Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to β2-agonist Treatment

Abstract

To present the case of a patient with persistent bronchospasm, refractory to treatment with β2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to β2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all β2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to β2-agonist therapy.

CASE REPORT

A 13-year-old boy with history of poorly controlled asthma since early childhood (he had at least 10 prior admissions to various hospitals), developed an exacerbation consisting of progressive “chest tightness” and cough after exposure to cigarette smoke (a known trigger of his asthma). His maintenance medications consisted of inhaled steroids and inhaled albuterol, but he was using only albuterol as needed (usually 2 puffs up to 5–6 times/day). He was treated with 7 sequential treatments of nebulized albuterol (2.5 mg/dose) with minimal relief, and he was taken to a local emergency room where he received multiple additional doses of nebulized albuterol, as well as 1 dose of subcutaneous terbutaline (0.3 mg), a bolus of intravenous (IV) magnesium sulfate (1 g), and a bolus of IV dexamethasone 10 mg. A chest radiograph was interpreted as suggestive of a left lower lobe infiltrate, and he was started on oral cefuroxime before he was transferred to the pediatric intensive care unit (PICU) for further management.

Upon arrival to the PICU, he was tachypneic (respiratory rate 36–58 breaths/minute) with intercostal and subcostal retractions and poor chest excursion. He was alert and oriented, but he could only speak in very short sentences. His oxyhemoglobin saturation was 88% to 90% on room air. He had poor air exchange with diminished coarse breath sounds and expiratory as well as intermittent inspiratory wheezing. Treatment was initiated with continuous nebulization of albuterol at 20 mg/hr, and continuous IV terbutaline at a starting dose of 0.1 mcg/kg/min (the patient was obese, weighing 83.4 kg, so his dose was calculated according to a weight of 55 kg that corresponds to the 75th percentile for age). In addition, he received nebulized ipratropium bromide 500 mcg every 6 hours and IV dexamethasone 10 mg every 6 hours (the dexamethasone was used due to a shortage of IV methylprednisolone). Antibiotics were not continued because the patient was afebrile and the radiograph was thought to show mucus plugging and not an infiltrate. Over the course of the next 12 hours, the terbutaline infusion was increased to 0.6 mcg/kg/min while the continuous nebulization of albuterol was decreased to 15 mg/hr. His condition remained essentially unchanged for the next 48 hours, so azithromycin was added empirically for the possibility of mycoplasma pneumonitis as a complicating factor. He remained significantly hypoxemic with an arterial oxyhemoglobin saturation (HbSaO₂) of 82% on room air combined with persistent wheezing, so at 54 hours post-admission the nebulized albuterol was changed to continuous nebulized levalbuterol at 7 mg/hr that he received for 49 hours without discernible improvement. Due to concern that he may have developed tolerance to β2-agonists, the IV terbutaline was weaned off and eventually stopped at 87 hours post-admission, without notable change in his condition. He remained tachypneic with poor air movement, scattered wheezes, significant use of accessory muscles, and still requiring oxygen at 6 L/min via facemask. At 106 hours post-admission, the levalbuterol was also discontinued and he was started on continuous nebulized IB at a dose of 1000 mcg/hr. His peak expiratory flow rate (PEFR) at that time was 230 L/min (approximately 60% predicted). Over the next 3 hours, his PEFR increased by 52% above the baseline, and the patient stated that he was feeling much better. His heart rate and blood pressure remained stable, and there were no gastrointestinal or neurologic complications. His respiratory rate decreased from 32 to 20 breaths/min, and his HbSaO₂ increased to 97% on room air. The continuous ipratropium was discontinued after 4 hours of administration, and 90 minutes after its cessation, he was still breathing comfortably at 20 breaths/min with PEFR of 350 L/min (approximately 95% predicted) and HbSaO₂ of 97% on room air (See Table). His ipratropium bromide dosing regimen was changed to 500 mcg every 2 hours, and he was discharged from the PICU that evening.

Table.

Timetable of Changes in Vital Signs and in Medications

DISCUSSION

Our report suggests that large doses of continuously inhaled ipratropium bromide may be effective and safe for the treatment of bronchospasm, not responsive to β2-agonists. It also raises 2 separate but related questions: 1) why the patient showed no response to β2-agonists, and 2) why did he seem to respond to the ipratropium bromide.

We believe that the failure to respond to the adrenergic agents can be explained by the development of tolerance to β2-agonists.^1–4 Tolerance can develop due to the desensitization of the β2 adrenergic receptor (b2-AR) after repeated exposure to β2 agonists.¹ Proposed mechanisms for the desensitization include the uncoupling of the receptor from the cell membrane, and the sequestration or internalization of the receptors after exposure to β2-agonists, that makes them unavailable for further binding.^5–7 These mechanisms are reversible, and lost receptors can recover after withdrawal of the β2-agonist(s). A third mechanism is associated with decreased mRNA stability that leads to decreased β2 adrenergic receptor gene (ADRb2) transcription and permanent loss of cellular receptors at the cell surface.⁶ Tolerance can develop after brief exposure,⁸ but it is more likely after prolonged exposure to large doses of short acting β2-agonists.^5–7 Our patient had received large amounts of β2-agonists prior to and certainly after his admission to the hospital, so he was at risk for developing tolerance.

There is evidence that the response and/or the development of tolerance to β2-agonists are genetically determined.^9–11 Functional data have shown that variant alleles of the single nucleotide polymorphisms (SNPs) codons 16, 27, and 164 of the b2AR gene (ADRb2), may significantly affect the functions of the receptor,¹² whereas the polymorphisms at positions 16 and 27 appear to be important in the development of tolerance.^13–15 Interestingly, patients who develop tolerance to β2-agonists (e.g., those homozygous for the Arg/Arg phenotype) do improve with ipratropium bromide.¹⁰ There was no genetic testing done in our patient, but his course was consistent with the described Arg/Arg phenotype.

Ipratropium bromide is currently used in combination with albuterol in the initial management of acute severe asthma, but its effectiveness beyond the first 24 hours of treatment has been questioned.^16–18 The reasons that its efficacy varies is not completely understood. One possibility is that the efficacy is the same but not as noticeable at different time periods. Specifically, during the first 24 hours of an asthma exacerbation, the adrenergic receptors that constitute the vast majority of receptors in the airways are down-regulated and thus temporarily non-responsive to β2-agonists. In contrast the muscarinic receptors remain functional and therefore their relative contribution increases substantially. After the adrenergic receptors become upregulated (a function that is attributed to the action of the systemic steroids and usually occurs after the first 24 hours), the effect of ipratropium bromide becomes less obvious because most of the bronchodilation is provided by the adrenergic receptors.

Because there are no guidelines for the dosing of continuous ipratropium bromide, the regimen was selected empirically using as basis the experience from continuous administration of albuterol. When albuterol is administered continuously, the hourly dose ranges from 10 to 20 mg/hr that is 4 to 8 times larger than the standard dose (2.5 mg). The hourly dose of ipratropium bromide in our patient was only double the standard dose he was already receiving (from 500 mcg to 1000 mcg). We were hoping that this was a large increase with the potential of having an increased therapeutic effect (if there is indeed a dose-response effect), and yet relatively close to the already tolerated dose. The plan was to adjust the dose upwards or downwards depending on its therapeutic effect and/or the development of possible side effects. Because of the resolution of the symptoms this was not necessary. Since our patient was treated empirically and not as part of a research protocol, it is not possible to determine whether his dramatic improvement was due to the larger dose of ipratropium bromide (something that suggests a dose-response effect) or to the different mode of administration or possibly due to both. His response suggests that the continuous administration of ipratropium bromide in large doses may be a successful regimen for patients non-responsive to intermittent lower dosing.

There are several other factors that may have played a role in our patient's course. For example, it is possible that he might have had an equally good or better response if he had received continuous ipratropium bromide during the first 24 hours of his exacerbation. Another factor that might have played a role was the introduction of the azithromycin after the first 48 hours of his illness. In addition to its antimicrobial properties, azithromycin is known to have anti-inflammatory properties as well that may have added additional benefit.^19,20 Although such an effect cannot be ruled out, we believe that it is rather unlikely to be the main factor for our patient's improvement because his condition did not change until after the switch to the continuous ipratropium bromide.

In summary, continuous nebulization of ipratropium bromide may be an effective and safe therapeutic alternative in patients with acute asthma refractory to β2-agonist treatment. Further studies will be necessary to determine the optimal dose.

ABBREVIATIONS

HbSaO₂

arterial oxyhemoglobin saturation

IB

ipratropium bromide

IV

intravenous

PEFR

peak expiratory flow rate

PICU

pediatric intensive care unit