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.
Summary of Magnesium Sulfate Studies In Asthma
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
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.
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.
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Summary of Magnesium Sulfate Studies In Asthma
Clinical Data for Patients Pre- and Posttreatment With Magnesium Sulfate*