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Fatal asthma—Is treatment incriminated?
VOLUME NUMBER
80 3, PART 2
Cardiac pathology
31. Jack D. Sniffing syndrome. Br Med J 1971;2:708-9. 32. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-4. 33. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972;287:987-8. 34. Cochrane GM, Clark TJH. A survey of asthma mortality in
Fatal asthma-Is Desmond Poynter,
in asthma
patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax 1975;30:300-5. 35. Muller JE, Stone PH, Turi Z, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-22.
treatment
incriminated?
Ph.D. Ware, Hertfordshire, United Kingdom
In fatal asthma the exacerbation of the disease will doubtless have demanded treatment, which in some cases may well have been repeated with more than one drug. This inevitably leads to the suggestion that such treatment or its excess may play a part in any ensuing tragedy. The purpose of this article is to discuss those drugs used in asthma treatment and to refer to some of the studies, experimental and otherwise, performed with them to see if there are any facets of their toxicologic profiles that might indicate a potential hazard. It is relevant to inquire at the outset whether any specific pulmonary diseases are associated with those substances used for the therapy of asthma. In his review of iatrogenic lung disease Cuthbert’ mentions the paradoxic effect that sympathomimetic amines may have in also relaxing smooth muscle in the pulmonary vasculature, thus producing pulmonary vasodilation with resultant hypoxia. However, in their review of drug-induced lung disease Whimster and de Poitiers’ refer to only one compound that is used to treat asthma. They note that steroids may induce thoracic changes by way of mediastinal fat deposition, which may be recognizable radiologically. Fifteen caseswere summarized as part of the generalized known effects of high-level steroid therapy, with the changes taking 5 years to become noticed when a dose of 7.5 mg/day was used and only 7 months when a dose of 30 mglday was used. The current therapeutic agents used in asthma are generally not incriminated in producing pulmonary
From the Pathology Division, Glaxo Group Research, Ware, Hertfordshim, United Kingdom. Reprint requests: Desmond Poynter, Ph.D., Glaxo Group Research Limited, Ware, Hertfordshire, SGl2 ODJ, United Kingdom.
disease as such. However, they are potent compounds and if used inappropriately some of them may produce significant toxic effects that will not improve the course of the disease. SYMPATHOMlMETlC
AMIMES
Sympathomimetic amines may produce myofibrillar lesions in animal hearts, and the epidemiologic association between an increased death rate in young people with asthma and the abuse of pressurized aerosols containing isoproterenol 3-5has provoked much interest. Much experimental work has been undertaken in animals but its extrapolation to humans is not easy. Thus, although it is well documented that isoproterenol can cause myocardial necrosis in rats,6 hamsters,’ and rabbits,* no such effect has been described in humans. However, isoproterenol has cardiotoxic effects in the dog9 that are exacerbated by hypoxia, and in the cat heart-lung preparation” there is evidence that a fatigued heart working at a high level is ten times as sensitive as a normal heart. The introduction of more selective P-agonists that are markedly more active on bronchial smooth muscle than on cardiac muscle provided safer medication. In a direct comparison of nonselective isoproterenol and selective albuterol, isoproterenol was lethal to the hypoxic dog but albuterol was not.’ Thus there is experimental evidence that nonselective P-agonists may under certain circumstances be lethal to animals. That the selective P-agonist albuterol has a very different effect upon the heart was well illustrated by the work of Nayler” who, using papillary muscle from dogs and from humans, concluded that the action of albuterol on P-adrenergic receptors in heart muscle was minimal compared with that of equipotent bronchodilator doses of isoproterenol . 423
424
Poynter
Since their introduction the &-agonists have proved to be safe and effective drugs. In reviewing reactions to them, Lulich et al.‘* drew attention to skeletal muscle tremor as the most frequent dose-limiting side effect. They also mentioned that cardiac arrhythmias and reductions in PaO, may be of significance in susceptible patients with asthma. In this connection they emphasize that side effects are minimized by use of the inhaled route, which requires far less drug than the oral route. Although the rise in asthma mortality reported in the 196Os”- ” seemed to implicate the increased use of isoproterenol inhalers,‘, Is this relationship was never really established and was not supported by observations from Australia.‘” Certainly isoproterenol, now superceded by selective B-agonists, cannot be incriminated in the rise in asthma mortality reported from New Zealand,” the United States,” and England and Wales. ” CORTlCOSTEROtDS The changes resulting from the systemic or topical administration of corticosteroids are well documented. Consequently, in the early experimental studies of the inhalation of beclomethasone dipropionate aerosols it was possible to predict any possible adverse effects. In particular, concern was expressed that the direct application of a corticosteroid to pulmonary tissue might result in adverse effects on epithelial surfaces or, more importantly perhaps, in an effect on the collagen content of the lung, possibly leading to a breakdown of blood vessel integrity with subsequent hemorrhage. In a l-year study performed in beagle dogs, doses of beclomethasone dipropionate were administered by both the inhaled and oral route?’ to produce suppression of the hypothalamic-pituitary-adrenal axis. Indeed, some dogs developed a Cushingoid appearance. Detailed examination of the respiratory tracts from these animals, including electron microscopic examinations, revealed no changes associated with treatment. These findings were substantiated by a biopsy study in patients with asthma who were treated for up to 18 months in whom no adverse pulmonary changes were found.2’ It is particularly relevant that the biopsy wounds all healed normally, indicating that collagen synthesis was functional. It is also relevant that there was no effect on healing in a biopsy study performed on patients being treated intranasally for allergic rhinitis with beclomethasone dipropionate aerosols.” Other biopsy studies on both bronchi and nasal passages have yielded similar results. In 1978 we had the opportunity to examine the lungs of three patients who had been receiving heclometh-
J. ALLERG?
CiiN. IMMIJNCK. ‘XPTEMBER !9R7
asone dipropionate inhalants for up to h years. Iwo had died as a result of carcinoma, one of the bladde’ and the other of the lung. The third died suddenly as a result of status asthmaticus and change> typicai ci this condition were present. In all lungs the coliagcnous layers appeared of normal distribution and consistency. Because beclomethasone dipropionatc is intended for prolonged use, we subjected it to ti iifetimc rat study, the main purpose of which was to seek reassurance that no chronic effects, such as neoplasia or atrophic collagenous changes, would appear. Rats, which are relatively insensitive to the compound. were treated for 95 weeks at a maximum oral dose of 2 mg/kg/day. The inhaled dose was calculated to attain a pulmonary concentration 52 times that estimated to occur in a human patient after one 50 p.g burst. The rats were exposed on nine separate occasions during any 24 hours. At the end of the study there were no treatment-related changes in the lungs. There is now abundant clinical evidence that treatment with inhaled beclomethasone dipropionate is not (with the exception of candidiasis) associated with any increased susceptibility to infection. The doses of beclomethasone dipropionate used are not immunosuppressive. This was recently demonstrated by Gerblich et al..‘” who administered prednisone (60 or 20 mg), beclomethasone dipropionate aerosol (336 Fg as a single dose), placebo. or beclomethasone dipropionate vehicle in a double-blind protocol to IS patients with atopic asthma and ten nonatopic subjects. No differences were found in the baseline number of T ceils with T4, T8, Ml: and Ia antigens, nor the ratio of T4 + (helper) to T8 + (suppressor) cells. Five hours after beclomethasone dipropionate aerosol. beclomethasone dipropionate vehicle, and oral placebo, there was no change of these values in either the atopic or the nonatopic group. In contrast, prednisone, 20 and 60 mg, caused a fall in the T4/TX ratio in the atopic but not the nonatopic population. Atopic asthma was not associated with baseline imbalances in peripheral blood T cells. but it was associated with an abnormal response to systemic but not inhaled corticosteroid. The adverse effects of steroid therapy are of a sustained nature. Steroids are rarely toxic in an acute fashion and there are, to my knowledge, no experimental data to show that toxic synergism with other drugs used for treating asthma is incriminated. Indeed the opposite is true. In our laboratory we recently treated four dogs with aerosolized beclomethasone dipropionate. giving ten 250 Fg bursts twice a day for 14 days. They and appropriate untreated controls were then challenged with subcutaneous Jbuterol or iso-
VOLUME NUMBER
Fatal asthma-Is treatment incriminated?
80 3, PART 2
proterenol at increasing doses of 4, 8, 16, and 32 pglkg. No obvious changes were detected in heart rhythm or wave configuration that could be attributed to treatment, and all displayed equivalent degrees of anticipated tachycardia.
425
The first reports of the use of methylxanthines for the treatment of asthma appeared in the 1920s. These drugs (particularly theophylline) have been used successfully for many years. The therapeutic plasma concentration range is established at lo-20 p.g/ml, at which level adverse reactions are rare. Gastrointestinal complications are frequent when theophylline levels are greater than 20 pg/ml, and when levels are in excess of 50 pg/ml there is a high incidence of seizures, hypotension, and tachyarrhythmias leading in some cases to death. Individual variations in the rate of metabolism are also known to occur. Although the methylxanthines were introduced some 60 years ago, the amount of animal experimental work carried out on them is less than with some of the newer substances used in the treatment of asthma. In rats theophylline ( 100 to 150 mg/kg intraperitoneally) produces tachycardia, hypermetabolism, and hypotension with a myocardial necrosis similar to that seen with isoproterenol. 24When viewed 48 hours after treatment the lesions consisted of multiple foci of eosinophilic degeneration, nuclear pyknosis, and cellular infiltration. They showed a definite preference for subendocardial layers, and the left ventricle was more affected than the right. The authors believed these effects to result from myocardial hypoxia.
mias were infrequent, occurring only in patients with trough theophylline concentrations over I.5 p,g/ml . They appeared unrelated to P-agonist therapy. The concomitant use of aerosolized bitolterol and theophylline was also investigated by Kemp et al.” who also used Holter ECG monitoring. It was concluded that there was no evidence that therapeutic doses had cardiotoxic effects in patients with stable, chronic, reversible airway obstruction. In 1981 Wilson et a1.3” reviewed 22 fatal asthma cases in New Zealand and commented on the increase in the use of oral theophylline. Of 14 patients whose deaths were sudden, unexpected, and suggestive of cardiac arrest, one died of a self-administered theophylline overdosage and thirteen were receiving combined therapy with oral theophylline and inhaled P-agonists, the latter being administered frequently. Although it was not possible to establish a definite causal link between the increase in deaths and combination therapy, it was suggested that there may be an additive toxicity between theophylline and inhaled &-agonists at high doses that produce a cardiac arrest. However, the inhaled effective dose of selective p,-stimulants is very low, so that attempts to measure plasma levels after the inhalation of labeled albuterol have revealed only insignificant quantities.“. 32 It is difficult to visualize that inhalation even of several bursts will lead to concentrations that might affect the toxicity of any theophylline present. Indeed, several authors” believed that the deaths were more likely caused by inadequate supervision of potentially severe asthma and the decision to prescribe oral theophylline instead of oral steroids.
COMBINATION
PROPELLANTS
METHYLXANTHINES
THERAPY
Experiments with heavy rats” have shown that the severity of the myocardial lesions produced by the subcutaneous injections of isoproterenol or bitolterol were significantly enhanced by subcutaneous aminophylline. An extension of these studies by Whitehurst et a1.‘6 showed that terbutaline produced arrhythmia and severe cardiac lesions in rats pretreated with aminophylline. Indeed, Nicklas et a1.27called for careful monitoring of patients receiving routine therapy with oral P-agonists and methylxanthines, pointing out that the former are best administered by inhalation. However, the cardiac effects produced in animals by high levels of drugs are not easily extrapolated to the clinical situation in humans. In this event the studies by Lloyd et al.Ix using theophylline with or without aerosolized metaproterenol or albuterol in 20 patients with severe chronic obstructive pulmonary disease are pertinent, since Holter ECG monitoring for 72 hours was performed and significant dysrhyth-
Some years ago concern was expressed3”l j4 that the propellants used in aerosols might be responsible for cardiac arrhythmias and deaths. There was much publication and speculation on this subject, but its resolution depended upon the accurate measurement of arctons in the blood and the heart to determine the level necessary to sensitize that organ to adrenalin. Clark and Tinston”’ found that cardiac sensitization (i.e., significant arrhythmias) could be produced in dogs by 5 pg/kg intravenous adrenalin when the venous blood concentration of Arcton 11 was 20 kg/ml and that of Arcton 12 was 35 pg/ml. Taylor et a1.36 observed cardiac sensitization in monkeys at 60 pg/ml Arcton 12 and 20 kg/ml Arcton 114 as measured in arterial blood. My colleague Dr. L. E. Martin (personal communication) also carried out some stud-
*Correspondence.
Lancer
1981;2:36-8.
426 Poynter ies in monkeys, observing arrhythmias in three out of four when the arterial concentration of Arcton I1 was 30 p,g/ml and that of Arcton 12 was 40 p.g/ml. In humans Dollery et al.<’ determined the blood Arcton I 1 concentrations of volunteers and patients with asthma who inhaled 3 to 30 puffs of “Medihaler” propellants and found a peak arterial concentration of I .7 pg/ml. They also determined the blood Arcton 1I concentration of volunteers who inhaled one burst (25 ~1) propellant mixture every 10 minutes for 6 hours and did not find any rise in concentration. Martin (personal communication) also performed studies in human volunteers inhaling IO bursts of “Ventolin” propellants and found a maximum blood concentration of 2.7 pg/ml Arcton 12 and 1.20 pg/ml Arcton 11. The maximum levels found in humans are much lower than the sensitizing levels seen in an’imals,which led Martin to speculatethat humans would have to use an inhaler about 20 times over a period of 2 minutes, and not breathe out, before the myocardial fluorocarbon concentration became critical.
CONCLUSION There are no experimental data to show that any of the drugs usedto treat asthmaare responsiblefor the increasesin deaths reported in various parts of the world. However, someof the compoundsusedare of greater toxic potential than others, and it is a matter for clinical judgment how and when they are used. Deaths are still reported in circumstancesthat suggest that treatment has proved inadequate.
REFERENCES I. Cuthbert MF. latrogenic lung disease. In: D’Arcy PF. Griffin JP, eds. latrogenic diseases. 2nd ed. Oxford: Oxford University Press, 1979. 2. Whimster WF, de Poitiers W. The lung. In Riddel RH, ed. Pathology of drug-induced and toxic diseases. New York: Churchill Livingstone, 1982. 3. Grant IWB, Kennedy WPV, Malone DN. Deaths from asthma Br Med J 1968;2:429-30. 4. Gresham GA, Caldcr IM. Sudden death in young asthmatics. Br Med J 1%8;3:186-7. 5. lnman WHW, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1%9;2:279-85. 6. Wexlar BC, Judd JT, Kittinger GW. Myocardial necrosis induced by isoproterenol in rats. Angiology 1%8;19:665-82. 7. Handforth CP. lsoproterenol induced myocardial infarction in animals. Arch Path01 1%2;73:161-5. 8. Poynter D, Spurling NW. Some cardiac effects of betaadrenergic stimuhmts in animals. Postgrad Med J 1971; 47(suppI):21-5. 9. Collins JM, McDevitt DG, Shanks RG, Swanton JG. The cardiotoxicity of isoprenaline during hypoxia. Br J Pharmacol 1%9;36:35-45.
IO. Lockett MF. Dangerous effects of iqnrenaliuc ::: !u:‘.tl. ::r.l;di failurc. Lancet 19632: 104-6. I I. Nayler WG. Some observations on the l~l~ilrlli‘!t.,~ii~~,Ir ;I: ci!.>‘i. of salbutamol. with particular refercncc to the ~:!:I~III~~;\,..~‘.II system. Postgrad Met1 J I97 I :47lbuppl): IO ..’ ! 12. Lulich KM. Goldie RG. Ryan G. Peterson !\i’ ‘\;i:c!.:s :,‘. action to bctn-2-agonist bronchodilator~. Sl$:,! ‘I’, !\i\ aa! ! ‘~Q’!‘I. I :1X6-99. 13. Morrison Smith J. Death from asthma. Lancc~ I’-iho: I : Illi.’ 14. Fraser P. Doll R. Geographical variations in the ,:pi,lcmIc t,i asthma deaths. Br J Prev Sot Mcd 1971:25: 34-c 15. Stolley PD. Asthma mortzality: why the Lnitcd States wzi\ spared an epidemic of deaths due to asthma .Zm Kec Rcspir Dis 1972: 105:883-90. 16. Gandevia B. Prcsxurised sympathomimetic acro\ol> and thcit lack of relationship to asthma mortality in .Australia bled J Aust 1973;1:273-7. 17. Jackson RT, Beaglehole R, Rea HH, Sutherland DC Momrliry from asthma: a new epidemic in New Zealand. Br MUI J 19X2:285:77 l-4. 18. Sly RM. lncreases in deaths from asthma. Ann Allergy 1‘)X4:.52:20-5. 19. Bumey PGJ. Asthma mortality in England and Wales: evidcncc for a further increase. 1974-84. Lance1 19X6:2:323-6. 20. Poyntcr D. Spurling NW, Ainge G. A toxicity study wuh heclomcthasone dipropionate in the dog with particular rclcr.. cncc to the respiratory tract Postgrad Med J 19755 I(supp1): 27-9. 21. Andersson E, Smidt CM, Sikjaer B. Aingc G, Poynter I). Bronchial biopsies after beclomethasone dipropionatc aerosol. Br J Dis Chest 1977;77:35-43. 22. Poynter 1~. Beclomethasone dipropionate aerosol and irasal mucosa. Br J Clin Pharmacol 1977;4:295S-3018. 23. Gerblich A. Urdu G, Schuylor M. Atopic asthma: T-cell responses to corticosteroids. Chest 1985:X7:44-9. 24. Strubelt 0, Hoffman A. Siegers CP. Sierra-C;illcjas JI.. On the pathogenesis of cardiac necroses induced by theophylline and caffeine. Acta Pharmacol Toxicol 1976:39:3X3-92. 25. Joseph X. Whitehurst VE. Bloom S, Balazs T. Enhancement of cardiotoxic effects of B-admnergic bronchodilators by aminophyllinc in experimental animals. Fund Appl Toxicol 1981;1:443-7. 26. Whitchurst VE. Joseph X, Hohmann JR. Pledger Cl. Balazs T. Cardiotoxic effects in rats and rabbits treated with tcrbutaline alone and in combination with aminophylline. J Am Coil Toxicol 1983~2: 147-53. 27. Nicklas R, Whitehurst VE, Donohoe RF, Balazs T. Concomitant use of beta adnmergic agonists and methylxanthines. J AI.I.EROY CI.IN IMMUNOI. 1984;72:20-4. 28. Lloyd PR, Covelli HD, Hill JC. Dysrhythmic effects of combined theophylline and beta agonist therapy in patients with severe obstructive lung disease. Chest 1984:86:282-340. 29. Kemp JP. Chervinsky P, Grgel HA, Meltzer EO, Noyes JH. Mingo TS. Concomitant bitolterol mcsylate aerosol and theophylline for asthma therapy. with 24 br electrocardiographic monitoring. I ALL.ERGY C1.m IMUIMUNOI. 1984;73:32-43. 30. Wilson JD, Sutherland DC, Thomas AC. Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma‘? Lancet I98 I ; I : 1235-7. 3 I. Simpson WT. Initial studies on the human pharmacology of salbutamol. Postgrad Med J 1971;47t,suppl):35-8. 32. Walker SR. Evans ME, Richards AJ, Paterson W. Plasma levels and percentage increase in FEV, after oral and aerosol administration of lH-salbutamol in asthmatic paients. Clin Pharmacol Ther 1972;13:861.
VOLUME NUMBER
80 3. PART 2
33. Bass M. Sudden sniffing death. JAMA 1970;212:2075-9. 34. Taylor GJ. Harris WS. Cardiac toxicity of aerosol propellants. JAMA 1970;214:81. 35. Clark DC, Tinston DJ. The influence of fluorocarbon propellants on the arrhythmogenic activities of adrenaline and isoprenalinc. Proc Eur Sot Drug Tox 1972;13:212. 36. Taylor CT, Harris WS, Bogdonoff MD. Ventricular arrhyth-
Fatal asthma-is
treatment
incriminated?
427
mias induced m monkeys by the inhalation of aerosol propellams. J Clin Invest Toxic01 197 I ;50: 1546-50. 37. Dollery CT, Draffan GH, Davies DS, Williams FM, Conolly ME. Blood concentrations in man of fluorinated hydrocarbons after inhalation of pressurised aerosols, Lancet 1970~2: 1164-6.
80 3, PART 2
Cardiac pathology
31. Jack D. Sniffing syndrome. Br Med J 1971;2:708-9. 32. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-4. 33. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972;287:987-8. 34. Cochrane GM, Clark TJH. A survey of asthma mortality in
Fatal asthma-Is Desmond Poynter,
in asthma
patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax 1975;30:300-5. 35. Muller JE, Stone PH, Turi Z, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-22.
treatment
incriminated?
Ph.D. Ware, Hertfordshire, United Kingdom
In fatal asthma the exacerbation of the disease will doubtless have demanded treatment, which in some cases may well have been repeated with more than one drug. This inevitably leads to the suggestion that such treatment or its excess may play a part in any ensuing tragedy. The purpose of this article is to discuss those drugs used in asthma treatment and to refer to some of the studies, experimental and otherwise, performed with them to see if there are any facets of their toxicologic profiles that might indicate a potential hazard. It is relevant to inquire at the outset whether any specific pulmonary diseases are associated with those substances used for the therapy of asthma. In his review of iatrogenic lung disease Cuthbert’ mentions the paradoxic effect that sympathomimetic amines may have in also relaxing smooth muscle in the pulmonary vasculature, thus producing pulmonary vasodilation with resultant hypoxia. However, in their review of drug-induced lung disease Whimster and de Poitiers’ refer to only one compound that is used to treat asthma. They note that steroids may induce thoracic changes by way of mediastinal fat deposition, which may be recognizable radiologically. Fifteen caseswere summarized as part of the generalized known effects of high-level steroid therapy, with the changes taking 5 years to become noticed when a dose of 7.5 mg/day was used and only 7 months when a dose of 30 mglday was used. The current therapeutic agents used in asthma are generally not incriminated in producing pulmonary
From the Pathology Division, Glaxo Group Research, Ware, Hertfordshim, United Kingdom. Reprint requests: Desmond Poynter, Ph.D., Glaxo Group Research Limited, Ware, Hertfordshire, SGl2 ODJ, United Kingdom.
disease as such. However, they are potent compounds and if used inappropriately some of them may produce significant toxic effects that will not improve the course of the disease. SYMPATHOMlMETlC
AMIMES
Sympathomimetic amines may produce myofibrillar lesions in animal hearts, and the epidemiologic association between an increased death rate in young people with asthma and the abuse of pressurized aerosols containing isoproterenol 3-5has provoked much interest. Much experimental work has been undertaken in animals but its extrapolation to humans is not easy. Thus, although it is well documented that isoproterenol can cause myocardial necrosis in rats,6 hamsters,’ and rabbits,* no such effect has been described in humans. However, isoproterenol has cardiotoxic effects in the dog9 that are exacerbated by hypoxia, and in the cat heart-lung preparation” there is evidence that a fatigued heart working at a high level is ten times as sensitive as a normal heart. The introduction of more selective P-agonists that are markedly more active on bronchial smooth muscle than on cardiac muscle provided safer medication. In a direct comparison of nonselective isoproterenol and selective albuterol, isoproterenol was lethal to the hypoxic dog but albuterol was not.’ Thus there is experimental evidence that nonselective P-agonists may under certain circumstances be lethal to animals. That the selective P-agonist albuterol has a very different effect upon the heart was well illustrated by the work of Nayler” who, using papillary muscle from dogs and from humans, concluded that the action of albuterol on P-adrenergic receptors in heart muscle was minimal compared with that of equipotent bronchodilator doses of isoproterenol . 423
424
Poynter
Since their introduction the &-agonists have proved to be safe and effective drugs. In reviewing reactions to them, Lulich et al.‘* drew attention to skeletal muscle tremor as the most frequent dose-limiting side effect. They also mentioned that cardiac arrhythmias and reductions in PaO, may be of significance in susceptible patients with asthma. In this connection they emphasize that side effects are minimized by use of the inhaled route, which requires far less drug than the oral route. Although the rise in asthma mortality reported in the 196Os”- ” seemed to implicate the increased use of isoproterenol inhalers,‘, Is this relationship was never really established and was not supported by observations from Australia.‘” Certainly isoproterenol, now superceded by selective B-agonists, cannot be incriminated in the rise in asthma mortality reported from New Zealand,” the United States,” and England and Wales. ” CORTlCOSTEROtDS The changes resulting from the systemic or topical administration of corticosteroids are well documented. Consequently, in the early experimental studies of the inhalation of beclomethasone dipropionate aerosols it was possible to predict any possible adverse effects. In particular, concern was expressed that the direct application of a corticosteroid to pulmonary tissue might result in adverse effects on epithelial surfaces or, more importantly perhaps, in an effect on the collagen content of the lung, possibly leading to a breakdown of blood vessel integrity with subsequent hemorrhage. In a l-year study performed in beagle dogs, doses of beclomethasone dipropionate were administered by both the inhaled and oral route?’ to produce suppression of the hypothalamic-pituitary-adrenal axis. Indeed, some dogs developed a Cushingoid appearance. Detailed examination of the respiratory tracts from these animals, including electron microscopic examinations, revealed no changes associated with treatment. These findings were substantiated by a biopsy study in patients with asthma who were treated for up to 18 months in whom no adverse pulmonary changes were found.2’ It is particularly relevant that the biopsy wounds all healed normally, indicating that collagen synthesis was functional. It is also relevant that there was no effect on healing in a biopsy study performed on patients being treated intranasally for allergic rhinitis with beclomethasone dipropionate aerosols.” Other biopsy studies on both bronchi and nasal passages have yielded similar results. In 1978 we had the opportunity to examine the lungs of three patients who had been receiving heclometh-
J. ALLERG?
CiiN. IMMIJNCK. ‘XPTEMBER !9R7
asone dipropionate inhalants for up to h years. Iwo had died as a result of carcinoma, one of the bladde’ and the other of the lung. The third died suddenly as a result of status asthmaticus and change> typicai ci this condition were present. In all lungs the coliagcnous layers appeared of normal distribution and consistency. Because beclomethasone dipropionatc is intended for prolonged use, we subjected it to ti iifetimc rat study, the main purpose of which was to seek reassurance that no chronic effects, such as neoplasia or atrophic collagenous changes, would appear. Rats, which are relatively insensitive to the compound. were treated for 95 weeks at a maximum oral dose of 2 mg/kg/day. The inhaled dose was calculated to attain a pulmonary concentration 52 times that estimated to occur in a human patient after one 50 p.g burst. The rats were exposed on nine separate occasions during any 24 hours. At the end of the study there were no treatment-related changes in the lungs. There is now abundant clinical evidence that treatment with inhaled beclomethasone dipropionate is not (with the exception of candidiasis) associated with any increased susceptibility to infection. The doses of beclomethasone dipropionate used are not immunosuppressive. This was recently demonstrated by Gerblich et al..‘” who administered prednisone (60 or 20 mg), beclomethasone dipropionate aerosol (336 Fg as a single dose), placebo. or beclomethasone dipropionate vehicle in a double-blind protocol to IS patients with atopic asthma and ten nonatopic subjects. No differences were found in the baseline number of T ceils with T4, T8, Ml: and Ia antigens, nor the ratio of T4 + (helper) to T8 + (suppressor) cells. Five hours after beclomethasone dipropionate aerosol. beclomethasone dipropionate vehicle, and oral placebo, there was no change of these values in either the atopic or the nonatopic group. In contrast, prednisone, 20 and 60 mg, caused a fall in the T4/TX ratio in the atopic but not the nonatopic population. Atopic asthma was not associated with baseline imbalances in peripheral blood T cells. but it was associated with an abnormal response to systemic but not inhaled corticosteroid. The adverse effects of steroid therapy are of a sustained nature. Steroids are rarely toxic in an acute fashion and there are, to my knowledge, no experimental data to show that toxic synergism with other drugs used for treating asthma is incriminated. Indeed the opposite is true. In our laboratory we recently treated four dogs with aerosolized beclomethasone dipropionate. giving ten 250 Fg bursts twice a day for 14 days. They and appropriate untreated controls were then challenged with subcutaneous Jbuterol or iso-
VOLUME NUMBER
Fatal asthma-Is treatment incriminated?
80 3, PART 2
proterenol at increasing doses of 4, 8, 16, and 32 pglkg. No obvious changes were detected in heart rhythm or wave configuration that could be attributed to treatment, and all displayed equivalent degrees of anticipated tachycardia.
425
The first reports of the use of methylxanthines for the treatment of asthma appeared in the 1920s. These drugs (particularly theophylline) have been used successfully for many years. The therapeutic plasma concentration range is established at lo-20 p.g/ml, at which level adverse reactions are rare. Gastrointestinal complications are frequent when theophylline levels are greater than 20 pg/ml, and when levels are in excess of 50 pg/ml there is a high incidence of seizures, hypotension, and tachyarrhythmias leading in some cases to death. Individual variations in the rate of metabolism are also known to occur. Although the methylxanthines were introduced some 60 years ago, the amount of animal experimental work carried out on them is less than with some of the newer substances used in the treatment of asthma. In rats theophylline ( 100 to 150 mg/kg intraperitoneally) produces tachycardia, hypermetabolism, and hypotension with a myocardial necrosis similar to that seen with isoproterenol. 24When viewed 48 hours after treatment the lesions consisted of multiple foci of eosinophilic degeneration, nuclear pyknosis, and cellular infiltration. They showed a definite preference for subendocardial layers, and the left ventricle was more affected than the right. The authors believed these effects to result from myocardial hypoxia.
mias were infrequent, occurring only in patients with trough theophylline concentrations over I.5 p,g/ml . They appeared unrelated to P-agonist therapy. The concomitant use of aerosolized bitolterol and theophylline was also investigated by Kemp et al.” who also used Holter ECG monitoring. It was concluded that there was no evidence that therapeutic doses had cardiotoxic effects in patients with stable, chronic, reversible airway obstruction. In 1981 Wilson et a1.3” reviewed 22 fatal asthma cases in New Zealand and commented on the increase in the use of oral theophylline. Of 14 patients whose deaths were sudden, unexpected, and suggestive of cardiac arrest, one died of a self-administered theophylline overdosage and thirteen were receiving combined therapy with oral theophylline and inhaled P-agonists, the latter being administered frequently. Although it was not possible to establish a definite causal link between the increase in deaths and combination therapy, it was suggested that there may be an additive toxicity between theophylline and inhaled &-agonists at high doses that produce a cardiac arrest. However, the inhaled effective dose of selective p,-stimulants is very low, so that attempts to measure plasma levels after the inhalation of labeled albuterol have revealed only insignificant quantities.“. 32 It is difficult to visualize that inhalation even of several bursts will lead to concentrations that might affect the toxicity of any theophylline present. Indeed, several authors” believed that the deaths were more likely caused by inadequate supervision of potentially severe asthma and the decision to prescribe oral theophylline instead of oral steroids.
COMBINATION
PROPELLANTS
METHYLXANTHINES
THERAPY
Experiments with heavy rats” have shown that the severity of the myocardial lesions produced by the subcutaneous injections of isoproterenol or bitolterol were significantly enhanced by subcutaneous aminophylline. An extension of these studies by Whitehurst et a1.‘6 showed that terbutaline produced arrhythmia and severe cardiac lesions in rats pretreated with aminophylline. Indeed, Nicklas et a1.27called for careful monitoring of patients receiving routine therapy with oral P-agonists and methylxanthines, pointing out that the former are best administered by inhalation. However, the cardiac effects produced in animals by high levels of drugs are not easily extrapolated to the clinical situation in humans. In this event the studies by Lloyd et al.Ix using theophylline with or without aerosolized metaproterenol or albuterol in 20 patients with severe chronic obstructive pulmonary disease are pertinent, since Holter ECG monitoring for 72 hours was performed and significant dysrhyth-
Some years ago concern was expressed3”l j4 that the propellants used in aerosols might be responsible for cardiac arrhythmias and deaths. There was much publication and speculation on this subject, but its resolution depended upon the accurate measurement of arctons in the blood and the heart to determine the level necessary to sensitize that organ to adrenalin. Clark and Tinston”’ found that cardiac sensitization (i.e., significant arrhythmias) could be produced in dogs by 5 pg/kg intravenous adrenalin when the venous blood concentration of Arcton 11 was 20 kg/ml and that of Arcton 12 was 35 pg/ml. Taylor et a1.36 observed cardiac sensitization in monkeys at 60 pg/ml Arcton 12 and 20 kg/ml Arcton 114 as measured in arterial blood. My colleague Dr. L. E. Martin (personal communication) also carried out some stud-
*Correspondence.
Lancer
1981;2:36-8.
426 Poynter ies in monkeys, observing arrhythmias in three out of four when the arterial concentration of Arcton I1 was 30 p,g/ml and that of Arcton 12 was 40 p.g/ml. In humans Dollery et al.<’ determined the blood Arcton I 1 concentrations of volunteers and patients with asthma who inhaled 3 to 30 puffs of “Medihaler” propellants and found a peak arterial concentration of I .7 pg/ml. They also determined the blood Arcton 1I concentration of volunteers who inhaled one burst (25 ~1) propellant mixture every 10 minutes for 6 hours and did not find any rise in concentration. Martin (personal communication) also performed studies in human volunteers inhaling IO bursts of “Ventolin” propellants and found a maximum blood concentration of 2.7 pg/ml Arcton 12 and 1.20 pg/ml Arcton 11. The maximum levels found in humans are much lower than the sensitizing levels seen in an’imals,which led Martin to speculatethat humans would have to use an inhaler about 20 times over a period of 2 minutes, and not breathe out, before the myocardial fluorocarbon concentration became critical.
CONCLUSION There are no experimental data to show that any of the drugs usedto treat asthmaare responsiblefor the increasesin deaths reported in various parts of the world. However, someof the compoundsusedare of greater toxic potential than others, and it is a matter for clinical judgment how and when they are used. Deaths are still reported in circumstancesthat suggest that treatment has proved inadequate.
REFERENCES I. Cuthbert MF. latrogenic lung disease. In: D’Arcy PF. Griffin JP, eds. latrogenic diseases. 2nd ed. Oxford: Oxford University Press, 1979. 2. Whimster WF, de Poitiers W. The lung. In Riddel RH, ed. Pathology of drug-induced and toxic diseases. New York: Churchill Livingstone, 1982. 3. Grant IWB, Kennedy WPV, Malone DN. Deaths from asthma Br Med J 1968;2:429-30. 4. Gresham GA, Caldcr IM. Sudden death in young asthmatics. Br Med J 1%8;3:186-7. 5. lnman WHW, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1%9;2:279-85. 6. Wexlar BC, Judd JT, Kittinger GW. Myocardial necrosis induced by isoproterenol in rats. Angiology 1%8;19:665-82. 7. Handforth CP. lsoproterenol induced myocardial infarction in animals. Arch Path01 1%2;73:161-5. 8. Poynter D, Spurling NW. Some cardiac effects of betaadrenergic stimuhmts in animals. Postgrad Med J 1971; 47(suppI):21-5. 9. Collins JM, McDevitt DG, Shanks RG, Swanton JG. The cardiotoxicity of isoprenaline during hypoxia. Br J Pharmacol 1%9;36:35-45.
IO. Lockett MF. Dangerous effects of iqnrenaliuc ::: !u:‘.tl. ::r.l;di failurc. Lancet 19632: 104-6. I I. Nayler WG. Some observations on the l~l~ilrlli‘!t.,~ii~~,Ir ;I: ci!.>‘i. of salbutamol. with particular refercncc to the ~:!:I~III~~;\,..~‘.II system. Postgrad Met1 J I97 I :47lbuppl): IO ..’ ! 12. Lulich KM. Goldie RG. Ryan G. Peterson !\i’ ‘\;i:c!.:s :,‘. action to bctn-2-agonist bronchodilator~. Sl$:,! ‘I’, !\i\ aa! ! ‘~Q’!‘I. I :1X6-99. 13. Morrison Smith J. Death from asthma. Lancc~ I’-iho: I : Illi.’ 14. Fraser P. Doll R. Geographical variations in the ,:pi,lcmIc t,i asthma deaths. Br J Prev Sot Mcd 1971:25: 34-c 15. Stolley PD. Asthma mortzality: why the Lnitcd States wzi\ spared an epidemic of deaths due to asthma .Zm Kec Rcspir Dis 1972: 105:883-90. 16. Gandevia B. Prcsxurised sympathomimetic acro\ol> and thcit lack of relationship to asthma mortality in .Australia bled J Aust 1973;1:273-7. 17. Jackson RT, Beaglehole R, Rea HH, Sutherland DC Momrliry from asthma: a new epidemic in New Zealand. Br MUI J 19X2:285:77 l-4. 18. Sly RM. lncreases in deaths from asthma. Ann Allergy 1‘)X4:.52:20-5. 19. Bumey PGJ. Asthma mortality in England and Wales: evidcncc for a further increase. 1974-84. Lance1 19X6:2:323-6. 20. Poyntcr D. Spurling NW, Ainge G. A toxicity study wuh heclomcthasone dipropionate in the dog with particular rclcr.. cncc to the respiratory tract Postgrad Med J 19755 I(supp1): 27-9. 21. Andersson E, Smidt CM, Sikjaer B. Aingc G, Poynter I). Bronchial biopsies after beclomethasone dipropionatc aerosol. Br J Dis Chest 1977;77:35-43. 22. Poynter 1~. Beclomethasone dipropionate aerosol and irasal mucosa. Br J Clin Pharmacol 1977;4:295S-3018. 23. Gerblich A. Urdu G, Schuylor M. Atopic asthma: T-cell responses to corticosteroids. Chest 1985:X7:44-9. 24. Strubelt 0, Hoffman A. Siegers CP. Sierra-C;illcjas JI.. On the pathogenesis of cardiac necroses induced by theophylline and caffeine. Acta Pharmacol Toxicol 1976:39:3X3-92. 25. Joseph X. Whitehurst VE. Bloom S, Balazs T. Enhancement of cardiotoxic effects of B-admnergic bronchodilators by aminophyllinc in experimental animals. Fund Appl Toxicol 1981;1:443-7. 26. Whitchurst VE. Joseph X, Hohmann JR. Pledger Cl. Balazs T. Cardiotoxic effects in rats and rabbits treated with tcrbutaline alone and in combination with aminophylline. J Am Coil Toxicol 1983~2: 147-53. 27. Nicklas R, Whitehurst VE, Donohoe RF, Balazs T. Concomitant use of beta adnmergic agonists and methylxanthines. J AI.I.EROY CI.IN IMMUNOI. 1984;72:20-4. 28. Lloyd PR, Covelli HD, Hill JC. Dysrhythmic effects of combined theophylline and beta agonist therapy in patients with severe obstructive lung disease. Chest 1984:86:282-340. 29. Kemp JP. Chervinsky P, Grgel HA, Meltzer EO, Noyes JH. Mingo TS. Concomitant bitolterol mcsylate aerosol and theophylline for asthma therapy. with 24 br electrocardiographic monitoring. I ALL.ERGY C1.m IMUIMUNOI. 1984;73:32-43. 30. Wilson JD, Sutherland DC, Thomas AC. Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma‘? Lancet I98 I ; I : 1235-7. 3 I. Simpson WT. Initial studies on the human pharmacology of salbutamol. Postgrad Med J 1971;47t,suppl):35-8. 32. Walker SR. Evans ME, Richards AJ, Paterson W. Plasma levels and percentage increase in FEV, after oral and aerosol administration of lH-salbutamol in asthmatic paients. Clin Pharmacol Ther 1972;13:861.
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33. Bass M. Sudden sniffing death. JAMA 1970;212:2075-9. 34. Taylor GJ. Harris WS. Cardiac toxicity of aerosol propellants. JAMA 1970;214:81. 35. Clark DC, Tinston DJ. The influence of fluorocarbon propellants on the arrhythmogenic activities of adrenaline and isoprenalinc. Proc Eur Sot Drug Tox 1972;13:212. 36. Taylor CT, Harris WS, Bogdonoff MD. Ventricular arrhyth-
Fatal asthma-is
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mias induced m monkeys by the inhalation of aerosol propellams. J Clin Invest Toxic01 197 I ;50: 1546-50. 37. Dollery CT, Draffan GH, Davies DS, Williams FM, Conolly ME. Blood concentrations in man of fluorinated hydrocarbons after inhalation of pressurised aerosols, Lancet 1970~2: 1164-6.