Infrequent Cardiac Deaths Occur in Bronchial Asthma* lnoin Ziment, M.D., F.C.C.R
S
(Cheat 1992; 101:1703-05)
udden death in asthma can be a devastating and inexplicable event that forces physicians to seek an explanation. Over the years, this problem appears to have been increasing, although a sizeable proportion of the 4,500 or so deaths a year in the United States occur in older people 1 and asthma may reflect the one obvious diagnosis given to patients who are terminally ill with multiple geriatric disorders. Truly unexpected deaths, some of which occur suddenly in patients who are not regarded as having severe asthma, 2 constitute a very minor but highly disturbing subset in the population of over 10 million patients with asthma in the United States. Reviews of unexpected deaths suggest that little beyond good education of patients and their families could be done to anticipate or prevent deaths, unless costly evaluations and precautions were to be directed at the huge population of asthmatic subjects of all ages.1.3,4 The current review by Dr. Robin offers an approach to identifying the small number of patients who may be at risk of fatal complications from aerosol bronchodilator therapy. OVERTREATMENT OR UNDERTREATMENT?
In his overview of the problem, Dr. Robin notes that the increase in deaths in the United Kingdom from 1961 to 1967 was correlated with sympathomimetic metered dose inhaler (MDI) use, and that the subsequent decrease in this use was paralleled by a decrease in asthma mortality. However, this relationship applied particularly to a potent form of isoproterenol, and it is relevant that no correlation has been made in the last 30 years in the United Kingdom or the United States between increased asthma mortality and the newer beta-agonist MDIs that have replaced isoproterenol. 3 Furthermore, Dr. Robins suggestion that "overtreatment" was the cause fails to give sufficient attention to the fact that the worldwide excess mortality seems to be related primarily to overall undertreatment with steroids, oxygen, and other interventions. Indeed, it is possible that panicky patients with severe escalating asthma who rely on MDIs alone are getting almost no treatment, since their dyspnea may make it impossible to breathe in sufficient aerosol to have any effect. Evidence that overuse ofsympathomimetic aerosols is not a factor in the increasing death rate from asthma *From Olive View Medical Center, Sylmar, California. Reprint requests: Dr. Ziment, Olive Vaew Medical Center, 14445 Olive View Drive, Sylmor CA 91342-1495
in the United States is readily found. Thus, epinephrine aerosol can be bought ove~the-counter without prescription, and it cannot be doubted that massive unsupervised overuse of this drug must occur in many patients with severe asthma. Nevertheless, no reports have suggested that deaths have resulted from unrestrained use of aerosolized epinephrine. The treatment of severe asthma in emergency rooms places heavy emphasis on the use of the aerosolized sympathomimetics, albuterol, metaproterenol, and isoetharine. Typical recommended dosages are for "unit doses" (equivalent to 27 puffs of albuterol, 23 puffs of metaproterenol and 15 puffs of isoetharine) to be given every 20 min for three treatments, followed by further dosing every hour. 1,5,6 Thus, in 2 to 3 hours, a patient may be given the equivalent of over 100 puffs of an MDI preparation of albuterol or metaproterenol or over 75 puffs of isoetharine. There is no proof that such treatment is hazardous, even in the absence of concomitant steroid or aminophylline therapy. In New Zealand, where the concerns about the dangers ofbet~-agonist therapy may now have reached proportions that exceed the actual epidemic of asthma deaths, 75 deaths were reported by Sears et al7 between 1981 and 1983 that occurred in asthmatic patients who used a beta-agonist in home nebulizers. Sears and colleagues7 concluded that, "the probability that inhalation ofbeta-sympathomimetics by nebulizer contributed to death was lower than the probability that death would have occurred without treatment:' It is curious that currently Sears is the name attached to the school of thought that beta-agonist use per se is hazardous in asthmas when he formerly emphasized that the main problem was ove~reliance on this therapy once the drug or its administration had become ineffective, and that evidence for direct toxicity of high dose beta-agonist therapy was not found. 6 Sears and colleagues9 have pointed out that, "cardiac arrhythmia due to drugs (ie, beta-agonist and theophylline) in the presence ofhypoxia might explain the very few extremely sudden deaths, but we have no evidence for or against this hypothesis."9 This antipodal conclusion is echoed by SlylO who, in his detailed analysis of deaths from asthma between 1979 and 1984, stressed that in New Zealand after 1980, a decrease in asthma deaths corresponded with an increase in sales of beta-agonist MDIs and other antiasthmatic drugs. Overall, Sly endorsed the current conclusion that deaths at both ends of the world can CHEST I 101 I 6 I JUNE. 1992
1703
best be explained by undertreatment rather than by drug toxicity. It is relevant that in the United Kingdom, where an ongoing concern with deaths from asthma has led to stringent examination of drug usage, it was recently reported by the Committee on Safety of Medicine, Hthat existing data did not support the suggestion that beta-agonist had an unfavorable riskbenefit ratio."8 In the UK, prescriptions for inhaled beta-agonists tripled since 1980, without any corresponding increase in mortalit~ II CARDIAC DEATHS IN ASTHMA
Nevertheless, as Dr. Robin emphasizes, beta-adrenergic aerosols may have the potential for causing adverse cardiac effects in susceptible patients. There is substantial evidence for this in the case of isoproterenol, an agent with potent betal-adrenoceptor activity. Extrapolation of this concern to the selective bet~-sympathomimetics in current use does not appear to be warranted, with the possible exception of fenoterol. I2 In the United States, where most aerosol bronchodilator therapy in the past few years has been based on albuterol and metaproterenol, there is little to support the occasional claims that these latter drugs destabilize asthma or cause sudden cardiac death. Studies that suggest these aerosols can induce hypokalemia l3-15 do not appear to be relevant to the subjects who are at risk of dying, since study patients are relatively healthy, and, in many cases, they have not been taking be~-aerosol therap~ whereas deaths occur in stressed asthmatic subjects with deteriorating lung function who are usually taking escalating doses of their aerosol. Godden et al l6 have suggested that regular dosing with a beta-agonist may protect against hypokalemia, possibly as a result of tolerance. The true incidence of this adverse electrolyte effect is uncertain, but the evidence accumulated in asthmatic patients who have been studied over the years suggests that clinically relevant hypokalemia must be a rare occurrence following aerosol bronchodilator therap~ Moreover, the degree of hypokalemia, even when associated with hypoxemia and catecholamine-induced tachycardia, does not appear to be sufficient to cause sudden fatal arrhythmias. Presumably, patients with heart failure who are receiving diuretics are far more likely to be harmed by hypokalemia, but there does not appear to be an epidemic of deaths in these patients. It must also be recognized that steroids and theophylline can each cause hypokalemia, and if this concern leads to the suggestion that asthmatic patients be forbidden to use these drugs as well as be~ adrenergic agents for acute exacerbations of bronchospasm, we will surely condemn many more to die of suffocation than we could possibly save from the rare and unproven consequence of a hypokalemic arrhythmia. 1704
Any theory as to what may cause unexpected deaths in asthmatic subjects must take into consideration the larger and generally older population of patients with chronic obstructive pulmonary disease. This category of patients is at higher risk of cardiac arrhythmias and myocardial infarction, since ischemic heart disease, pulmonary hypertension, ventricular hypertrophy, dysrrhythmias, heart failure, hypoxia and hypokalemia are more likely to be present. Patients with COPD rely on beta-adrenergic drugs and theophylline; only in recent years has ipratropium therapy been introduced. In spite of bronchitis being an inHammatory disease, patients with COPD derive no benefit from cromolyn, and the majority is unlikely to be helped by steroids. Moreover, if a patient with COPD suffers a myocardial infarction, the presence ofairway disease contraindicates subsequent protective therapy with beta-blockers, and the patient usually continues to use be~-bronchodilators. In spite of this multiplied risk of cardiac misadventure, there is no published evidence to suggest that there is an increased risk of cardiac death in COPD patients with underlying ischemic heart disease. THE DANGER OF LABELLING A DRUG AS DANGEROUS
Asthma deaths have been attributed to both excess drugs and insufficient drug therapy and also to synergistic drug toxicity, to hypoxemia, electrolyte disturbance, arrhythmias, myocardial necrosis, panic exacerbated by catecholamines, greater penetration of antigens in overly dilated airways, rebound bronchospasm, paradoxic response to bronchodilators, subsensitivity, competitive blockade by bronchodilator drug metabolites, overactivity ofalpha-adrenoceptor mechanisms when be~-receptorsubsensitivity occurs, and so on. A few years ago, Dr. Robin mused that asthmatic deaths might be attributed to methylxanthine toxicit}; but he also pointed out that the epidemic of excess deaths could not be explained by a simple onemedication overdose theory;17 indeed, massive polypharmacy was clearly of greater potential danger. Although his viewpoint has evolved, Dr. Robin is still convinced that the excess deaths are iatrogenic in origin. However, his focus on the beta-agonist as the villain may not serve a useful purpose at this time, since it can only add to the confusion and undermine confidence in established, effective therapy. Even if a very small minority ofpatients is susceptible to adverse outcomes when treating severe asthmatic attacks with sympathomimetics, what effective alternatives can we offer with certainty as to safety? Theophylline preparations may be safer, but current thinking hardly supports this possibility. Cromolyn does not provide effective therapy in severe asthma, and the aerosol may even exacerbate the bronchospasm. Should severe Cardiac Deaths in Bronchial Asthma (Irwin Ziment))
asthma be treated only with aerosol or oral steroids? They certainly have no acute benefit in alleviating sudden ~ttacks ofasthma. And what guidelines should we offer patients with increasing bronchospasm.particularly in infirm older patients or the impoverished children that are at greatest risk of death from asthma because they lack ready access to medical care pI To deprive these needy groups of their betaadrenergic therapy would compound their misery and would possibly jeopardize their lives by allowing progress ofthe respiratory failure that is already known to be the major cause of death in asthma. Let us applaud Dr. Robin for encouraging more research into the "sudden asthmatic death syndrome;' and for focusing attention on the possibility of a subgroup of patients who may have a heightened propensity to develop hypokalemia and cardiac arrhythmias. But let us be certain that in our anxiety to detect the small number of patients at risk we do not condemn larger numbers of asthmatic patients to succumb from the "slow asthmatic death syndrome" that would result from inadequate sympathomimetic aerosol bronchodilator therap~ At present, there is little reason to doubt that prescribed aerosol therapy with the beta-adrenergic drugs that are available in the United States constitutes reasonable first-line, effective, benign, and even life-saving therapy for millions of patients with asthma and COPD. While seeking to prevent the relatively uncommon sudden deaths, we must not undermine the true advance that inhaled be~ drugs have enabled us to offer huge numbers of patients suffering from bronchospasm during the last half centu~ REFERENCES 1 Expert Panel Report. Guidelines for the diagnosis and manage-
2 3 4
5
6 7
8
9
10 11 12
13
ment of asthma. Bethesda: US Department of Health and Human Services; Public Health Service, National Institutes of Health, 1991; publication No. 91-3042 Robin ED, Lewiston N. Unexpected, unexplained death in young asthmatic subjects. Chest 1989; 96:790-93 Higenbottam T, Hay I. Has the treatment of asthma improved? Chest 1990; 98:706-12 Sly RM. Increase in deaths from asthma. Ann Allergy 1984; 53:20-25 Willcins W Jr, ed. In: Emergency medicine. Scienti6c foundations and current practice. 3rd 00. Baltimore: Williams & Wilkins, 1989; 153 Stanescu DC. High doses of sympathomimetics in severe bronchial asthma. Eur Respir J 1989; 2:597-98 Sears MR, Rea HH, Fenwick J, Gillies AJD, Holst PE, O'DonneD ~ et a1. 75 deaths in asthmatics prescribed home nebuIisers. Br Med J 1987; 294:477-80 Noticeboard. p-agonists and asthma. Lancet 1992; 339:422 Sears MR, Rea HH, BothweD RPG, O'Donnell ~ Holst PE, Gillies AJD, et a1. Asthma mortality: comparison between New Zealand and England. Br Moo J 1986; 293:1342-45 Sly aM. Mortality from asthma, 1979-1984. J Allergy Clio Immunoll988; 82:705-17 Noticeboard. Safety ofbeta-agonists. Lancet 1992; 339:486 Spitzer WO, Suissa S, Ernst ~ Horwitz RI, Habbick B, Cockcroft D, et a1. The use of p-agonists and the risk of death and near death from asthma. N Eng} J Moo 1992; 326:501-06 Gelmont DM, Balmes JR, Yee A. Hypokalemia induced by inhaled broncbodilators. Chest 1988; 94:763-66
14 Kfing M, Croley S~ Phillips BA. Systemic cardiovascular and metabolic effects associated with the inhalation of an increased dose of albuterol. Chest 1987; 92:382-87 15 Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 336:1396-99 16 Godden DJ, Seymor DNA, Robertson DA. 75 deaths in asthmatics prescribed borne nebulisers. Br Moo J 1987; 294:1356 17 Robin ED. Death from bronchial asthma. Cbest 1988; 93:61418
CHEST I 101 I 6 I JUNE, 1992
1705
S
(Cheat 1992; 101:1703-05)
udden death in asthma can be a devastating and inexplicable event that forces physicians to seek an explanation. Over the years, this problem appears to have been increasing, although a sizeable proportion of the 4,500 or so deaths a year in the United States occur in older people 1 and asthma may reflect the one obvious diagnosis given to patients who are terminally ill with multiple geriatric disorders. Truly unexpected deaths, some of which occur suddenly in patients who are not regarded as having severe asthma, 2 constitute a very minor but highly disturbing subset in the population of over 10 million patients with asthma in the United States. Reviews of unexpected deaths suggest that little beyond good education of patients and their families could be done to anticipate or prevent deaths, unless costly evaluations and precautions were to be directed at the huge population of asthmatic subjects of all ages.1.3,4 The current review by Dr. Robin offers an approach to identifying the small number of patients who may be at risk of fatal complications from aerosol bronchodilator therapy. OVERTREATMENT OR UNDERTREATMENT?
In his overview of the problem, Dr. Robin notes that the increase in deaths in the United Kingdom from 1961 to 1967 was correlated with sympathomimetic metered dose inhaler (MDI) use, and that the subsequent decrease in this use was paralleled by a decrease in asthma mortality. However, this relationship applied particularly to a potent form of isoproterenol, and it is relevant that no correlation has been made in the last 30 years in the United Kingdom or the United States between increased asthma mortality and the newer beta-agonist MDIs that have replaced isoproterenol. 3 Furthermore, Dr. Robins suggestion that "overtreatment" was the cause fails to give sufficient attention to the fact that the worldwide excess mortality seems to be related primarily to overall undertreatment with steroids, oxygen, and other interventions. Indeed, it is possible that panicky patients with severe escalating asthma who rely on MDIs alone are getting almost no treatment, since their dyspnea may make it impossible to breathe in sufficient aerosol to have any effect. Evidence that overuse ofsympathomimetic aerosols is not a factor in the increasing death rate from asthma *From Olive View Medical Center, Sylmar, California. Reprint requests: Dr. Ziment, Olive Vaew Medical Center, 14445 Olive View Drive, Sylmor CA 91342-1495
in the United States is readily found. Thus, epinephrine aerosol can be bought ove~the-counter without prescription, and it cannot be doubted that massive unsupervised overuse of this drug must occur in many patients with severe asthma. Nevertheless, no reports have suggested that deaths have resulted from unrestrained use of aerosolized epinephrine. The treatment of severe asthma in emergency rooms places heavy emphasis on the use of the aerosolized sympathomimetics, albuterol, metaproterenol, and isoetharine. Typical recommended dosages are for "unit doses" (equivalent to 27 puffs of albuterol, 23 puffs of metaproterenol and 15 puffs of isoetharine) to be given every 20 min for three treatments, followed by further dosing every hour. 1,5,6 Thus, in 2 to 3 hours, a patient may be given the equivalent of over 100 puffs of an MDI preparation of albuterol or metaproterenol or over 75 puffs of isoetharine. There is no proof that such treatment is hazardous, even in the absence of concomitant steroid or aminophylline therapy. In New Zealand, where the concerns about the dangers ofbet~-agonist therapy may now have reached proportions that exceed the actual epidemic of asthma deaths, 75 deaths were reported by Sears et al7 between 1981 and 1983 that occurred in asthmatic patients who used a beta-agonist in home nebulizers. Sears and colleagues7 concluded that, "the probability that inhalation ofbeta-sympathomimetics by nebulizer contributed to death was lower than the probability that death would have occurred without treatment:' It is curious that currently Sears is the name attached to the school of thought that beta-agonist use per se is hazardous in asthmas when he formerly emphasized that the main problem was ove~reliance on this therapy once the drug or its administration had become ineffective, and that evidence for direct toxicity of high dose beta-agonist therapy was not found. 6 Sears and colleagues9 have pointed out that, "cardiac arrhythmia due to drugs (ie, beta-agonist and theophylline) in the presence ofhypoxia might explain the very few extremely sudden deaths, but we have no evidence for or against this hypothesis."9 This antipodal conclusion is echoed by SlylO who, in his detailed analysis of deaths from asthma between 1979 and 1984, stressed that in New Zealand after 1980, a decrease in asthma deaths corresponded with an increase in sales of beta-agonist MDIs and other antiasthmatic drugs. Overall, Sly endorsed the current conclusion that deaths at both ends of the world can CHEST I 101 I 6 I JUNE. 1992
1703
best be explained by undertreatment rather than by drug toxicity. It is relevant that in the United Kingdom, where an ongoing concern with deaths from asthma has led to stringent examination of drug usage, it was recently reported by the Committee on Safety of Medicine, Hthat existing data did not support the suggestion that beta-agonist had an unfavorable riskbenefit ratio."8 In the UK, prescriptions for inhaled beta-agonists tripled since 1980, without any corresponding increase in mortalit~ II CARDIAC DEATHS IN ASTHMA
Nevertheless, as Dr. Robin emphasizes, beta-adrenergic aerosols may have the potential for causing adverse cardiac effects in susceptible patients. There is substantial evidence for this in the case of isoproterenol, an agent with potent betal-adrenoceptor activity. Extrapolation of this concern to the selective bet~-sympathomimetics in current use does not appear to be warranted, with the possible exception of fenoterol. I2 In the United States, where most aerosol bronchodilator therapy in the past few years has been based on albuterol and metaproterenol, there is little to support the occasional claims that these latter drugs destabilize asthma or cause sudden cardiac death. Studies that suggest these aerosols can induce hypokalemia l3-15 do not appear to be relevant to the subjects who are at risk of dying, since study patients are relatively healthy, and, in many cases, they have not been taking be~-aerosol therap~ whereas deaths occur in stressed asthmatic subjects with deteriorating lung function who are usually taking escalating doses of their aerosol. Godden et al l6 have suggested that regular dosing with a beta-agonist may protect against hypokalemia, possibly as a result of tolerance. The true incidence of this adverse electrolyte effect is uncertain, but the evidence accumulated in asthmatic patients who have been studied over the years suggests that clinically relevant hypokalemia must be a rare occurrence following aerosol bronchodilator therap~ Moreover, the degree of hypokalemia, even when associated with hypoxemia and catecholamine-induced tachycardia, does not appear to be sufficient to cause sudden fatal arrhythmias. Presumably, patients with heart failure who are receiving diuretics are far more likely to be harmed by hypokalemia, but there does not appear to be an epidemic of deaths in these patients. It must also be recognized that steroids and theophylline can each cause hypokalemia, and if this concern leads to the suggestion that asthmatic patients be forbidden to use these drugs as well as be~ adrenergic agents for acute exacerbations of bronchospasm, we will surely condemn many more to die of suffocation than we could possibly save from the rare and unproven consequence of a hypokalemic arrhythmia. 1704
Any theory as to what may cause unexpected deaths in asthmatic subjects must take into consideration the larger and generally older population of patients with chronic obstructive pulmonary disease. This category of patients is at higher risk of cardiac arrhythmias and myocardial infarction, since ischemic heart disease, pulmonary hypertension, ventricular hypertrophy, dysrrhythmias, heart failure, hypoxia and hypokalemia are more likely to be present. Patients with COPD rely on beta-adrenergic drugs and theophylline; only in recent years has ipratropium therapy been introduced. In spite of bronchitis being an inHammatory disease, patients with COPD derive no benefit from cromolyn, and the majority is unlikely to be helped by steroids. Moreover, if a patient with COPD suffers a myocardial infarction, the presence ofairway disease contraindicates subsequent protective therapy with beta-blockers, and the patient usually continues to use be~-bronchodilators. In spite of this multiplied risk of cardiac misadventure, there is no published evidence to suggest that there is an increased risk of cardiac death in COPD patients with underlying ischemic heart disease. THE DANGER OF LABELLING A DRUG AS DANGEROUS
Asthma deaths have been attributed to both excess drugs and insufficient drug therapy and also to synergistic drug toxicity, to hypoxemia, electrolyte disturbance, arrhythmias, myocardial necrosis, panic exacerbated by catecholamines, greater penetration of antigens in overly dilated airways, rebound bronchospasm, paradoxic response to bronchodilators, subsensitivity, competitive blockade by bronchodilator drug metabolites, overactivity ofalpha-adrenoceptor mechanisms when be~-receptorsubsensitivity occurs, and so on. A few years ago, Dr. Robin mused that asthmatic deaths might be attributed to methylxanthine toxicit}; but he also pointed out that the epidemic of excess deaths could not be explained by a simple onemedication overdose theory;17 indeed, massive polypharmacy was clearly of greater potential danger. Although his viewpoint has evolved, Dr. Robin is still convinced that the excess deaths are iatrogenic in origin. However, his focus on the beta-agonist as the villain may not serve a useful purpose at this time, since it can only add to the confusion and undermine confidence in established, effective therapy. Even if a very small minority ofpatients is susceptible to adverse outcomes when treating severe asthmatic attacks with sympathomimetics, what effective alternatives can we offer with certainty as to safety? Theophylline preparations may be safer, but current thinking hardly supports this possibility. Cromolyn does not provide effective therapy in severe asthma, and the aerosol may even exacerbate the bronchospasm. Should severe Cardiac Deaths in Bronchial Asthma (Irwin Ziment))
asthma be treated only with aerosol or oral steroids? They certainly have no acute benefit in alleviating sudden ~ttacks ofasthma. And what guidelines should we offer patients with increasing bronchospasm.particularly in infirm older patients or the impoverished children that are at greatest risk of death from asthma because they lack ready access to medical care pI To deprive these needy groups of their betaadrenergic therapy would compound their misery and would possibly jeopardize their lives by allowing progress ofthe respiratory failure that is already known to be the major cause of death in asthma. Let us applaud Dr. Robin for encouraging more research into the "sudden asthmatic death syndrome;' and for focusing attention on the possibility of a subgroup of patients who may have a heightened propensity to develop hypokalemia and cardiac arrhythmias. But let us be certain that in our anxiety to detect the small number of patients at risk we do not condemn larger numbers of asthmatic patients to succumb from the "slow asthmatic death syndrome" that would result from inadequate sympathomimetic aerosol bronchodilator therap~ At present, there is little reason to doubt that prescribed aerosol therapy with the beta-adrenergic drugs that are available in the United States constitutes reasonable first-line, effective, benign, and even life-saving therapy for millions of patients with asthma and COPD. While seeking to prevent the relatively uncommon sudden deaths, we must not undermine the true advance that inhaled be~ drugs have enabled us to offer huge numbers of patients suffering from bronchospasm during the last half centu~ REFERENCES 1 Expert Panel Report. Guidelines for the diagnosis and manage-
2 3 4
5
6 7
8
9
10 11 12
13
ment of asthma. Bethesda: US Department of Health and Human Services; Public Health Service, National Institutes of Health, 1991; publication No. 91-3042 Robin ED, Lewiston N. Unexpected, unexplained death in young asthmatic subjects. Chest 1989; 96:790-93 Higenbottam T, Hay I. Has the treatment of asthma improved? Chest 1990; 98:706-12 Sly RM. Increase in deaths from asthma. Ann Allergy 1984; 53:20-25 Willcins W Jr, ed. In: Emergency medicine. Scienti6c foundations and current practice. 3rd 00. Baltimore: Williams & Wilkins, 1989; 153 Stanescu DC. High doses of sympathomimetics in severe bronchial asthma. Eur Respir J 1989; 2:597-98 Sears MR, Rea HH, Fenwick J, Gillies AJD, Holst PE, O'DonneD ~ et a1. 75 deaths in asthmatics prescribed home nebuIisers. Br Med J 1987; 294:477-80 Noticeboard. p-agonists and asthma. Lancet 1992; 339:422 Sears MR, Rea HH, BothweD RPG, O'Donnell ~ Holst PE, Gillies AJD, et a1. Asthma mortality: comparison between New Zealand and England. Br Moo J 1986; 293:1342-45 Sly aM. Mortality from asthma, 1979-1984. J Allergy Clio Immunoll988; 82:705-17 Noticeboard. Safety ofbeta-agonists. Lancet 1992; 339:486 Spitzer WO, Suissa S, Ernst ~ Horwitz RI, Habbick B, Cockcroft D, et a1. The use of p-agonists and the risk of death and near death from asthma. N Eng} J Moo 1992; 326:501-06 Gelmont DM, Balmes JR, Yee A. Hypokalemia induced by inhaled broncbodilators. Chest 1988; 94:763-66
14 Kfing M, Croley S~ Phillips BA. Systemic cardiovascular and metabolic effects associated with the inhalation of an increased dose of albuterol. Chest 1987; 92:382-87 15 Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 336:1396-99 16 Godden DJ, Seymor DNA, Robertson DA. 75 deaths in asthmatics prescribed borne nebulisers. Br Moo J 1987; 294:1356 17 Robin ED. Death from bronchial asthma. Cbest 1988; 93:61418
CHEST I 101 I 6 I JUNE, 1992
1705
