Date sent: Wed, 22 Nov 1995 00:13:55 -0600 (CST) From: Harvey Louzon To: emed-l@itsa.ucsf.edu Subject: emed-l paradoxical bronchospasm Imagine the following senario: A known asthmatic presents to the ED with an acute exacerbation. He is given continuous nebulized albuterol but appears to worsen by the minute. Although ill for perhaps 24 hours he has a sudden decompensation during treatment which requires intubation. This is not an uncommon occurance. We've all seen it dozens of times. Is this merely a failure of therapy with rapid progression of disease? I've had my doubts for quite awhile. A case that I saw about one month ago heightened my suspicions. A fifty year old asthmatic presented with an acute exacerbation. He seemed to be worsening dramatically with each treatment. To fail to improve is one thing--to actually get worse by the minute is quite another. For once I made the decision to simply stop the nebulization. I also gave him a dose of magnesium. (He had received solumedrol on presentation). Within less than 10 minutes he was comfortable, lying back in bed, talking in full sentences. Ten minutes earlier he was diaphoretic and on the verge of being intubated. Coming home I sat down and wrote a letter to the list about this event and my suspicions. With uncharacteristic reluctance I did not send it. Recently I came across several articles detailing the occurence of paradoxical bronchospasm with inhaled beta-agonists--both MDI and nebulized solutions. One study (1) looked at ADRs reported to the FDA. Between 1974 and 1988 126 cases had been reported related to the use of MDI and between 1983 and 1988 58 cases related to the use of nebulized solutions. Paradoxical bronchospasm associated with MDI usually occurs in patients between the ages of 11 and 40. Many occur when a new cannister is used but not upon rechallege with a different cannister. Propellants and other ingredients implicated in causing this reaction include alcohol,oleic acid, sorbitan, saccharin etc. Placebo inhalers used in some blinded studies have also caused this reaction which appears to occur as a result of these 'contaminants' rather than the drug itself. In the case of nebulized solutions, on the other hand, the patients are usually younger than 10 or older than 40 years of age. The presence of sulfites, benzalkonium chloride and edatate disodium has been implicated. With both delivery methods, symtoms of a systemic anaphylactic reaction have been present (in some cases) as well, including urticaria, laryngospasm, tachycardia, syncope and angioedema. Paradoxical bronchospasm usually resolves in a time interval of from 5 minutes to 3 hours but reactions resulting in death or requiring intubation have been reported. Several case reports of paradoxical bronchospasm from the use of parenteral methylprednisolone and hydrocortisone have also been reported (2). This reaction is much more likely to occur in asthmatics that have aspirin sensitivity with or without nasal polyps. The reaction typically occurs within 5 minutes of administration and is dose-related. Corticostreoid induced bronchospasm (CIB) can occur alone or the steroid may induce uritcaria or angioedema. When these patients are re-challenged with the solvent it fails to reproduce the reaction suggesting that the steroid itself is responsible. These patient develop an immediate wheal and flare reaction to intradermal steroid injection. When challeged with other parenteral steroids or oral prednisone these reactions do not occur. It is hypothesized that certain steroids may inhibit the release of prostaglandin precursers needed for bronchodilatation. All of this gives one cause to stop and wonder. How many asthmatics have we seen that get acutely worse during treatment? How do we know if this is a 'natural' progression of the disease process or an effect of the treatment itself? How under-reported are these reactions anyway? H. Louzon MD (1) Paradoxical Bronchospasm Associated with the Use of Inhaled Beta Agonists. Nicklas R.A. J Allergy Clin Immun 1990;85:959-64 (2) Status Asthmaticus With Acute Decompensation with Therapy in a 27-Year Old Women. Judson et.al. Chest 1995;107:563-565 This latter reference has several other references to CIB from hydrocortisone and methylprednisolone. That's a good (additional) point. The exacerbation of V/Q mismatch and worsening hypoxemia is a well known complication of beta-agonist therapy. However it does not explain the occurence of bronchospasm that has been described as occuring with placebo inhalers in some blinded studies. Some of these patients have concomitantly developed symptoms of a systemic reaction, including urticaria and angioedema which suggest an atopic component. Also of note is that these reactions to inhaled medications have been described as occuring with inhaled cromolyn and steroids which one would not expect to affect V/Q ratios directly in any immediate way (2,4,5). (And, incidently, to atrovent as well). Some patients have been observed to develop bronchospasm secondary to sulfite preservatives in the nebulized solution and but not when it was removed. Propellants, emulsifiers and preservatives have been implicated in causing these reactions. Even the use of nebulized saline, alone, has precipitated bronchospasm in some individuals suggesting that an effect related, perhaps, to turbulent airflow may casue this in suseptible individuals (1,3). Finally in the case of reactions to intravenous steroids, that I mentioned previously, an allergy to the steroid itself (hydrocortisone and methylprednisolone) _without_ preservative has been manifested by immediate wheal and flare reactions to intradermal injections. Undoubtedly precipitation of hypoxemia by worening V/Q mismatching plays a role in some cases but in others I think that it is clear that a true allergy is present to the inhaled medication. H. Louzon MD See Also (1) Sheppard D Rizk NW Boushey HA Bethel RA Mechanism of cough and bronchoconstriction induced by distilled water aerosol. In: Am Rev Respir Dis (1983 Jun) 127(6):691-4 We studied therelationship between cough and bronchoconstriction caused by inhaled distilled water aerosol in 8 subjects with asthma by measuring specific airways resistance (SRaw) and recording cough while subjects breathed serially increasing volumes of distilled water or normal saline aerosol produced by an ultrasonic nebulizer. We performed the distilled water dose-response curves after no treatment and after treatment with cromolyn aerosol, lidocaine aerosol, or atropine aerosol in doses of 0.2 mg and 2.0 mg on separate days. Without prior treatment, distilled water aerosol caused cough in 7 of 8 subjects and a marked increase in SRaw in every subject, whereas saline aerosol did not cause cough or a greater than 50% increase in SRaw in any subject. The 2 doses of atropine caused an equivalent reduction in baseline SRaw, but 2.0 mg caused greater inhibition of water-induced bronchoconstriction than did 0.2 mg. Neither dose of atropine inhibited cough. These data suggest that water-induced bronchoconstriction involves cholinergic nerves and that water-induced cough is not dependent on bronchoconstriction. Lidocaine inhibited cough but not bronchoconstriction, whereas cromolyn inhibited bronchoconstriction but not cough, suggesting that cromolyn does not inhibit bronchoconstriction by a generalized inhibition of airway afferent nerves. (2) Shim CS Williams MH Jr Cough and wheezing from beclomethasone dipropionate aerosol are absent after triamcinolone acetonide. In: Ann Intern Med (1987 May) 106(5):700-3 Study Objective: To test the hypothesis that patients with asthma who develop cough and wheezing after the use of beclomethasone aerosol would have a better tolerance for triamcinolone aerosol. Design: Randomized, double-blinded, crossover trial. Setting: Pulmonary function laboratory. Patients: Volunteer sample of 24 patients attending an asthma clinic who had developed cough, with or without wheezing, after inhaling beclomethasone aerosol. All patients completed the study. Interventions: Aerosols were used in habitual manufacturers' preparations and canisters, but both were administered in three puffs through the delivery system used for triamcinolone. The preparations differed in drug (beclomethasone dipropionate or triamcinolone acetonide), propellant (trichloromonofluoromethane and dichlorodifluoromethane, or dichlorodifluoromethane alone, respectively) and dispersant (oleic acid or dehydrated alcohol, respectively). Patients inhaled three puffs of one aerosol on one day and three of the other on the next. Measurements and Main Results: Forced expiratory volume in one second (FEV1) was measured before and after each aerosol application. The FEV1 decreased a mean of 17.7% from baseline after inhalation of beclomethasone, and 0.8% after triamcinolone (difference, 16.9; 95% confidence limits, 12.36 to 21.34; p less than 0.001). Coughs were counted after each puff. The mean number of coughs after beclomethasone aerosol inhalation was 35.8, and after triamcinolone, 0.5 (difference, 35.3; 95% confidence limits, 22.62 to 47.98, p less than 0.001). Conclusions: Asthmatic patients who are unable to inhale beclomethasone aerosol due to cough or wheezing can inhale triamcinolone aerosol without difficulty. Our investigation does not determine the exact cause of the coughing and wheezing with the beclomethasone aerosol, but we suspect the dispersant as the source. (3) Schoeffel RE Anderson SD Altounyan RE Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline. In: Br Med J (Clin Res Ed) (1981 Nov 14) 283(6302):1285-7 To assess non-specific bronchial reactivity the effect of inhaling ultrasonically nebulised solutions of distilled water and hypotonic (0.3%), isotonic (0.9%), and hypertonic (2.7%, 3.6%) saline was investigated in 10 asthmatic patients and nine normal subjects. Expired ventilation and the maximum percentage fall in forced expiratory volume in one second (FEV1) were recorded. The sensitivity to the inhaled solutions was determined by measuring the ventilation required to induce a fall in FEV1 of 20% from the prechallenge value. Hypotonic and hypertonic but not isotonic solutions caused a significant fall in FEV1 in the asthmatic subjects. Normal subjects showed no response to either distilled water or 3.6% saline, the only solutions with which they were challenged. The method used for this challenge is rapid, simple, and inexpensive and provides a new means of diagnosing non-immunologically mediated bronchial hyperreactivity. (4) Shim C Williams MH Jr Cough and wheezing from beclomethasone aerosol. In: Chest (1987 Feb) 91(2):207-9 Cough and wheezing are frequent side effects of inhaling beclomethasone dipropionate aerosol (BA) in patients with asthma. Twenty percent of our outpatient asthmatic subjects are unable to take BA due to these side effects. Twelve patients with history of severe cough and wheezing after inhaling BA were tested. Three puffs of either BA or placebo (Plc) were administered from a metered dose inhaler (MDI) in a double-blind crossover design. They coughed a mean of 31 times after BA and 19 times after Plc. Forced expiratory volume in one sec (FEV1) declined a mean of 22.6 percent after BA and 22.0 percent after Plc. Pretreatment with albuterol attenuated both the cough and the drop in FEV1. Follow-up study showed that regular pretreatment with bronchodilator enabled seven of 12 patients to tolerate BA therapy. The remaining five required a short course of increased dose oral steroid therapy. Cough and wheezing are frequent side effects of BA therapy that interfere with regular compliance. Pretreatment with a bronchodilator is effective in attenuating these side effects in some patients; in others, a short course of oral steroid therapy may be necessary. (5) Cacoub P Royer I Guillevin L Warot D [Acute respiratory insufficiency following inhalation of disodium cromoglycate (letter)] Insuffisance respiratoire aigue secondaire a l'inhalation de cromoglycate disodique. In: Presse Med (1986 Apr 26) 15(17):803 (Published in French) Adverse Effects of Inhaled Corticosteroids AJM 98:196(1995)