Pediatric Annals

Use of Magnesium Sulfate in Asthma in Childhood

Gamal F Monem, MD; Niranjan Kissoon, MD; Lucian DeNicola, MD

Abstract

Severe status asthmaticus is one of the lifethreatening emergencies in children. It is defined as prolonged small airway obstruction unresponsive to the usual standard treatment, which usually includes oxygen, beta2-agonists, and corticosteroids.1"4 It is clear that oxygen and inhaled beta,- agonist are the therapeutic modalities of greatest efficacy for acute bronchospasm with early administration of steroids as a helpful adjunct in decreasing inflammation.5'7 Most asthma attacks respond to the treatment outlined above; however, 3% to 16% of patients will progress to frank respiratory failure.8

To prevent respiratory failure, high doses of intravenous steroids and beta2-agonists (inhaled or intravenous) in varying doses and frequency of administration have been tried in the treatment of severe asthma in children.9'17 When conventional measures fail, alternatives such as ketamine infusion,18,19 inhalation anesthetics,20'23 mechanical controlled hypoventilation,24 or even extracorporeal membrane oxygenation25 have been used with varying efficacy. Mechanical ventilation in status asthmatics, in particular, is associated with high incidence of complications and increased mortality rate.26 Recently, the use of magnesium sulfate in asthma has emerged as a useful adjunct to beta2-agonist therapy in the emergency treatment of acute severe bronchospasm. Its role in less severe attacks and chronic asthma is not yet defined. This article summarizes the available literature pertaining to the use of magnesium sulfate in the treatment of asthma.

ROLE IN ASTHMA

Almost 60 years ago, Rosello and PIa27 observed that intravenous injection of magnesium sulfate "relieved" a case of asthma that was not affected by routine medical therapy. The first published study was reported in 194? by Hurry28 who reported the immediate relief of bronchospasm due to acute asthma in two patients after being treated with parenteral magnesium sulfate. Recently, several investigators have studied the bronchodilating effects of magnesium sulfate on patients with moderate to severe asthma who did not respond adequately to conventional therapy. Most of these studies were undertaken in adult patients29*38 Table 1). The outcomes in these studies were dissimilar and may be due to differences in the study designs, wide variability of the doses of magnesium sulfate used, and failure to correlate clinical effectiveness with serum magnesium levels.

Table

In 1989, the first controlled trial of the use of magnesium sulfate in asthma was reported by Skobeloff et al.32 In their study, 38 patients with moderate to severe asthma who failed to double their peak expiratory flow after two albuterol inhalations and intravenous methylprednisone were given 1.2 g of magnesium sulfate intravenously or placebo in a doubleblind manner. Significant improvement in peak expiratory flow rate was noted in the treatment group (32%) compared with the placebo group (3.4%). The rate of hospitalization was also significantly lower in the treatment group (7 of 14 versus 15 of 19). The authors, however, cited the small sample size as a limitation of their study. Additionally, their placebo group had a lower initial peak expiratory flow rate compared with the treatment groups, suggesting that patients in the control group were sicker and hence likely to have a poorer response and higher rate of hospitalization.

In 1992, with a larger sample size of 120 patients and using a higher dose of 2 g of magnesium sulfate intravenously over 20 minutes, Green et al36 evaluated its efficacy in asthmatic patients in a nonblinded manner. Both groups (treatment and control) were similar demographically and had similar initial peak expiratory flow rates. All patients were on hourly albuterol inhalation therapy. There were no significant differences in hospitalization rate, duration of emergency department treatment, or in peak expiratory flow rates between the treated and control groups. Although the magnesium sulfate dose used in this study was higher than…

Severe status asthmaticus is one of the lifethreatening emergencies in children. It is defined as prolonged small airway obstruction unresponsive to the usual standard treatment, which usually includes oxygen, beta2-agonists, and corticosteroids.1"4 It is clear that oxygen and inhaled beta,- agonist are the therapeutic modalities of greatest efficacy for acute bronchospasm with early administration of steroids as a helpful adjunct in decreasing inflammation.5'7 Most asthma attacks respond to the treatment outlined above; however, 3% to 16% of patients will progress to frank respiratory failure.8

To prevent respiratory failure, high doses of intravenous steroids and beta2-agonists (inhaled or intravenous) in varying doses and frequency of administration have been tried in the treatment of severe asthma in children.9'17 When conventional measures fail, alternatives such as ketamine infusion,18,19 inhalation anesthetics,20'23 mechanical controlled hypoventilation,24 or even extracorporeal membrane oxygenation25 have been used with varying efficacy. Mechanical ventilation in status asthmatics, in particular, is associated with high incidence of complications and increased mortality rate.26 Recently, the use of magnesium sulfate in asthma has emerged as a useful adjunct to beta2-agonist therapy in the emergency treatment of acute severe bronchospasm. Its role in less severe attacks and chronic asthma is not yet defined. This article summarizes the available literature pertaining to the use of magnesium sulfate in the treatment of asthma.

ROLE IN ASTHMA

Almost 60 years ago, Rosello and PIa27 observed that intravenous injection of magnesium sulfate "relieved" a case of asthma that was not affected by routine medical therapy. The first published study was reported in 194? by Hurry28 who reported the immediate relief of bronchospasm due to acute asthma in two patients after being treated with parenteral magnesium sulfate. Recently, several investigators have studied the bronchodilating effects of magnesium sulfate on patients with moderate to severe asthma who did not respond adequately to conventional therapy. Most of these studies were undertaken in adult patients29*38 Table 1). The outcomes in these studies were dissimilar and may be due to differences in the study designs, wide variability of the doses of magnesium sulfate used, and failure to correlate clinical effectiveness with serum magnesium levels.

Table

TABLE 1Summary of Magnesium Sulfate Studies In Asthma

TABLE 1

Summary of Magnesium Sulfate Studies In Asthma

Table

TABLE 2Clinical Data for Patients Pre- and Posttreatment With Magnesium Sulfate*

TABLE 2

Clinical Data for Patients Pre- and Posttreatment With Magnesium Sulfate*

In 1989, the first controlled trial of the use of magnesium sulfate in asthma was reported by Skobeloff et al.32 In their study, 38 patients with moderate to severe asthma who failed to double their peak expiratory flow after two albuterol inhalations and intravenous methylprednisone were given 1.2 g of magnesium sulfate intravenously or placebo in a doubleblind manner. Significant improvement in peak expiratory flow rate was noted in the treatment group (32%) compared with the placebo group (3.4%). The rate of hospitalization was also significantly lower in the treatment group (7 of 14 versus 15 of 19). The authors, however, cited the small sample size as a limitation of their study. Additionally, their placebo group had a lower initial peak expiratory flow rate compared with the treatment groups, suggesting that patients in the control group were sicker and hence likely to have a poorer response and higher rate of hospitalization.

In 1992, with a larger sample size of 120 patients and using a higher dose of 2 g of magnesium sulfate intravenously over 20 minutes, Green et al36 evaluated its efficacy in asthmatic patients in a nonblinded manner. Both groups (treatment and control) were similar demographically and had similar initial peak expiratory flow rates. All patients were on hourly albuterol inhalation therapy. There were no significant differences in hospitalization rate, duration of emergency department treatment, or in peak expiratory flow rates between the treated and control groups. Although the magnesium sulfate dose used in this study was higher than that in the study by Skobeloff et al,32 there is some doubt whether this dose (2 g intravenously over 20 minutes) is sufficient to produce clinical effectiveness. It is not possible to determine whether this dose is low since serum magnesium levels were not measured in either study.

It appears, however, that a magnesium level of 2 to 4 mg/dL is necessary to produce a bronchodilatory effect. In an earlier study, Okayama et al29 administered about 2.5 g of magnesium sulfate to 10 asthmatic adults and found that serum levels rose from 2.1 to 5.1 mg/dL. They also noted a correspondent improvement in forced expiratory volume at 1 second (FEV1) and forced vital capacity (FVC) (18%) and reduction of respiratory resistance (29%). Noppen et al33 administered a dose of 3 g of magnesium sulfate intravenously in 12 asthmatics and found that the level increased from 2.1 to 4.7 mg/dL with a correspondent increase in FEV,. Most recently, Sydow et al38 used a dose of 10 to 20 g of magnesium sulfate over 1 hour followed by continuous administration of 400 mg/hour for 24 hours in five mechanically ventilated asthmatics. The baseline magnesium level (from 0.9 to 1.2 mg/dL) increased almost threefold to a range of 2.4 to 3.2 mg/dL in 1 hour. This was associated with a significant increase in peak airway pressure and respiratory resistance.

In the pediatric literature, few clinical trials have evaluated the use of magnesium sulfate in children with acute bronchospasm. In a double-blind placebocontrol prospective trial, Clark et al37 tested the effect of nebulized magnesium sulfate alone and as a diluent to albuterol in 22 pediatric patients with acute bronchospasm and a clinical asthma score <4. No bronchodtlating effects from the use of nebulized magnesium sulfate could be demonstrated in this study. Additionally, nebulized magnesium sulfate appeared to blunt the bronchodilating and chronotropic effects of aerosolized albuterol. These findings are difficult to interpret because no serum magnesium levels were obtained.

Pabon et al39 reviewed their data in four children in whom magnesium sulfate infusion (40 to 50 mg/kg over 20 minutes) was used when conventional therapy (oxygen, albuterol, and steroids) did not result in the expected improvement. Table 2 shows the clinical data for the four patients before and after magnesium sulfate administration. Although the authors demonstrated a beneficial response to magnesium sulfate infusion, this response was not seen uniformly in all four patients. The lack of consistent response could be partially explained by the low serum levels (<4 mg/dL) obtained in these patients postinfusion. Additionally, due to lack of a control group and the concomitant administration of other bronchodilators, it is not possible to provide any firm conclusion as to the efficacy of magnesium sulfate. Based on these data and review of the available literature, Pabon et al39 recommend a dose of 50 mg/kg administered intravenously to produce a serum magnesium level 2*4 mg/dL.

MECHANISM OF ACTION

Magnesium is the fourth most abundant cation in the body and the second most common intracellular cation. It is known to regulate a host of enzyme systems that are critical to cellular metabolism. In addition, it is an essential cofactor for oxidative metabolism. In smooth muscles, excess magnesium may act by both extracellular and intracellular mechanisms to decrease the amount of calcium available for light chain phosphorylation of myosin.40 Increased extracellular magnesium competes with calcium at the same binding sites and also may increase the activity of magnesium-calcium adenosine triphosphatase in the cell membrane, leading to increased calcium extrusion from the smooth muscle cells. At the intracellular level, increased magnesium may promote calcium uptake by the sarcoplasmic reticulum.40

The exact mechanism of action of magnesium in asthma is not completely clear. However, the main theoretical basis for its therapeutic effect is the fact that magnesium acts principally as a "physiologic" calcium antagonist thereby directly affecting calcium uptake in smooth muscles and resulting in smooth muscle relaxation. Other possible mechanisms of action include inhibition of acetylcholine release at the neuromuscular junction,41 inhibition of histamine release,42 direct inhibition of smooth muscle contraction,43 and sedation.34 In addition to these mechanisms, hypomagnesemia has been reported in patients with bronchial asthma.28

METABOLISM

The human body contains about 2000 mEq of magnesium. At least 50% is found in bone and the remainder is equally distributed in muscular and nonmuscular tissue.44,45 Seventy percent to 80% of serum magnesium is ionized and diffusible. The ionized fraction is believed to be the physiologically active portion of circulating magnesium.46 Several factors such as arterial blood pH, serum protein concentration, and severity of illness may affect total ion concentration but may not necessarily affect the ionized fraction.47,48 This is particularly significant when using total serum magnesium levels as a guide for therapy. When administered parenterally, magnesium is principally excreted in the urine as only 1% to 2% is recovered in the feces.49 Enteral magnesium is absorbed mainly in the small intestine.

DOSING GUIDELINES IN ASTHMA

The oral route of magnesium has no role in the treatment of acute severe asthma. Magnesium sulfate can be given intramuscularly but administration by this route is painful. It also can be administered by aerosol; however, this route is not effective in relieving bronchospasm.36,37 Currently, intravenous infusion of magnesium sulfate is the preferred method of administration in acute bronchospasm. The dose and frequency of administration in pediatric asthma patients has not been determined. However, as previously discussed, there is increasing evidence suggesting that a serum magnesium level >4 mg/dL is necessary for clinically relevant bronchodilating effect.29,33 In obstetric use, a level between 5 to 7.5 mg/dL is required to produce relaxation of the uterine smooth muscles.50 However, whether the same levels are required to produce bronchial smooth muscle relaxation is an area of controversy.

After an infusion of high doses of magnesium sulfate (10 to 20 g over 1 hour) to five mechanically ventilated adult asthmatics, the resulting magnesium levels after 1 hour increased as much as three times the preinfusion levels (maximum 8 mg/dL).38 Significant reductions in peak airway flow resistance within 1 hour of the infusion were demonstrated in all five patients with mild to moderate hypotension occurring in two out of the five patients.38

In our ongoing study, we administered magnesium sulfate in a dose of 50 mg/kg intravenously over 20 minutes to 10 asthmatic children ages between 2 and 16 years old. Average magnesium levels rose from 2 mg/dL to 3.3 mg/dL after 20 minutes and to 2.5 mg/dL after 60 minutes. Based on these data, we have modified our initial recommendation and now use a dose of 75 mg/kg intravenously over 20 minutes instead of 50 mg/kg for children with acute bronchospasm. This dose may be repeated every 6 hours depending on the response. In addition, magnesium levels should be checked routinely in patients receiving this drug to avoid possible toxicity. As suggested by Noppen et al33 and Okayama et al,29 the therapeutic goal should be to achieve a serum magnesium level of 2 to 4 mg/dL to achieve measurable bronchospasm. Because most authors agree that early signs of magnesium toxicity appear with a level of >8 mg/dL, we recommend keeping magnesium levels between 4 and 6 mg/dL to achieve clinical improvement. The significance of measuring serum ultrafiltrable (ionized) magnesium level instead of the usual total serum magnesium was highlighted in a recent study that reported that low ionized fraction of serum magnesium was closely associated with the need for mechanical ventilation in sick neonates.51

The onset of action of intravenous magnesium sulfate has been reported to occur within minutes from the start of the infusion and lasts for approximately 2 hours.29,32,33 At this time, there is insufficient evidence to support administering magnesium sulfate by continuous infusion in asthmatics.

SIDE EFFECTS AND CONTRAINDICATIONS

Side effects of magnesium sulfate are mild and if they occur are usually most pronounced immediately during the infusion. This includes transient sensation of facial warmth, flushing, nausea and vomiting, dry mouth, and malaise. Significant adverse effects have not been reported.29,31,32,39 Transient alterations of pulse and blood pressure usually are not seen when magnesium is given by slow intravenous infusion but may occur with rapid intravenous infusion (<20 minutes). At high total serum magnesium level (> 12.S mg/dl), absent reflexes, muscle weakness, respiratory depression, and abnormalities in the cardiac conduction system can occur. However, to achieve this level, a dose of more than 150 mg/kg usually is required.29,33,52 Generally, there is little risk associated with magnesium sulfate infusion as long as deep tendon reflexes, respiratory rate, and urine output are monitored closely. Magnesium is contraindicated in patients with renal failure, myasthenia gravis, and heart block as well as in patients with myocardial damage.

INDICATIONS

There are no specific indications for the use of magnesium sulfate in the asthmatic child. However, early use of magnesium sulfate in acute moderate to severe asthma may be beneficial when response to conventional therapy is not favorable. The role of magnesium as a drug for chronic therapy and in the outpatient setting is yet undetermined. Further studies are needed to address the pharmacodynamics and the kinetics of this drug as well as its interactions with other medications currently used in pediatric asthma.

REFERENCES

1. DeNicola LX, Manera G, GayJe MO, et a). Treatment of critical .warns asthmarics in children. Pediarr CIm Norm Am. 1994;41:1293-1323.

2. DeNicola LK. Severe pediatric asthma. Journal of Respiratory Disease. 1992:13:144172.

3. Mathison DA. Asthma in adults, diagnosis and treatment. In: Middleton E Jr1 Reed CE, Ellis EF, eds. Allergy- Principia, and Practices. St Louis. Mo: CV MoAy O1 1988:1063-1092.

4. jaimovich D1 fCecskes SA. Management of reactive airway disease. Crit Care Can. 1992;8:147-162.

5. Littcnbcrg B1 Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314:150-152.

6. Murata GH1 Gorby MS1 Chick TW1 et al. Intravenous and oral corticosteroids for the prevention of relapse after treatment of decompensated COPD. Chest. 1990;98:845-849.

7. Stein LM1 Cole RP. Early administration of corticosteroids in emergency room treatment of acute asthma. Ann Intern Med. 1990-.1 12:822-827.

8. Santiago SM Jt, Klausrenneyer WB. Mortality in status asthmaticus; nine year» experience in a respiratory intensive care unit. J Asthma Res. 1980;17:75-79.

9. Schuh S1 Parkin P, Rajan A, et al. High versus low dose frequently administered nebulized albuterol in children with severe acute asthma. Pediatrics. 1989;83:513-518.

10. Robertson CF1 Smith F, Beck R1 et al. Response to frequent low doses of nebulized salbutamol in acute asthma. J Pedina. 1985;106:672-674.

11. Ba M, Thiverge RL, Lapierre JG, et al. Effects of continuous inhalation of salbutamole in acute asthma. Am Rev Respfr Dis. 1987;135:A326.

12. Salazar RO, Joos T. Treatment of status asthmaticus with continuous nebulized albuterol in children. J Allergy CIm Immunol. 1990;85A:196.

13. Katz RW1 Kelly HW1 Crowley MR1 et ai. Safety of continuous nebulized albuterol for bronchospasm in infants and children. Pediatrics. 1993;92:666-669.

14. Colacone A1 Wolkove N1 Stern E1 et al. Continuous nebulization of albuterol in acute asthma. Chest. 1990;97:693-697.

15. Thiringtr G1 Svedmyr N. Comparison of infused and inhaled terbutaline in patients with asthma. Scand J Respfr Dis. 1976;57:17-24.

16. Bohn D, Kalloghlian A1 Jenkins J1 et al. Intravenous salbutamol in the treatment of status asthmaticus in children. Crit Care Med. 1984;12:892-896.

17. FugUang G, Pedersen S, Borgstrom L. Dose-response relationships of intravenously administered terbutaline in children with asthma. J Pediarr. 1989;1 14:31 5-320.

18. Rock MJ1 Reyes de Ia Rocha S1 L'Hommedieu CS1 et al. Use of ketamine In asthmatic children to treat respiratory failure refractory to conventional therapy. Cnz Care Med. 1986;14:514-516.

19. Strube PJ, Hallam PL. Ketamine by continuous infusion in status asthmaticus. Anaeckesia. 19S6.-41:1017-1019.

20. O'Rourke PP, Crone RK. Halothane in status asthmaticus. Crit Care Med. 1982;10:341-343.

21. Revell S1 Greenhalgh D, Absalom SR, et al. Isoflurane in the treatment of asthma. Anaesthesia. 1988;43:477-9.

22. Johnston RG1 Noseworthy TW1 Friesen KG1 et al. Isoflurane therapy for status asthmaticus in children and adults. Chest. 1990;97:698-701.

23. DeNicola LK1 Aboudan K. Resistant status asthmaticus in children. J FIa Med Assoc. 1990;77:809-813.

24. Darioli R1 Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respfr Dis. 1984;129:385-387.

25. MacDonnell KF1 Moon HS1 Sekar TS1 et al. Extracorporeal membrane oxygenator support in a case of severe asthmaticus. Arm Thoroc Surg. 1981;31:171-175.

26. Manse! JK, Stogner SW, Pettini MP. et al. Mechanical ventilation in patients with acute severe asthma. AmJ Med. 1990;89:42-48.

27. Rosello HJ, PIa JC. Sulfato de magnesia en Ia crisis de asma. Presna Med Argentina. 1936;23:1677-1680.

28. Hurry VG. Blood serum magnesium in bronchial asthma and its treatment by administration of magnesium sulfate. J Lab CIm Med. 1940;26:340-344.

29. Okayama H1 Aikawa T1 Okayama M. et al. Bronchodialating effect of intravenous magnesium sulfate in bronchial asthma. JAMA. 1987;257:1076-1078.

50. Rolla G, Bucea C1 Bugiani M, et al. Reduction of histamine induced bronchoconstriction by magnesium in asthmatic subjects. Allergy. 1987;42:186-188.

31 . Rolla G1 Bucea C1 Caria E, et al. Acute effect of intravenous magnesium sulfate on airway obstruction of asthmatic patients. Ann Allergy. 1989;61:388-391.

32. Skobeloff E. Spivey W1 McNamara R, et al. Intravenous magnesium sulfate for the treatment of acute asthma in the emergency department. JAMA. 1989:262:12101213.

33. Noppen N, Vanmaele U lmpens N, et al. Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest. 1990;97:373-376.

34. Okayama H, Okayama M, Aikawa T, et al. Treatment of status asthmaticus with intravenous magnesium sulfate. J Asthma. 1991 i28:1 1-17.

35. Chande V1 Skoner DP. A trail of nebulized magnesium sulfate to reverse bronchospasm in asthmatic patients. Arm Emerg Sied. 1 992;2 J : 1 1 1 1 - 1 1 1 5.

36. Green SM1 Rothrock SG. Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization, Ann Emerg Med. 1992;21:260-265.

37. Clark MC, Wright GD, Falk JL, et al: Aerosolized magnesium sulfate as acute therapy for pediatric asthma. Ann Emerg Med. 1991 i20:448.

38. Sydow M, Crozier TA, Zielmann S, et al. High-dose intravenous magnesium sulfate in the management of life-threatening status asthmaticus. intensive Care Med. 1993;19:467-471.

39. Pabon H, Monem G, Kissoon N. Safety and efficacy of magnesium sulfate infusion in children with status asthmaticus. Pediatr Emerg Care. 1994;10:200-203.

40. Huszar G, Naftolin F. The myometrium and uterine cervix in normal and preterm labor. N EngtJ Med. 1984-.3U-.571-581.

41. Del Castillo J, Engback L. The nature of the neuromuscular block produced by magnesium. J Physiol. 1954;124:370-384.

42. Bois P. Effect of magnesium deficiency on mast cells and urinary histamine in rats. British Journal of Experimental Pathology. 1963;44:151-155.

43. Altura BM, Altura BT, Cerella A. Magnesium deficiency induced spasms of umbilical vessels: relation to preeclampsia, hypertension, growth retardation. Science. 1983:221:376-378.

44. Widdowson EM, McCane RA, Spray CM. Chemical composition of human body. Clin Sci. 1951;10:113-125.

45. Wacker WE, Parisi AF. Magnesium metabolism. N Engl J MeA 1968;278:712-717.

46. Zaloga G, Wilkens R, Tourville J, et al. A simple method for determining physiologically active calcium and magnesium concentrations in critically ill patients. Crit Care Med. 1987;15:813-816.

47. Salem M, Munoz R, Chemow B. Hypomagnesemia in critical illness: a common and clinically important problem. Cm Care Clin. 1991;7:225-252.

48. Zaloga C, Chemow B. Hypocalcemia in critical illness. ./AMA. 1986;256:I9241929.

49. Silver L, Robertson JS, Dahl LK. Magnesium turnover in humans studied with Mg28J Clin Invest. 1960;39:420-423.

50. Elliot JP. Magnesium sulfate as a tocolytic agent. Am ) Offset Gynecol. 1983;147:277-284.

51. Munoz R, Khilnani P, Ziegler J, et al. Ulrrafilterable hypomagncsemia in neonates admitted to the neonatal intensive care unit. Cm Care Med. 1994;22:815-820.

52. Mudge GH, Weiner IM. Agents affecting volume and composition of body fluids. In: Oilman AG, Rail TW, Nies AS, et al, eds. Goodman and Oilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY: Pergamon Press; 1990:682-713.

TABLE 1

Summary of Magnesium Sulfate Studies In Asthma

TABLE 2

Clinical Data for Patients Pre- and Posttreatment With Magnesium Sulfate*

10.3928/0090-4481-19960301-06

Sign up to receive

Journal E-contents