevalence has increased worldwide,^5,⁶ with life-threatening episodes affecting an estimated 0.5% of asthmatics per year.⁷ Australia, New Zealand and the UK have amongst the highest incidences.⁷ In Australia, 9% have asthma as a long-term condition⁸ and up to 40% of children have asthma symptoms at some time.⁵

Although the prevalence of asthma is increasing, many countries have achieved reductions in hospital presentations and admissions,^9,¹⁰ reduced intensive care admissions and reduced overall asthma mortality.^9,¹⁰ Improved community management of asthma,^1,² more widespread use of inhaled corticosteroids³ and other preventive measures have been given the credit for these improvements.

Despite reducing admissions, significant and potentially preventable mortality continues to occur in those patients who do require intensive care or mechanical ventilation.^11,¹²

CLINICAL DEFINITION

Asthma has been defined as a lung disease with the following characteristics:¹³

• airway obstruction that is reversible (completely or partially), either spontaneously or with treatment

• airway inflammation

• increased airway responsiveness to a variety of stimuli

Exacerbations of asthma are characterised by increasing dyspnoea, cough, wheeze, chest tightness and decreased expiratory airflow. Status asthmaticus has had varying definitions. However, for practical purposes, any patient not responding to initial doses of nebulised bronchodilators should be considered to have status asthmaticus.¹⁴

AETIOLOGY

The pathogenesis of asthma is complex, with both genetic and environmental influences. The increase in asthma prevalence has been attributed to the ‘hygiene hypothesis’¹⁵ which suggests that reduced exposure to childhood infections as a result of antibiotics and hygienic lifestyle promotes an imbalance in T-cell phenotype leading to inflammatory cytokine overproduction. Immunoglobulin (Ig) E-dependent mechanisms appear to be particularly important in generating the characteristic state of airway inflammation and bronchial hyperreactivity with the allergens in the local environment dictating the specificity of the antibody response.¹⁶ Triggers of acute asthma can be non-specific (cold air, exercise, atmospheric pollutants), specific allergens (housemite, pollen, animal danders), modifiers of airway control (aspirin, β-blockers) or stress and emotion. No precipitant can be identified in over 30% of patients.

PATHOPHYSIOLOGY

The postmortem airway pathology of patients who die from acute asthma includes bronchial wall thickening from oedema and inflammatory cell infiltrate, hypertrophy and hyperplasia of bronchial smooth muscle and submucosal glands, deposition of collagen beneath the epithelial basement membrane and prominent intraluminal secretions. These secretions may narrow or occlude the small airways and postmortem studies frequently report extensive plugging and atelectasis.^17,¹⁸ When interpreting the latter findings it is important to remember that during life in very severe asthma, the lungs are hyperinflated close to total lung capacity (TLC) by maximal inspiratory effort and to beyond TLC during mechanical ventilation. At this time radiological atelectasis is rare, suggesting that most airways are communicating at these high lung volumes, even if airways are very narrowed. Only at death does the prolonged apnoea allow lung deflation, widespread airway closure and alveolar gas absorption to give the postmortem appearance of extensive complete occlusion that was not present to the same degree during life.

In some deaths bronchial mucus is absent; in these cases airway obstruction may be mainly due to intense smooth bronchoconstriction.

This observation may account for two patterns of progression of asthma:

1 Acute severe asthma is the more common group (80–90%), with progression of symptoms over many hours or days, often with a background of poor control and recurrent presentations. The majority of patients in this group are female. Upper respiratory infections are frequent triggers. It responds more slowly to treatment; this may reflect greater contribution from mucous inspissation and chronic bronchial wall inflammation with eosinophilia.¹⁹

2 Hyperacute, fulminating or asphyxic asthma is where the interval between onset of symptoms and intubation is less than 3 hours.¹⁹^–²¹ This presentation is less common (approximately 10–20% of life-threatening presentations) and tends to occur in younger patients with relatively normal lung function but high bronchial reactivity, and the majority of patients are male. Respiratory allergens, cold air or exercise and psychosocial stress are the most frequent triggers. This pattern typically responds quickly to bronchodilators and is thought to be mainly due to bronchial smooth-muscle contraction.

The characteristic pathology of asthma leads to increased airway resistance and dynamic pulmonary hyperinflation. This has a number of consequences:

• Increased work of breathing results from increased airway resistance and reduced pulmonary compliance as a result of high lung volumes. When asthma is severe, dynamic hyperinflation may bring the lung volume close to TLC.²² This causes a severe mechanical disadvantage of inspiratory muscles with diaphragm flattening and results in a large inspiratory muscle effort affecting a small change in inspiratory pressure. The final outcome can be respiratory muscle failure with insufficient alveolar ventilation and consequent hypercapnia.²³

• Ventilation–perfusion mismatch is the result of airway narrowing and closure. This leads to impaired gas exchange and increases the minute ventilation requirement, further adding to the work of breathing.²³

• Adverse cardiopulmonary interactions are seen when the marked changes in lung volume and pleural pressure impact on the function of both left and right ventricles.^24,²⁵ Spontaneous breathing during acute asthma can generate inspiratory pleural pressures as low as -35 cmH₂O.^24,²⁵ This increases venous return to the right ventricle (RV) and increases RV volume during inspiration. However, increased RV afterload as a result of hypoxic pulmonary vasoconstriction, acidosis, increased lung volume^24,²⁵ and increased pulmonary capacitance decrease return to the left ventricle (LV). These negative intrapleural pressures also cause increased LV afterload^24,²⁵ and increased RV volume with septal shift reduces LV volume,^24,²⁵ further reducing LV output during inspiration. Pulsus paradoxus is the most direct result of these cardiopulmonary interactions in severe asthma. This is a decrease in systolic blood pressure during inspiration of > 10 mmHg (typically 15–25 mmHg, normal = 5 mmHg). The degree of pulsus paradoxus may not correlate with the severity of asthma as it may be reduced by inspiratory muscle weakness or fatigue.

CLINICAL FEATURES AND ASSESSMENT OF SEVERITY

The symptoms of asthma are well known and include wheeze, cough, dyspnoea and chest discomfort or tightness.

Triage and assessment of severity of the acute asthma attack are crucial. Underestimation or non-measurement of asthma severity is associated with increased mortality.^26,²⁷ Assessment has two key features: assessment of initial severity and ongoing assessment of response to treatment.

HISTORY

Any history of prior intubation and mechanical ventilation for asthma is a predictor for life-threatening asthma.^26,²⁷ A history of poor asthma control and multiple recent medical presentations for asthma are recognised risk factors. Other risk factors include a poor response to prior treatments and poor psychosocial circumstances.

PHYSICAL EXAMINATION

The general appearance and level of distress can be an important indicator of severity (Table 31.1). Use of accessory muscles, suprasternal retraction, markedly diminished breath sounds or a silent chest, central cyanosis, inability to speak (sentences, phrases, single words), a disturbance in the level of consciousness, upright posture and diaphoresis all suggest a severe attack.²⁸ A respiratory rate > 30 breaths/min, pulse rate > 120 beats/min and pulsus paradoxus of > 15 mmHg are associated with severe asthma, though their absence does not preclude life-threatening asthma.

Table 31.1 Assessment of asthma severity

VENTILATORY FUNCTION TESTS

The patient may not be able to perform these due to breathlessness. However, forced expiratory volume in 1 second (FEV₁) and peak expiratory flow rate (PEFR) are useful indicators of severity and response to treatment when done serially. An FEV₁ < 1.0 litre or PEFR < 100 l/min indicates very severe asthma at significant risk of requiring mechanical ventilation. In some patients forced expiration may worsen symptoms; these measurements should cease if this occurs.²⁹

PULSE OXIMETRY

Pulse oximetry (SpO₂) is usually readily available and provides a rapid assessment of oxygenation. It is also very valuable in regulation oxygen therapy, both for avoiding hypoxia (SpO₂ > 90%)³⁰ and avoiding potential side-effects of hyperoxia (SpO₂ < 95%).³¹ Of course, pulse oximetry cannot assess arterial PCO₂ or acid–base state or lactate and hence does not replace the need for blood gases

ARTERIAL BLOOD GASES

Arterial hypoxaemia is almost invariably present in a patient with severe asthma breathing room air, though it usually responds well to low-level oxygen supplementation (28–35%).³⁰ Blood gases should not delay initiation of treatment, and are not required in mild asthma or moderate asthma that is responding well to treatment. They are very important in severe asthma, or moderate asthma with inadequate treatment response. The arterial PaCO₂ is an important measure of severity and, if hypercapnia is present, an important guide to treatment response.

Ventilation is initially increased in an acute attack, leading to hypocapnia and a respiratory alkalosis.³⁰ As the asthmatic attack worsens, the work of breathing, V/Q mismatch and adverse cardiopulmonary interactions all increase, and the minute ventilation required to maintain the same alveolar ventilation and PaCO₂ increases. Eventually the patient is incapable of meeting this demand and the PaCO₂ rises. The presence of hypercapnic acidosis is associated with an FEV₁ of < 20% predicted and reliably indicates that asthma is severe. A metabolic acidosis may also be present, and this is most commonly due to lactic acidosis³² associated with intravenous or continuous nebulised β-agonists.^33,³⁴

CHEST X-RAY

Although not generally helpful in assessing severity,³⁵ a chest X-ray should be performed when asthma is severe or refractory to treatment, when barotrauma or lower respiratory tract infection is suspected or when the diagnosis is in doubt. It is not required in milder attacks that respond well to treatment.

ASSESSMENT OF TREATMENT RESPONSE

Repeated evaluation of the patient’s response to treatment is a valuable tool in assessing severity of acute asthma. The response to the first 2 hours of treatment is an important predictor of outcome.³⁶ Adverse events are associated with underestimation of severity, inadequate observation after initial assessment and under treatment. Ongoing evaluation of response to therapy is critical. This evaluation should include repeated assessments of:

1 appearance and physical indicators of severity

2 objective measurements: FEV₁ or PEFR, heart rate, respiratory rate, pulsus paradoxus

3 SpO₂ and oxygen requirements

4 progress of PaCO₂ or metabolic acidosis if present on blood gases

Admission to intensive care is preferred if the patient fulfils the above criteria for severe asthma. Indications for immediate admission to intensive care include respiratory arrest, altered mental status, arrhythmias or associated myocardial ischaemia.

DIFFERENTIAL DIAGNOSIS

The diagnosis of asthma is usually obvious. However wheeze and dyspnoea may be caused by other illnesses such as left ventricular failure, aspiration, upper-airway obstruction, inhaled foreign body, pulmonary embolism or hyperventilation syndromes. Wheeze and dyspnoea arising in hospitalised patients who were not admitted with asthma are less likely to be due to asthma. Difficult asthma, as opposed to severe asthma, can present acutely and is a diagnostic dilemma. Such patients are well medicated (often self-medicating with high-dose steroids and may appear cushingoid or with high-dose β-agonists with lactic acidosis) and have seen many doctors and attended many hospitals. Lung function may be normal or indicate upper-airway dysfunction, indicative of an underlying vocal cord dysfunction or psychiatric condition, and upon intubation the patient is very easy to ventilate. Clues to another or additional diagnosis include:

1 no past history of asthma

2 sudden onset following vomiting or food intake

3 focal or asymmetrical chest auscultation findings

4 risk factors for thromboembolism

5 onset during hospitalisation when admitted with another condition

MANAGEMENT

ESTABLISHED TREATMENTS

Initial therapy of acute severe asthma should include the following.

OXYGEN

Hypoxaemia contributes to life-threatening events that complicate acute severe asthma.³⁷ Humidified supplemental oxygen should be titrated to achieve a SpO₂ > 90%. The risk of oxygen-induced increasing hypercapnia with coexisting chronic obstructive pulmonary disease or pre-existing chronic hypercapnia is a well-known reason to maintain a lower SpO₂ (e.g. 90–92%). This phenomenon was not believed to be relevant to the majority of patients with acute asthma; however, there is now emerging evidence that hyperoxia may be harmful to a more widespread group³⁸ by releasing pulmonary hypoxic vasoconstriction, worsening V/Q matching and increasing hypercapnia. A recent randomised controlled trial³¹ showed a decrease in PaCO₂ in a group receiving 28% O₂ and an increase in PaCO₂ in a group receiving 100% O₂.

β-AGONISTS

Short-acting β-agonists remain the first-line bronchodilator therapy of choice.^6,³⁹^–⁴¹ Agents include salbutamol (albuterol), terbutaline, isoprenaline and epinephrine. Salbutamol is generally the agent of first choice as it has relative β₂-selectivity, with decreased β₁-mediated cardiac toxicity. Long-acting β-agonists such as salmeterol have no role in status asthmaticus due to slow onset of action and association with fatalities in this setting.¹⁴ Eformotarol is a combined long- and short-acting β-agonist which could theoretically be used for acute asthma; however it is in dry powder form and unlikely to be helpful in intubated and mechanically ventilated patients. β-agonists cause bronchodilatation by stimulation of β₂-receptors on airway smooth muscle and may reduce bronchial mucosal oedema.⁴²

β-agonists are best given by metered-dose inhaler (MDI) and a spacer device. There are data to suggest that, in non-intubated patients, MDIs combined with a spacer device are more effective than nebulisers and are cheaper to use.^43,⁴⁴ In intubated patients both nebulisers and MDIs have been used effectively.⁴⁵ The dose per MDI inhalation is 100 μg and this can be given, in severe asthma, in repeated doses at 1–5-minute intervals.

Alternatively, β-agonists can be given by nebuliser in high and repeated doses.⁴⁶ The typical adult dose of salbutamol is 5–10 mg (in 2.5–5.0 ml diluent volume) every 2–4 hours but more frequent doses with a higher total dose are often required in severe asthma. It should be noted that less than 10% of the nebulised drug reaches the lung even under ideal conditions.⁴⁷ Continuous nebulisation appears to be superior to intermittent doses and is commonly used at the beginning of treatment in severe asthma.^14,⁴⁸ The nebuliser should be driven by oxygen with the flow at 10–12 l/min and a reservoir volume of 2–4 ml so as to produce particles in the desired 1–3 μm range.⁴⁹ The total dose should be modulated by response to treatment and the level of toxic side-effects.

Two-thirds of patients presenting acutely will respond well to inhaled β-agonists,⁵⁰ irrespective of the method of administration. The remaining one-third are refractory even to high doses and usually require longer periods of intense treatment, including multiple other agents.

Intravenous β-agonists remain controversial. There is no clear evidence of benefit ⁵¹ and significant side-effects. Despite this, intravenous β-agonists have a theoretical benefit of additional access to lung units with severe airflow obstruction and poor nebulised drug delivery, and some studies have demonstrated improved response when intravenous β-agonist is used.⁵² Intravenous β-agonists continue to be considered if the patient is not responding to continuous nebulisation.⁵³ The typical dose is 5–20 μg/min but doses > 10 μg/min should be used with caution because of side-effects, which should be monitored closely. Salbutamol 100–300 μg may also be given intravenously to non-intubated patients in extremis or delivered down an endotracheal tube if there is not time to gain intravenous access.

Side-effects of β-agonists include tachycardia, arrhythmias, hypertension, hypotension, tremor, hypokalaemia, worsening of ventilation–perfusion mismatch and hyperglycaemia,⁵⁴ but the most common side-effect of parenteral β-agonist – also occasionally seen with continuous nebulised β-agonists – is lactic acidosis. This occurs in over 70% of patients, has an onset within 2–4 hours of commencing an infusion or following an intravenous statim dose, levels may reach 4–12 mmol/l and may significantly add to respiratory acidosis and respiratory distress.^34,^55,⁵⁶ Parenteral infusions should be initially limited to 10 μg/min and statim doses should not exceed 250 μg. Serum bicarbonate and lactate should be regularly monitored. If lactic acidosis becomes significant, the salbutamol infusion should be reduced or ceased. Lactic acidosis will generally resolve within 4–6 hours of infusion cessation and is seldom a problem with infusions in place for more than 24 hours.

Long-term high-dose β-agonist use has been associated with increased mortality,⁵⁷ but whether high-dose β-agonists are a marker of disease severity, an indicator of suboptimal inhaled steroids or a direct cause of death is unclear. These concerns do not apply in the treatment of the acute asthma attack.

ANTICHOLINERGICS

Anticholinergics cause bronchodilatation by decreasing parasympathetic-mediated cholinergic bronchomotor tone.⁵⁸ Ipratropium bromide is the most commonly used anticholinergic for asthma and is a quaternary derivative of atropine. A number of studies and meta-analyses now suggest clear additional benefit and few side-effects when ipratropium bromide is added to the β-agonist regimen^59,⁶⁰ and ipratropium is now considered accepted first-line therapy for acute severe asthma in conjunction with β-agonist therapy. Preservative-induced bronchoconstriction has been reported in a few patients and can be prevented by using preservative-free solutions.⁶¹ The bronchodilatation effect of ipratropium bromide appeared to be maximal with a dose of 250 μg when studied in children between 9 and 17 years of age. The optimal dose is not known in adults; a reasonable regimen would be to add 500 μg ipratropium bromide to the salbutamol nebuliser every 2–6 hours; however, initial dose intervals as low as 10–20 minutes have been recommended.⁶²

CORTICOSTEROIDS

The role of corticosteroids in the acute asthma attack has been well established. Systemic steroids should be considered in all but mild exacerbations of asthma.⁴¹ Their benefits include increased β-responsiveness of airway smooth muscle, decreased inflammatory cell response and decreased mucus secretion. Early treatment with corticosteroids has been shown to decrease the likelihood of hospitalisation and decrease the mortality rate from acute asthma. Systematic reviews^41,⁶³ suggest that effects commence within 6–12 hours, that oral administration is as effective as intravenous and that there is little evidence of benefit for initial daily doses exceeding 800 mg/day hydrocortisone (160 mg/day methylprednisolone) given in four divided doses.

Inhaled steroids have established long-term benefit and are believed to be a major factor in asthma mortality reduction.¹^–³ There is now emerging evidence that inhaled steroids may also have a role during an acute attack^64,⁶⁵ and it appears reasonable to use them routinely from day 1 as they may also enable more rapid dose reduction of parenteral steroids, potentially reducing side-effects.

Parenteral corticosteroid dose reductions should commence after 1–3 days according to the severity of the attack, the degree of chronic inflammation and the response to treatment, and should be converted to a reducing dose of oral steroids within 4–7 days (e.g. oral prednisolone starting at 0.5 mg/kg body weight or 40–60 mg/day).

Side-effects of corticosteroids include hyperglycaemia, hypokalaemia, hypertension, acute psychosis and myopathy,^66,⁶⁷ though they are usually well tolerated acutely. The immunosuppressive effects can increase the risk of infections, including Legionella, Pneumocystis carinii and varicella,^68,⁶⁹ especially when the patient is on long-term corticosteroids. Allergic reactions including anaphylaxis have been reported with the use of most corticosteroid preparations.

AMINOPHYLLINE

There have been conflicting reports regarding the efficacy of aminophylline in acute asthma ranging from no benefit ⁷⁰ to improved lung function and improved outcome.⁷¹ However it is accepted that aminophylline is an inferior bronchodilator, with a narrow therapeutic range and frequent side-effects,⁷² including headache, nausea, vomiting and restlessness; cardiac arrhythmias and convulsions can occur at serum levels above 200 μmol/l (40 mg/l).

As a result, aminophylline is not a first-line treatment.^40,^41,⁵³ Aminophylline may be given to patients with acute asthma who are not showing a favourable response to full treatment with first-line agents. Careful administration and monitoring are required with an initial loading dose of 3 mg/kg (maximum 6 mg/kg, omitted if the patient is already taking oral theophylline) and an infusion of 0.5 mg/kg per hour. This should be reduced in patients with cirrhosis, cardiac failure or chronic obstructive pulmonary disease and in patients taking cimetidine, erythromycin or antiviral vaccines. Drug levels should be taken after a loading dose (if given), and then 24 hours later, aiming for a level of 30–80 μmol/l (5–12 mg/l). Levels should be repeated daily thereafter until stability has been achieved. The duration should be based on the response to treatment.