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Suffer the Children
1 Doll R, Petro R, Wheatly K, et al. Mortality in relation to smoking: 40 years observations on male British doctors. BMJ1994; 309:901–911 Cigarette smoking makes asthma worse. That
simple tenet forms one of the most well-known 2 Sethi JM, Rochester CL. Smoking and chronic obstructive corner stones of asthma management.1 Nevertheless, pulmonary disease. Clin Chest Med 2000; 21:67– 86 3 Cigarette smoking and health: American Thoracic Society.
certain studies2,3 have suggested that 10 to 30% of Am J Respir Crit Care Med 1996; 153:861– 865 adults with asthma continue to smoke cigarettes.
4 Hughes JA, Hutchison DC, Bellamy D, et al. The influence of They smoke despite intensive efforts at education, cigarette smoking and its withdrawal on the annual change in smoking cessation therapies, and, most notably, the lung function in pulmonary emphysema Q J Med 1982; negative feedback from their own personal experi- 5 Prochazka AV. New developments in smoking cessation.
ence with acute exacerbations of asthma. Clinical studies3–5 have suggested that such patients want to 6 Fine MC, Smith SS, Jorenby RE, et al. The effectiveness of stop cigarette smoking but cannot, perhaps, to a the nicotine patch for smoking cessation. JAMA 1994; 271: large extent, because of the addictive properties associated with inhaling tobacco smoke.
7 Schneiter NG, Lunell E, Olmstead RE, et al. Clinical phar- macokinetics of nasal nicotine delivery: a review and compar- Worsening of asthma is not limited to active ison to other nicotine systems. Clin Pharmacokinet 1996; cigarette smoking. Data3 from adults convincingly show that environmental (involuntary) tobacco 8 Hjalmarson A, Franzon M, Westin A, et al. Effect of nicotine smoke inhalation profoundly impacts the manage- nasal spray on smoking cessation: a randomized, placebo- ment of asthma, causing greater hospitalization rates controlled, double-blind study. Arch Intern Med 1994; 154: and worsening of daily asthma symptoms. The im- 9 Ferry LH, Robbins AS, Scariati PD, et al. Enhancement of pact of environmental tobacco smoke on asthmatic smoking cessation using the antidepressant bupropion children is not quite as clear as that in adults, hydrochloride [abstract]. Circulation 1992; 86(4 suppl possibly because of the complexity of asthma diag- nosis and management, especially for younger chil- 10 Ferry LH, Burchette RG. Efficacy of bupropion for smoking dren. Nevertheless, studies6 generally show a pattern cessation in non depressed smokers [abstract]. J Addict Dis of more severe respiratory illness in association with childhood environmental tobacco smoke inhalation.
11 Hurt RD, Sachs DPL, Glover ED, et al. A comparison of sustained-release bupropion for smoking cessation. N Engl Investigators have commonly quantified the extent of environmental tobacco smoke exposure in adults by 12 Jorenby DE, Leischow SJ, Nides MA, et al. A controlled simply gauging the perceived extent of exposure trial of sustained release bupropion, a nicotine patch, or (questionnaire responses). Estimating smoking expo- both for smoking cessation. N Engl J Med 1999; 340: sure in children is more difficult, and many investi- gators have relied on biochemical markers of tobacco 13 Hays JT, Hurt RD, Rigotti NA, et al. Sustained release smoke inhalation. One of the most commonly uti- bupropion for pharmacologic relapse prevention after smok-ing cessation: a randomized controlled trial. Ann Intern Med lized markers is cotinine, a nicotine metabolite that accumulates in the blood and urine following to- 14 Gonzales DH, Nides MA, Ferry LH, et al. Bupropion SR as an aid to smoking cessation in smokers treated previously with Mannino and colleagues from the Centers for bupropion: a randomized placebo-controlled study. Clin Disease Control and Prevention have previously utilized blood cotinine and health outcome data from 15 Blondel T, Gudmundson LJ, Olafsdottir I, et al. Nicotine a United States-wide child health survey to provide nasal spray with nicotine patch for cessation: randomized trialwith six year follow-up. BMJ 1999; 318:285–288 important insights into the respiratory consequences 16 Hjalmarson A, Nilson F, Sjostrom L. The nicotine inhaler in of involuntary smoke inhalation.8 These data have smoking cessation. Arch Intern Med 1997; 157:1721–1728 shown that, among children within their survey who 17 Hall SM, Reus VI, Munoz RF, et al. Nortriptyline and were aged 4 through 6 years, high blood cotinine cognitive-behavioral therapy in treatment of cigarette smok- concentrations were associated with an increased ing. Arch Gen Psychiatry 1998; 55:683– 693 prevalence of asthma and wheezing. In this issue of 18 Prochazka AV, Weaver MJ, Keller RT, et al. A randomized trial of nortriptyline for smoking cessation. Arch Intern Med CHEST (see page 409), the authors extend these observations with analyses of the subset of children 19 Hughes JR, Stead LF, Lancaster T. Antidepressants for within their survey who already had received a smoking cessation (Cochrane Review). Cochrane Database diagnosis of asthma. In the broadest terms, they found that asthma severity generally correlated with 20 Blondal T, Gudmundsson LJ, Tomasson K. The effects of fluoxetine combined with nicotine inhalers in smoking cessa- blood cotinine concentrations. Worse lung function tion: a randomized trial. Addiction 1999; 94:1007–1015 and more days lost from school occurred for children with the highest blood cotinine concentrations.
underscore the need for additional studies of the These findings are consistent with the implications of components and methods involved in smoking ces- the data from other pediatric clinical studies.
sation counseling for parents who smoke, especially Two especially interesting features of the latest analyses by Mannino et al raise questions about the Mannino and colleagues provide a snapshot of the pathophysiologic correlates of smoking behavior.
consequences of exposing asthmatic children to to- The first is that weighted analyses showed that a bacco smoke. Because of the inherent methodolog- greater proportion of asthmatic children aged 4 ical features of their data, the snapshot is not com- though 6 years had higher blood cotinine concentra- pletely focused as many patients had to be tions than older children. The authors do not hypoth- eliminated from the analyses because of missing data esize as to the basis for this finding, but other studies points, and very extensive subsetting was performed.
of household smoke exposure suggest that younger Nevertheless, the photograph is clear enough to children may experience greater exposure because remind us of one of the common observations from they are inherently more home-bound than older studies of addictive behavior: addicted parents may children. In essence, younger children may be harm not only themselves but also their children.12 “trapped” within the smoking environment, while Notably, in a recently published study13 of children the more mobile older children manage to lessen seen in a Cincinnati emergency department because their environmental smoke exposure.6,9 The second of asthma exacerbations, 41% of the parents identi- interesting observation is that children with the fied themselves as cigarette smokers. The data of highest blood cotinine concentrations were less likely Mannino et al, combined with those from other to have been hospitalized for asthma within the past reports, provide evidence of the harm associated year. In addition to potential misreporting, the au- with involuntary smoke inhalation among children, thors hypothesize that this finding may be related to especially children with asthma. These observations the alteration of home smoking policies in response support the contention that the addictive properties to asthma hospitalization, which is an attractive of cigarette smoking may be profound. Indeed, hypothesis given the short half-life of cotinine within recovery from tobacco addiction is notoriously diffi- the blood and some evidence that parents modify cult, even for highly motivated smokers.14 Because their smoking behavior in response to their chil- the consequences of parental smoking impact not dren’s asthma exacerbations.4 Conceivably, a child’s only the smoker but the smoker’s children, it be- life-threatening asthma exacerbation might prompt hooves us all to work diligently with parents who the parents to eliminate cigarette smoke from the smoke to lower or eliminate tobacco smoke from In addition to facilitating epidemiologic studies, information on blood or urine cotinine levels might be a very effective tool in parental smoking cessationtechniques, the concentrations providing tangible Dr. Rieves is a medical officer with the US Public Health Service.
evidence to parents of cigarette smoke inhalation by The views expressed are those of the author and do not represent their children. Two recently published clinical stud- those of, nor imply endorsement by, any organization or institu- ies have examined the impact of this technique in Correspondence to: Dwaine Rieves, MD, FCCP, 1907 New counseling the parents of asthmatic children. Both Hampshire Ave NW, Washington, DC 20009 studies suggested that this information is not asuseful as one might anticipate. One of these studies10 compared “usual care” smoking cessation techniques 1 National Asthma Education and Prevention Program. Expert to counseling techniques that included provision of panel report 2: guidelines for the diagnosis and management the results of their children’s urine cotinine concen- of asthma. Bethesda, MD: National Institutes of Health, April trations. After 6 months, the proportion of homes in which smoking was banned was not remarkably 2 Althuis MD, Sexton M, Prybylski D. Cigarette smoking and different between the two groups; smoking was asthma symptom severity among adult asthmatics. J Asthma1999; 36:257–264 banned in 42% of homes in the usual care group and 3 Eisner M, Yelin E, Henke J, et al. Environmental tobacco in 50% of homes in the cotinine group. The second smoke and adult asthma. Am J Respir Crit Care Med 1998; study11 also showed no statistically significant differ- ence in banning cigarette smoke from the home.
4 Hovell M, Zakarian J, Matt G, et al. Effect of counseling mothers However, this second study showed that active coun- on their children’s exposure to environmental tobacco smoke:randomized controlled trial. BMJ 2000; 321:337–342 seling (with feedback on urine cotinine concentra- 5 de Granda-Orive J, Escobar J, Gutierrez T, et al. Smoking- tions) lowered the risk for acute asthma exacerba- related attitudes, characteristics, and opinions in a group of tions requiring medical attention. These results young men with asthma. Mil Med 2001; 166:959 –965 6 Gergen P. Environmental tobacco smoke as a risk factor for that functions to mobilize magnesium from bone or respiratory disease in children. Respir Physiol 2001; 128: elsewhere to maintain circulating extracellular lev- els.1 Magnesium is involved in maintaining the ionic 7 Greenberg R, Haley N, Etzel R, et al. Measuring the cellular balance, eg, by its role in the function of the exposure of infants to tobacco smoke: nicotine and cotinine inurine and saliva. N Engl J Med 1984; 310:1075–1078 cell membrane sodium-potassium adenosine triphos- 8 Mannino D, Moorman J, Kingsley B, et al. Health effects phatase pump.2 Magnesium is an obligate ion essen- related to environmental tobacco smoke exposure in children tial for the activation of Ͼ 300 enzymes,3 for virtually in the United States. Arch Pediatr Adolesc Med 2001; all hormonal reactions occurring in the body, and for the activity of adenylate cyclase.1 Finally, magnesium 9 Irvine L, Crombie I, Clark R, et al. What determines levels of also acts as a calcium channel blocker.4 Magnesium passive smoking in children with asthma? Thorax 1997;52:766 –769 thus undoubtedly is a major player in many cellular 10 Wakefield M, Banham D, McCaul K, et al. Effect of feedback and hormonal functions. And severe magnesium regarding urinary cotinine and brief tailored advice on home deficiency is dangerous: in critically ill patients, for smoking restrictions among low-income parents of children instance, hypomagnesemia occurs in up to 65% of with asthma: a controlled trial. Prev Med 2002; 34:58 – 65 patients, and is associated with increased mortality 11 Wilson S, Yamada E, Sudhakar R, et al. A controlled trial of an environmental tobacco smoke reduction intervention in low- rates.5,6 Severe magnesium deficiency can lead, income children with asthma. Chest 2001; 120:1709–1722 among other things, to a variety of dysrhythmias, 12 Hoffman R, Goldfrank L. The impact of drug abuse and seizures, muscle weakness, and mental status addiction on society. Emerg Med Clin North Am 1990; changes, various endocrine dysfunctions, but also to bronchospasm and respiratory failure.1 Magnesium 13 Mahabee-Gittens M. Smoking in parents of children with asthma and bronchiolitis in a pediatric emergency depart- replacement hence undoubtedly is useful in these critically ill patients.3 But is it useful for John Doe’s 14 Rigotti N. Treatment of tobacco use and dependence. N Engl asthma? To answer this question, it may be useful to apply Koch’s postulates: (1) Is magnesium a bron-chodilator? (2) Is asthma characterized by/associatedwith magnesium deficiency states? (3) Is magnesiumtherapy useful in treating asthma? Magnesium Treatment for
1. Magnesium has been shown to cause bronchial smooth-muscle relaxation in vitro,7 probably by itsaction as a “physiologic calcium antagonist,”8 or by its Where Do We Stand?
action on adenyl cyclase activation.9 Magnesium hasbeen shown to cause bronchodilation in vivo10–12 in My name is John Doe, and I have asthma. I am children as well as in adults. Yes, magnesium is a
concerned about my health, and I’m not sure whether I should take the steroids and other chem- 2. The question of whether asthma is character- icals my physician has ordered me to. A friend ized by/associated with magnesium deficiency is less suggested I should take magnesium. What shall I do? clear, and much more difficult to answer because of Well, I’m up-to-date and concerned, hence I consult the difficulties in measurement and interpretation of the World Wide Web. I search for “asthma and intracellular vs extracellular (protein-bound, che- magnesium,” and find . . . Ͼ 26,600 Web page lated, and ionized) forms.1,13 Although magnesium matches! When looking for “corticosteroids and asth- levels have been shown to appear similar in asthmat- ma,” or even for, eg, “anticholinergics and asthma,” I ics as compared to those in control subjects,14 other “only” find 17,400, and “only” 2,370 Web sites relate data suggest that low magnesium intake (which is a to anticholinergics and asthma. When browsing major determinant in magnesium homeostasis1) may through the 26,600 pages, the evidence in favor of be involved in the etiology of asthma and chronic magnesium seems overwhelming. My friend was obstructive airway disease. Britton et al,15 for in- stance, have shown in a random adult population You are a pulmonologist, and confronted with a sample study that a 100 mg/d higher magnesium concerned and allegedly well-informed John Doe, intake was independently associated with a 27.7 mL proudly facing you with Ͼ 25 kg of printouts. What (95% confidence interval, 11.9 to 43.5 mL) higher do you say? Well, here’s “magnesium and asthma in FEV1, and a reduction in the relative odds of bronchial hyperreactivity by a ratio of 0.82 (confi- Magnesium is primarily (99%) an intracellular dence interval, 0.72 to 0.93). Furthermore, ␤2-recep- cation. In contrast to calcium, the maintenance of tor agonist use can increase renal magnesium losses magnesium homeostasis is highly dependent on di- and thus lead to magnesium deficiency.1 Neverthe- etary intake, and there is no known regulatory system less, it remains unclear from the available data

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