Magnesium Treatment for Asthma

6 Gergen P. Environmental tobacco smoke as a risk factor for respiratory disease in children. Respir Physiol 2001; 128: 39 – 46 7 Greenberg R, Haley N, Etzel R, et al. Measuring the exposure of infants to tobacco smoke: nicotine and cotinine in urine and saliva. N Engl J Med 1984; 310:1075–1078 8 Mannino D, Moorman J, Kingsley B, et al. Health effects related to environmental tobacco smoke exposure in children in the United States. Arch Pediatr Adolesc Med 2001; 155:36 – 41 9 Irvine L, Crombie I, Clark R, et al. What determines levels of passive smoking in children with asthma? Thorax 1997; 52:766 –769 10 Wakefield M, Banham D, McCaul K, et al. Effect of feedback regarding urinary cotinine and brief tailored advice on home smoking restrictions among low-income parents of children with asthma: a controlled trial. Prev Med 2002; 34:58 – 65 11 Wilson S, Yamada E, Sudhakar R, et al. A controlled trial of an environmental tobacco smoke reduction intervention in lowincome children with asthma. Chest 2001; 120:1709–1722 12 Hoffman R, Goldfrank L. The impact of drug abuse and addiction on society. Emerg Med Clin North Am 1990; 8:467– 480 13 Mahabee-Gittens M. Smoking in parents of children with asthma and bronchiolitis in a pediatric emergency department. Pediatr Emerg Care 2002; 18:4 –7 14 Rigotti N. Treatment of tobacco use and dependence. N Engl J Med 2002; 346:506 –512

Magnesium Treatment for Asthma Where Do We Stand? name is John Doe, and I have asthma. I am M yconcerned about my health, and I’m not sure

whether I should take the steroids and other chemicals my physician has ordered me to. A friend suggested I should take magnesium. What shall I do? Well, I’m up-to-date and concerned, hence I consult the World Wide Web. I search for “asthma and magnesium,” and find . . . ⬎ 26,600 Web page matches! When looking for “corticosteroids and asthma,” or even for, eg, “anticholinergics and asthma,” I “only” find 17,400, and “only” 2,370 Web sites relate to anticholinergics and asthma. When browsing through the 26,600 pages, the evidence in favor of magnesium seems overwhelming. My friend was right: I should take magnesium! You are a pulmonologist, and confronted with a concerned and allegedly well-informed John Doe, proudly facing you with ⬎ 25 kg of printouts. What do you say? Well, here’s “magnesium and asthma in a nutshell”! Magnesium is primarily (99%) an intracellular cation. In contrast to calcium, the maintenance of magnesium homeostasis is highly dependent on dietary intake, and there is no known regulatory system 396

that functions to mobilize magnesium from bone or elsewhere to maintain circulating extracellular levels.1 Magnesium is involved in maintaining the ionic cellular balance, eg, by its role in the function of the cell membrane sodium-potassium adenosine triphosphatase pump.2 Magnesium is an obligate ion essential for the activation of ⬎ 300 enzymes,3 for virtually all hormonal reactions occurring in the body, and for the activity of adenylate cyclase.1 Finally, magnesium also acts as a calcium channel blocker.4 Magnesium thus undoubtedly is a major player in many cellular and hormonal functions. And severe magnesium deficiency is dangerous: in critically ill patients, for instance, hypomagnesemia occurs in up to 65% of patients, and is associated with increased mortality rates.5,6 Severe magnesium deficiency can lead, among other things, to a variety of dysrhythmias, seizures, muscle weakness, and mental status changes, various endocrine dysfunctions, but also to bronchospasm and respiratory failure.1 Magnesium replacement hence undoubtedly is useful in these critically ill patients.3 But is it useful for John Doe’s asthma? To answer this question, it may be useful to apply Koch’s postulates: (1) Is magnesium a bronchodilator? (2) Is asthma characterized by/associated with magnesium deficiency states? (3) Is magnesium therapy useful in treating asthma? 1. Magnesium has been shown to cause bronchial smooth-muscle relaxation in vitro,7 probably by its action as a “physiologic calcium antagonist,”8 or by its action on adenyl cyclase activation.9 Magnesium has been shown to cause bronchodilation in vivo10 –12 in children as well as in adults. Yes, magnesium is a bronchodilator. 2. The question of whether asthma is characterized by/associated with magnesium deficiency is less clear, and much more difficult to answer because of the difficulties in measurement and interpretation of intracellular vs extracellular (protein-bound, chelated, and ionized) forms.1,13 Although magnesium levels have been shown to appear similar in asthmatics as compared to those in control subjects,14 other data suggest that low magnesium intake (which is a major determinant in magnesium homeostasis1) may be involved in the etiology of asthma and chronic obstructive airway disease. Britton et al,15 for instance, have shown in a random adult population sample study that a 100 mg/d higher magnesium intake was independently associated with a 27.7 mL (95% confidence interval, 11.9 to 43.5 mL) higher FEV1, and a reduction in the relative odds of bronchial hyperreactivity by a ratio of 0.82 (confidence interval, 0.72 to 0.93). Furthermore, ␤2-receptor agonist use can increase renal magnesium losses and thus lead to magnesium deficiency.1 Nevertheless, it remains unclear from the available data Editorials

whether all asthmatics have a lower magnesium content, and the available data do not support the need for systematic magnesium supplementation in these patients. 3. Is magnesium therapy useful in treating acute asthma attacks? In this issue of CHEST (see page 489), Silverman and colleagues and three review articles (two meta-analyses16,17 and a Cochrane review18) supply a solid evidence-based answer: 2 g of MgSO4 in adults and 25 to 100 mg/kg in children administered as a 10- to 20-min IV infusion undoubtedly improves pulmonary function when used as an adjunct to standard therapy, albeit only in the most severe cases. And although it is still uncertain whether adding MgSO4 to conventional therapy significantly influences hospitalization rates, need for ICU treatment, or final outcome, all authors agree that MgSO4 is beneficial in patients presenting with acute severe asthma, also because MgSO4 is extremely safe, and inexpensive. So, I would inform John Doe of the following: (1) Magnesium certainly is an extremely important, essential ion, necessary for the normal function of numerous cellular functions. (2) Magnesium can relax (bronchial) smooth muscle. There is, however, no unequivocal evidence that all asthmatics have a shortage of magnesium (also because this is extremely difficult to measure), and there currently is no proof that using dietary magnesium supplements has a beneficial effect in asthma treatment. (3) It is proven, however, that in (very) severe acute asthma attacks, IV magnesium treatment improves pulmonary function when used in addition to conventional treatment. Some questions, however, remain unanswered: Are there subgroups of patients, eg, in terms of response to ␤-agonist therapy, or in terms of inhaled steroid use, in whom magnesium treatment is more or less useful? What is the optimal dosage and duration of treatment ? Are the measured beneficial effects of magnesium therapy only due to its bronchodilator effects, or do anti-inflammatory effects also play a role?19 Finally, Mr. Doe, there is no correlation between the number of Web citations on a therapeutic subject and its real importance. “Homeopathy and asthma” for instance, yields ⬎ 35,000 Web pages. Corticosteroids are much less “popular” on the Web, but their increasing use undoubtedly has decreased asthma morbidity and mortality! Strikingly, only approximately one third of patients in the population of Silverman and colleagues with severe asthma (as demonstrated by the previous hospitalizations and past intubation for asthma) received inhaled steroid therapy at the time of hospital admission. It is highly probable that the www.chestjournal.org

inadequate outpatient management of these patients may be, at least in part, responsible for their acute severe asthma in the first place! Therefore, Mr. Doe, I would advise you to meticulously take the inhaled corticosteroids that were prescribed to you, instead of your magnesium supplements. This probably will keep you out of the emergency department. But should acute severe asthma nevertheless occur, IV magnesium therapy certainly should be added to conventional treatment. Marc Noppen, MD, PhD, FCCP Brussels, Belgium Dr. Noppen is Associate Professor and Head of the Interventional Endoscopy Clinic, Respiratory Division, University Hospital AZ-VUB, and Faculty of Medicine, Free University of Brussels (VUB). Correspondence to: Marc Noppen, MD, PhD, FCCP, Respiratory Division, Academic Hospital AZ-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium; e-mail: [email protected]

References 1 Dacey JM. Hypomagnesemic disorders. Crit Care Clin 2001; 17:155–173 2 Flatman P, Lew V. The magnesium dependence of sodium pump mediated sodium-potassium and sodium-sodium exchange in intact human red cells. J Physiol 1981; 315:421– 446 3 Zaloga GP, Roberts PR. Calcium, phosphorus and magnesium disorders. In: Ayres SM, Greuvik NA, Holbrook PR, et al, eds. Textbook of critical care. 4th ed. Philadelphia, PA: WB Saunders, 2000; 905–928 4 White R, Hartzell H. Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes. Science 1988; 239:778 –780 5 Ryzen E, Wagers PW, Singer FR, et al. Magnesium deficiency in a medical ICU population. Crit Care Med 1985; 13:19 –21 6 Chernow B, Bamberger S, Stroiko M, et al. Hypomagnesemia in patients in the postoperative intensive care unit. Chest 1989; 95:391–397 7 Spivey WH, Skobellof EM, Levin RM. Effect of magnesium chloride on rabbit bronchial smooth muscle. Ann Emerg Med 1990; 19:1107–1112 8 Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J 1984; 108:188 –193 9 Brandt DR, Ross EM. Cathecholamine-stimulated GTPase cycle: multiple sites of regulation by ␤-adrenergic receptor and Mg2⫹ studied in reconstituted receptor-Gs vesicles. J Biol Chem 1986; 261:1656 –1664 10 Noppen M, Vanmaele L, Impens N, et al. Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest 1990; 97:373–376 11 Skobeloff EM, Spivey WH, McNamara RM, et al. Intravenous magnesium sulfate for the treatment of acute severe asthma in the emergency department. JAMA 1989; 262: 1210 –1213 12 Ciarallo L, Sauer A, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr 1996; 129: 809 – 814 13 Fiser R, Torres A, Butch A, et al. Ionized magnesium concentrations in critically ill children. Crit Care Med 1998; 26:2048 –2052 CHEST / 122 / 2 / AUGUST, 2002

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14 deValck HW, Struyvenberg A, Van Rijn HJM. Extracellular and intracellular magnesium concentrations in asthmatic subjects. Eur Respir J 1993; 6:1122–1125 15 Britton J, Pavord I, Richards K, et al. Dietary magnesium, lung function, wheezing and airway hyperreactivity in a random adult population sample. Lancet 1994; 344:357–362 16 Rowe BH, Bretzlaff JA, Bourdon C, et al. Intravenous magnesium sulfate for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med 2000; 36:181–190 17 Alter HJ, Koepsell TD, Hilty WM. Intravenous magnesium as an adjuvant in acute bronchospasm: a meta-analysis. Ann Emerg Med 2000; 36:191–197 18 Rowe BH, Bretzlaff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department (Cochrane Review). Available at: http://www. update-software.com/ccweb/cochrane/revabstr/ab001490.htm. Accessed July 2, 2002 19 Cairns CB, Kraft M. Magnesium attenuates the neutrophils respiratory burst in adult asthmatic patients. Acad Emerg Med 1996; 3:1093–1097

Snoring May Not Mean That You Had a Good Night’s Sleep tales are common in Asia as to what constiF olk tutes a good night’s sleep. “Snoring at night

means you have had a good night’s sleep” is one. “Drinking tea at night means you will have a good night’s sleep” is another. We now know that both of these conceptions may not be correct. The blending of various specialities into what we now know as sleep medicine has been an interesting journey. Neurologists began to investigate sleep, and what they uncovered at night was amazing. During the “silent” hours of sleep, abnormalities in breathing would scare even the most aggressive physician.1 Not long after, an article appeared in the British literature linking snoring to stroke, and questions began to arise as to the possible association.2 Soon, “everyone” began to investigate sleep. Sleep became one of the “uninvestigated horizons” that was open to all fields of medicine. Advances occurred rapidly, but a low point in such investigations was a report implying that sleep-disordered breathing was overdiagnosed and not of significant importance. That report only fueled further investigation. Much of the investigations required large-scale epidemiologic studies such as the Sleep Heart Health Study3 and other epidemiologic studies. Soon the evidence became clear that there was a probable association between sleep-disordered breathing and hypertension.4 “Now they’ll pay attention, now that the heart is involved,” was a statement made by one of the first investigators of sleep-disordered breathing. Soon, 398

reports began to add up, showing an association between sleep-disordered breathing and left ventricular dysfunction. Nasal continuous positive airways pressure had already become one of the primary treatments of congestive heart failure due to left ventricular dysfunction.5 The article in this issue of CHEST (see page 558) adds further documentation of the association between sleep-disordered breathing and the heart, and adds one more piece of information as to the association between the silent hours of sleep and the heart. No longer can sleep-disordered breathing/ sleep apnea be considered a comical and rare syndrome involving patients who are overweight and sleepy (the pickwickian syndrome). We now know that sleep-disordered breathing/sleep apnea is associated with vehicular accidents, and the evidence is mounting as to the association with the heart. The hard thing to understand about sleep apnea is that it is “sleep” apnea. For physicians, we can understand the implications. For the lay public, however, when one mentions that sleep apnea might be associated with hypertension, the lay response is that “my BP is normal.” Often, one needs to educate patients that it is sleep apnea, and not “day” apnea. The elevations in BP during an apnea can be astounding, particular when they occur at altitude. But even at sea level, the normal cardioprotective mechanisms are thwarted in patients with hypertension who have sleep-disordered breathing. The next chapter is in the journey of being written. This chapter is beginning to show us that abnormalities in breathing may differ in racial groups, some having mostly apneas whereas others having mostly hypopneas. The current standard of combining both apneas and hypopneas into a common number allows us to better evaluate patients in all parts of the world who might have an association between sleepdisordered breathing and the heart. “Snoring at night means you had a good night’s sleep” may no longer be a valid folk tale in the future. Edward Morgan, MD, FCCP Honolulu, HI Dr. Morgan is an Associate Professor at the University of Hawaii School of Medicine, and Director of the Sleep Center at the Kuakini Medical Center. Correspondence to: Edward Morgan, MD, FCCP, Suite 405, 321 N Kuakini St, Honolulu, HI 96817; e-mail:[email protected]

References 1 Coccagna G, Mantovani M, Brignani F, et al. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physiopathol Respir (Nancy) 1972; 8:1159 – 1172 Editorials