Use of intravenous salbutamol in acute severe asthma

Sellers & Messahel [1] in their paper report on seven patients (four of whom were children) with acute severe asthma managed in the conventional manner but who in addition received an immediate dose of intravenous salbutamol. They report good clinical response by these patients to intravenous salbutamol although two patients (one a child) eventually required intubation and assisted ventilation. From this experience, these authors suggest that the immediate use of intravenous salbutamol should be considered in every case of acute severe asthma and that if this had little clinical effect, a repeat dose of intravenous salbutamol should be immediately given, and in some cases several times over.

The severe asthmatic is easily recognised, but creating an all-encompassing definition of asthma severity has been difficult [2]. There is no single investigation that defines asthma. This has resulted in much confusion in the literature with regards to asthma management. In many cases, what is considered moderate asthma in the southern hemisphere is commonly classified as severe elsewhere. The management of these patients is clearly very different and any attempt at comparison will result in confusion. Most countries now have national guidelines [3] that are in agreement, but we must remain careful in interpreting data that have classified asthma in a non-discriminate way as we are most likely comparing ‘apples with oranges’. A recent meta-analysis on the use of intravenous β-agonists suffers from poor case definition as well and being poorly controlled for patient age. In addition, the study combines papers that use both β-agonists and aminophylline in treatment protocols that were so different as to be considered different approaches to management rather than equivalent therapies [4].

The paper by Sellers & Messahel again raises the perennial question of asthma definition and how they defined acute severe asthma in their report. In our original paper on the use of intravenous salbutamol in children [5], there was a difference between severe as defined in that paper, i.e. severe enough to come to the emergency department and not responding to the first dose of inhaled salbutamol, and that in the general asthma literature. Sellers & Messahel have defined severe asthma in the traditional way as used by PICU, these patients having refractory disease with significant respiratory failure mandating intensive care.

Asthma is an inflammatory disease that is typified by airway hyper reactivity and obstruction, producing variable airway resistance with a reduction in air flow [5]. The initial management of an acute attack involves a stepwise approach, although in cases of life-threatening asthma immediate intravenous therapy is recommended [6]. Traditionally, intravenous therapy, particularly in children, has been left for the most severe cases. This is often considered after the use of frequent doses of inhaled bronchodilators has failed. In cases of severe asthma, any delay in clinical response may render airways bronchodilator unresponsive due to progression of the inflammatory process in these airways. We believe there is a window of opportunity during initial presentation with severe asthma to the emergency department where the airways may continue to be bronchodilator responsive. If intravenous therapy is used early as shown by Sellers et al., then clinical response should be rapid with more rapid stabilisation of the patient.

The mainstay of treatment of acute asthma involves the frequent use of inhaled β-agonists, together with corticosteroids [6]. We have shown that inhaled β-agonists produce systemic plasma drug concentrations in the range 20–40 ng.ml⁻¹, within 2 h of commencement of therapy. In many patients, but particularly in children, with severe asthma, inhaled therapy can be unreliable as this is dependent on delivery technique and tidal volume, both of which are highly variable [5, 7, 8]. In addition, these patients fail to improve because severe bronchospasm and mucus plugging prevents distal drug delivery by the aerosol route. In this case, a better initial alternative, particularly if asthma is severe, is to use the intravenous route.

Intravenous β-agonist therapy can be highly effective in reversing bronchospasm, even in the presence of marked hypercapnia [9]. It has been shown that intravenous salbutamol was more effective than inhaled salbutamol in reversing airways obstruction. In addition, those patients receiving the intravenous preparation achieved earlier therapeutic level, more rapid clinical response and could be discharged earlier. With intravenous salbutamol, plasma levels similar to those achieved with inhaled therapy are reached with a 10-min infusion of salbutamol at a rate of 1.5 µg.kg⁻¹.min⁻¹[5, 7, 8]. We would ideally recommend in children that intravenous bronchodilator therapy be reserved for patients with acute severe asthma who are not responding to initial nebulised bronchodilators (Fig. 1). The tendency, however, to delay intravenous drug treatment in the most severe asthmatic patients has the potential to lead to a protracted clinical course.

Figure 1

Sellers & Messahel suggest in their paper that if after initial intravenous bolus no clinical effect is observed, repeated boluses of intravenous salbutamol should be considered. This is probably safe provided the patient is carefully monitored in the presence of an intensive care physician. In our institution, we would use a short-term continuous intravenous salbutamol infusion, commencing this in the emergency department. Although widely used, uncertainty currently exists as to the correct dose that should be used of a continuous intravenous salbutamol infusion (CIS). We would consider an infusion of 5 µg.kg⁻¹.min⁻¹ of salbutamol for 2 h in those children with acute severe asthma who are clinically stable and on maximal medical therapy a reasonable approach (Fig. 1). This dosage is considered safe and has not been shown to be associated with serious side-effects. The physician would thereafter titrate intravenous salbutamol therapy according to the patient's clinical response with admission to PICU mandatory if ongoing CIS is needed or clinical deterioration is detected during the administration of this therapy in the emergency department.

Our rationale for using CIS rather than repeated bolus doses of salbutamol is as follows. Over a 10-year period in our PICU, we have seen a two-fold increase in admissions for acute severe asthma. We have seen a three-fold increase in CIS use mirrored by a reduction in aminophylline use. Only a handful of patients were mechanically ventilated over this period but all received CIS. For those non-ventilated patients, CIS was ceased within 4–6 h after it had been commenced. This suggested to us that there is an opportunity to treat some of these patients effectively in the emergency department before being admitted to the PICU.

We reported the use of CIS in Australian and New Zealand Emergency Departments (ANZ-ED). CIS has been used for the treatment of acute severe asthma in children in 85% of ANZ-ED [10]. A wide variation in dose of CIS was reported. The use of a continuous infusion rather than repeated boluses of intravenous salbutamol is our preferred option if the initial single bolus fails to provoke an adequate clinical response. Salbutamol has a long half-life of 2–4 h in adults. This is consistent with it being excreted renally and occupying extracellular space. There are limited data in children but there is no reason to suppose different pharmacokinetics. An infusion of 5 µg.kg⁻¹.min⁻¹ will achieve a plasma level of 110 ng.ml⁻¹, and this level will then be maintained at a slower infusion of 1 µg.kg⁻¹.min⁻¹[11, 12]. Because in some patients salbutamol will have a shorter half-life, it would be prudent to allow overshoot, so we recommend continuing the infusion for 2 h. Overshoot will not result in toxicity as much higher levels are known to be well tolerated [13]. If the effect is inadequate, increasing the infusion to 2 µg. kg⁻¹.min⁻¹ preceded by a 1-h infusion at 10 µg.kg⁻¹.min⁻¹ will achieve a double plasma level. These infusion rates are a much higher dosing than suggested by Sellers & Messahel, in which up to six boluses amounts to the equivalent of no more than 30 min at 5 µg. kg⁻¹.min⁻¹.

As suggested by Shann [11], salbutamol takes approximately four half-lives to reach a plateau concentration of drug. If salbutamol is given as a constant infusion without an appropriate loading dose, 10–20 h is required to reach a plateau concentration. In these cases, there will be either subtherapeutic levels at the beginning of therapy, excessive levels after several hours of therapy or both. In this respect, salbutamol and terbutaline require similar plasma concentrations to produce a given effect and are therefore equivalent drugs, although salbutamol has been the preferred β-agonist owing to its greater margin of safety when administered intravenously.

The addition of ipratropium to β-agonist therapy offers a statistically significant, albeit modest, improvement in pulmonary function, as well as a reduction in the rate of hospital admissions. The use of inhaled ipratropium bromide in addition to intravenous salbutamol, frequent doses of inhaled salbutamol and corticosteroids as initial emergency department therapy have no clinical benefits for children with acute severe asthma [8].

Aminophylline has bronchodilator effects with an additional theoretical benefit of an inotropic effect on respiratory muscles [14]. A recent study in children suggests that aminophylline may be useful in reducing length of stay in hospital [15]. However, the window between therapeutic effect and toxicity is relatively narrow, and this can lead to serious side-effects. Given the potential for toxicity and the marginal benefit, we would not recommend this drug as a standard therapy for severe asthma but rather something to consider in refractory disease in the intensive care.

Although magnesium sulphate has been reported to improve bronchospasm in the emergency department or in the ICU, there is currently insufficient clinical evidence to support its routine use in severe asthma [16].

Asthma deaths in hospital should be very rare and so should intubation. Over the last 3 years since we have adopted this approach in our emergency department and regional hospitals, we have not had the need to intubate a single patient admitted to our PICU with acute severe asthma. The need for intubation, however, should be on the basis of clinical signs of respiratory failure, i.e. genuine exhaustion. We would expect that with appropriate assessment of patients with acute severe asthma in the emergency department in addition to the correct use of intravenous salbutamol in these patients, we can avoid progression to respiratory exhaustion and hence intensive care interventions such as intubation. This should be reserved for those rare patients who are unresponsive to aggressive salbutamol therapy and therefore have refractory disease in addition to rapidly progressive respiratory exhaustion.

We should therefore continue to use salbutamol in acute severe and life-threatening asthma because its appropriate use is both clinically very effective and has an extremely high margin of safety. Intravenous salbutamol for managing acute severe asthma in the emergency department has the potential to shorten the duration of an acute asthma attack, to reduce overall requirements for inhaled salbutamol and will result in earlier hospital discharge of these patients. We would like to remind the reader that salbutamol is called albuterol in USA. Salbutamol and albuterol are the same drug and we should not be confused by this difference in nomenclature nor get them mixed up when using these drugs clinically.