Pulmonary Pharmacology & Therapeutics 23 (2010) 432e437
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Usefulness of inhaled magnesium sulfate in the coadjuvant management of severe asthma crisis in an emergency department M.C. Gallegos-Solórzano a, *, Rogelio Pérez-Padilla b, Rafael J. Hernández-Zenteno b a b
Emergency Department, National Institute of Respiratory Diseases (INER), 14080 Mexico City, Mexico Asthma Ward, National Institute of Respiratory Diseases (INER), 14080 Mexico City, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 January 2010 Received in revised form 6 April 2010 Accepted 14 April 2010
Rationale: Treatment of severe asthma may be difficult despite the use of several medications including parenteral corticosteroids. Intravenous magnesium sulfate (MgSO4) is one ancillary drug for severe crisis; its inhaled use is controversial. Objectives: To evaluate the usefulness of inhaled MgSO4 compared to placebo in improving lung function, oxygen saturation, and reducing hospital admission as an adjunct to standard treatment in severe asthma crisis. Patients and methods: We conducted a placebo-controlled, double-blind clinical trial with asthmatic patients >18 years of age with asthmatic crisis and FEV1 < 60% of predicted (%p). All subjects received 125 mg of IV methylprednisolone followed by nebulization with the combination of albuterol (7.5 mg) and ipratropium bromide (1.5 mg) diluted in 3 ml of isotonic saline solution (as placebo) or 3 ml (333 mg) of MgSO4. After 90 min, subjects with FEV1 < 60%p or SpO2 < 88% or persistent symptoms were admitted to the emergency department (ED). Results: We included 30 patients per group who were similar at baseline. The MgSO4 group showed higher post-bronchodilator (post-BD) FEV1%p (69 13 vs. 61 12, p < 0.014) and SpO2 (92 4 vs. 88 5%, p < 0.006) than the placebo group. Fewer treated patients were admitted to the ED (5 vs. 13) (p < 0.047), with relative risk (RR) of 0.26 (95% CI 0.079e0.870). Conclusions: Adding inhaled MgSO4 treatment to standard therapy in severe asthma crisis improves FEV1%p and SpO2 post-BD and reduces the rate of ED admissions. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Asthma crisis treatment Inhaled magnesium sulfate
1. Introduction Asthma is an important public health chronic respiratory illness due to its frequency, altered quality of life, and significant health costs along with the impact of severe asthma being able to trigger prolonged hospitalizations and death. Of the total asthma expenditure in the U.S., 25% is attributed to emergency care [1]. Standard treatment for asthma crisis includes short-acting bronchodilator (SAB), b2-agonists and inhaled anticholinergics and corticosteroids, in addition to general management. Intravenous magnesium sulfate (MgSO4) may be added in severe crisis unresponsive to standard
Abbreviations: SAB, short-acting bronchodilator; MgSO4, magnesium sulfate; GINA, Global Initiative for Asthma; INER, National Institute of Respiratory Diseases; ED, Emergency Department; FEV1, forced expiratory volume in 1 s; CG, control group; TG, treatment group; SS, saline solution; pre-BD, before bronchodilator use; post-BD, after bronchodilator use; SpO2, oxygen saturation; MRC, Medical Research Council; ATS, American Thoracic Society; ERS, European Respiratory Society; EKG, electrocardiogram; QoL, quality of life. * Corresponding author. E-mail address: marcosgallegos@mexico.com (M.C. Gallegos-Solórzano). 1094-5539/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2010.04.006
treatment [2] but requires special monitoring [3]. MgSO4 produces smooth muscle relaxation, blocking acetylcholine and histamine release, and a reduction in the neutrophil burst [4], leading to improved pulmonary mechanics [5,6]. Inhaled MgSO4 use is controversial. Studies addressing this subject differ methodologically and are heterogeneous, non-comparable, and with different therapeutic interventions and primary outcomes. Nevertheless, the Global Initiative in National Asthma (GINA) recommendations supported by meta-analysis [7,8] approve its use during a crisis [2]. The objective of this study was to evaluate the usefulness of inhaled MgSO4 as an adjuvant to the standard treatment (compared with placebo), on spirometry and pulse oximetry in severe asthmatic crisis and to determine whether this effect decreases hospital admissions. 2. Material and methods We conducted a randomized, placebo-controlled, double-blind trial to assess the efficacy of standard management adding inhaled MgSO4 compared with the standard treatment plus placebo in
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Eligible patients
433
>18 years old History of asthma with exacerbation FEV1 <60% predicted
Methylprednisolone 125 mg IV O2 to achieve a SpO2 >90% (3 L/min)
Nebulization: albuterol 2.5 mg plus ipratropium bromide 0.5 mg + 3 ml of isotonic saline (3 doses), 20 min each
Randomized maneuvers
Nebulization: albuterol 2.5 mg plus ipratropium bromide 0.5 mg + 333 mg of magnesium sulfate (3 doses), 20 min each
Evaluation after 30 min: a) Symptom improvement b) FEV1 > 60% predicted c) O2 saturation at room air >88% d) Normal electrocardiogram YES NO Discharge
Admitted Application of Quality of Life Questionnaire
albuterol/ipratropium bromide (inhaler device) Prednisone pills 1mg/kg/day
30-day follow-up
Follow-up, hours in emergency department and days in general ward
Spirometry and Quality of Life Questionnaire Fig. 1. Design of the study.
patients with severe acute asthma at the National Institute of Respiratory Diseases (INER), a tertiary-care teaching-hospital and national referral center in Mexico City for respiratory disorders. The INER takes care of 1500 patients in asthmatic crisis each year, 2% of whom warrant hospitalization [9]. The protocol was approved by the institutional ethics committee and all participants provided written informed consent. For 10 months (June 2008eMarch 2009) we recruited adults (>18 years of age) in the Emergency Department (ED) with asthmatic crisis [2], all with a forced expiratory volume in 1 s (FEV1) < 60%p [10]. We recorded demographic and clinical characteristics as well as the complete clinical history. We excluded the following patients: smokers, those with ambulatory use of systemic steroids, with associated co-morbidities (neuropathy, nephropathy, heart disease, liver disease), fever at admission, use of dietary supplements with MgSO4, irreversible airway obstruction (persistent abnormal spirometry), near-fatal asthma, requirement of endotracheal intubation at admission, anatomic abnormalities of the bronchial tree (bronchiectasis, tuberculosis), history of pulmonary or thoracic surgery, hypersensitivity to MgSO4, and pregnancy or breastfeeding. To avoid delays in treatment of the asthmatic crisis, randomization was done on arrival, and several of the exclusion criteria were ascertained after initial treatment when a clinical history and studies were
completed. Irreversible airflow obstruction was defined at the follow-up visit, 1 month after arrival to the ED. 2.1. Design (Fig. 1) All included patients with signed informed consent were transported to an inhalotherapy room to receive standard treatment: one IV dose of 125 mg methylprednisolone [11e13], and nebulization with 7.5 mg of albuterol and 1.5 mg of ipratropium bromide in three divided doses (Combivent, Boehringer Ingelheim GmbH, Germany). Intervention was assigned blindly and randomly as follows: control group (CG) received the standard nebulization diluted in 3 ml of isotonic saline solution (SS) as placebo, whereas the treatment group (TG) received the standard nebulization but diluted with 3 ml (333 mg) of 10% isotonic MgSO4 (Magnefusin PISA, Guadalajara, Mexico; 1 g/10 ml). Each nebulization lasted for 20 min. MgSO4 is provided as an isotonic solution (280 mosm/l, Osmometer Model SOsmette Precision Systems, Natick, MA, USA) [3,14]. Both diluents are odorless, tasteless and colorless to the eye and did not differ when transparency was measured (SMART Spectro, LaMotte Company, Chestertown, MD, USA). We used a nebulizer mask (6 ml, Wenzhou Hongshun Industries and Trade Co., Zhejiang, China) along with a nasal clip with O2 flow at 12 l/min, creating an aerosol with an aerodynamic mass of 3.7 mm diameter and output of
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10 did not accept
122 Randomized
30 excluded 8 without follow-up 3 asbestos exposure 2 type 2 diabetes 1 pulmonary embolism 7 biomass exposure 1 second-hand smoke 6 current smokers 2 abnormal x-ray .
60 allocated to MgSO4
30 completed protocol
52 allocated to isotonic saline
30 completed protocol
5 admitted to ED
2 admitted to general ward
22 excluded 5 without follow-up 1 asbestos exposure 1 Sampter syndrome 5 biomass exposure 1 second-hand smoke 9 current smokers
13 admitted to ED
3 discharged
6 discharged
2 readmissions in 30 days
7 admitted to general ward
3 readmissions in 30 days
Fig. 2. Trial profile.
0.27 ml/min [3]. After randomization, diluents were prepared by a physician outside the study who was not responsible for the patients’ care and only had control of the prefilled syringes. The physician responsible for the patients’ care along with the nurse and inhalotherapists were blinded to the type of treatment. At 30-min post-nebulization, patients were clinically and functionally reevaluated. Variables measured for each patient before bronchodilator use (pre-BD) and after bronchodilator (post-BD) use were vital signs, oxygen saturation (SpO2), by pulse oximetry (Pulse Oximeter Datex Ohmeda 3800, Trutrak, Finland), wheezing, pulsus paradoxus, use of accessory muscle and inability to speak in complete sentences. Dyspnea was assessed in accordance with the Medical Research Council (MRC) scale. Spirometry (Jaeger FlowScreen, VIASYS Healthcare, Hochberg, Germany) was performed according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations [15] aiming for three acceptable and reproducible maneuvers using reference values for the Mexican population [10]. The spirometer was calibrated daily with a 3-l syringe [15]. Chest x-ray (to document normal pulmonary structure) and electrocardiogram (EKG) (to rule out alterations in myocardial membrane by inhaled MgSO4) were both done. We applied the asthma quality of life questionnaire [16] validated in the Mexican population [17]. Patients were admitted to the ED (and placed in an observation bed) if any of the following criteria were met after 30 min of initial treatment: FEV1 < 60%p, SpO2 < 88% or persistence of symptoms. Otherwise, patients were discharged with oral prednisone suspension (1 mg/kg/day) for 10 days [18,19], albuterol/ipratropium inhalation as
needed [2], and inhaled budesonide 200 mg twice daily [20]. Other treatments were administered according to the treating physician [2]. If symptoms persisted without satisfactory response to treatment after 4e6 h at the ED, they were then admitted to the hospital in the asthma ward. All patients were reevaluated 30 days later with spirometry and asthma quality of life questionnaire. The primary outcomes of the study were FEV1 post-BD (absolute in liters and as percentage of predicted), clinical improvement and oxygen saturation. Secondary endpoints include admission to the ED and to the asthma ward as well as hospital readmissions, which were monitored by phone call interview. 2.2. Statistical methods Analysis was done on an intention-to-treat basis using the c2 test with Fisher’s exact test for categorical variables or the Student t-test for paired and independent groups for quantitative variables. We also fitted multiple regression models to identify predictors of post-BD FEV1 and SpO2 and logistic regression models to find predictors of admission to the ED. A two-tailed p value <0.05 was considered significant. Statistical analysis was performed with SPSS software package v.15 (SPSS Inc., Chicago, IL, USA). 3. Results All spirometry tests fulfilled the quality criteria according to ATSeERS guidelines and were highly reproducible in FEV1, both pre-BD (0.07 0.06 ml) as well as post-BD (0.08 0.07 ml). The
M.C. Gallegos-Solórzano et al. / Pulmonary Pharmacology & Therapeutics 23 (2010) 432e437 Table 1 Demographic and clinical characteristics of the patients upon hospital arrival.a Variable
CG (n ¼ 30)
Age (years) 34.3 12.4 Gender (n/%) Male 9 (30) Female 21 (70) Family history of asthma (n/%) 8 (26) Asthma diagnosis (years) 11.8 10.6 Respiratory physician 15 (50) follow-up (n/%) Last evaluation (months) 4.2 5.9 Number of hospitalizations from 3.9 5.9 asthma Last hospitalization (months) 14.6 22.2 Medications for asthma (n/%) 24 (80) 14 (46) Use of rapid-acting b2-agonist (n/%) 1066 648 Estimated dose by number of puffs, mc # of MDI vials used in the last month 1.43 0.8 (n/%) Combined treatment (n/%) 4 (13) Use of inhaled 7 (23) glucocorticosteroids (n/%) Use of long-acting 3 (10) b2-agonist (n/%) Duration of the 23.5 37.8 exacerbation (days) Nocturnal symptoms (n/%) 26 (86) Awakenings per night (number) 3.1 1.5 Symptoms (n/%) Cough Sputum Purulence Shortness of breath Dyspnea (MRC) Self-reported fever Vital signs and spirometry at arrival Systolic/diastolic blood pressure (mmHg) Oral temperature ( C) Respiratory rate Pulse rate O2 saturation at air room (%) BMI (kg/m2) FEV1, l FEV1, %p FVC, l FVC, %p FEV1/FVC ratio Quality of life score Limited activities Emotions Symptoms Exposure Overall
TG (n ¼ 30)
p value
40.3 11.6
NS
9 (30) 21 (70) 11 (36) 14 10.3 21 (70)
NS NS NS NS NS
4.6 6.4 3.1 4.5
NS NS
16 19.5 30 (100) 19 (63) 1426 477
NS <0.05 NS <0.05
1.75 0.7
NS
11 (36) 11 (36)
NS NS
7 (23)
NS
15.5 17.7
NS
27 (90) 3.0 1.6
NS NS
29 (96) 10 (33) 9 (30) 24 (80) 3.3 1.2 6 (20)
25 (83) 14 (46) 11 (36) 26 (86) 2.7 1.2 10 (33)
NS NS NS NS NS NS
110.3 10.6/ 68 7 36.9 0.2 26.4 2.3 108.9 12.5 85.8 2.1 26.7 4.6 1.45 0.39 43.4 8.3 2.24 0.82 55.9 12.6 62.6 10.2
110.3 11.2/ 68 12 36.5 0.1 26.8 2.4 113.5 18.3 86 2.6 28.5 3.4 1.32 0.52 42.2 10.2 1.61 0.47 49 6.9 60.4 11.6
NS NS NS NS NS NS NS NS NS NS NS
3.1 1.3 3.2 1.2 2.9 1.0 3.5 1.4 3.2 1.03
3.0 1.2 2.8 1.2 2.5 0.9 3.0 1.4 2.8 0.9
NS NS NS NS NS
435
Table 2 Primary endpoints of the study after 90 min of treatment.a Variable
CG (n ¼ 30)
TG (n ¼ 30)
p value
Pulmonary function FEV1, l FEV1, %p FVC, l FVC, %p FEV1/FVC, %p O2 saturation at room air, % Admitted to ED (n/%) Duration in the area (h) Admitted to general ward (n/%) Time in hospitalization, days Readmissions to ED
2.01 0.51 61.13 12.7 3.21 0.97 79.7 16.7 67.1 10.9 88.9 5.3 13 (43) 7.9 6.9 7 (23) 2.3 4.6 3 (10)
2.16 0.66 69.7 13.3 2.94 0.79 77.2 11.8 77 13.3 92.5 4.2 5 (16) 3.4 3.5 2 (7) 0.8 3.0 2 (7)
NS <0.01 NS NS <0.003 <0.006 <0.04 <0.003 NS NS NS
ED, emergency department; NS, not significant; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; %p, percentage of predicted. a Data are presented as n (%) or mean SD. Student t-test used for continuous variables and Fisher’s exact test used for categorical variables.
were from the Mexico City metropolitan area. Educational level was low to medium, and half of the subjects had less than primary schooling and worked in non-skilled occupations. Subjects from the TG tended to have previous asthma crisis treatment and used a greater dose of bronchodilators and had a lower spirometric function but differences with the CG were non-significant. Seven patients were overweight in the TG vs. six patients in the CG. Main characteristics after treatment are shown in Table 2: 86% (n ¼ 26) of the TG perceived improvement in symptoms vs. 56% (n ¼ 17) of the CG (p < 0.020). The treated group had a higher FEV1% p (Fig. 3), SpO2 (Fig. 4) and a lower rate of ED admissions. Treated patients had an FEV1 improvement of 271 ml and 10%p and FVC improvement of 245 ml and 8% higher than the CG (p < 0.05). TG had 25% of the risk of ED admission compared to CG (RR 0.26, 95% CI 0.079e0.870). No differences in TG and CG were observed in hospital asthma ward admission or readmissions. We did not find variables associated with FEV1%p and SpO2 post-BD in the multivariate analysis. When analyzing the benefit of MgSO4 in the most serious cases of obstruction, we found that the patients with FEV1 < 40%p
NS, not significant; CG, control group; TG, treatment group; mc, micrograms; MDI, metered dose inhalers; MRC, Medical Research Council; BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity. a Data are presented as n (%) or mean SD. Student t-test used for continuous variables and Fisher’s exact test used for categorical variables. See text for additional comments.
study profile is shown in Fig. 2. There were 122 eligible patients, 10 of whom did not wish to participate in the study, and 30 (TG) and 22 (CG) patients had at least one of the exclusion criteria (Fig. 2), leaving 30 patients per group for the final analysis. In all 60 patients, normal spirometry and normal qualifications of the QoL questionnaire were documented after 30 days of the study (data not shown). When comparing baseline characteristics (Table 1), no differences between groups were found. The majority of patients
Fig. 3. Differences between groups according to bronchodilator response. ΔFEV1% (delta) predicted for each group; pre- and post-bronchodilator (BD) change was better in the magnesium sulfate group (28 vs. 18% predicted), p < 0.003. Differences in the post-BD response between treatments were 9% at 90 min. pre-BD, pre-bronchodilator; post-BD, post-bronchodilator; SS, saline solution; MgSO4, magnesium sulfate inhaled.
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Fig. 4. Differences between groups in the change of O2 saturation at room air, %. SpO2 for each group; the change was better in the magnesium sulfate group (6.5 vs. 3.1%), p < 0.006. The difference in the post-BD response between treatments was 3.4%. preBD, pre-bronchodilator; post-BD, post-bronchodilator; SS, saline solution; MgSO4, magnesium sulfate inhaled.
presented a higher reversibility (DFEV1%p ¼ 104 61 vs. 52 27) than the group with FEV1 > 40%p (p ¼ 0.004); nevertheless, it did not have an impact on the admission to the ED. Of the admitted patients for each group, the TG had poorer baseline FEV1 in liters, more tachycardia, more obese subjects and deteriorated QoL, indicators of a more severe airflow obstruction (data not shown). The most common adverse reaction associated with MgSO4 was dry and bitter mouth, but no other side effect was associated with treatment. EKG was abnormal in some patients (43 vs. 36%): most commonly sinus tachycardia (40 vs. 36%) but similar in TG and CG. One patient in the TG developed supraventricular extrasystole that did not require additional management. One patient from each group presented dizziness.
and none used ipratropium bromide, recommended in the emergency treatment of asthma [2]. None of the studies, with the exception of one, assessed the effects of systemic absorption of MgSO4 after use [24]; several lack the use of steroids [14,22,24] or included current smokers [14,22,26]. Thus, our study has demonstrated several improvements over previous designs: standard treatment of the crisis including the combination of albuteroleipratropium, use of systemic steroids [2], evaluation with high-quality spirometry and FEV1 [15], inclusion of SpO2, quality of life assessed by a specific asthma questionnaire and all studied patients had a complete reversal of the obstruction after treatment discarding as much as possible patients with chronic obstructive pulmonary disease [14,22e26]. We have shown that inhaled MgSO4 improves FEV1%p when added to standard treatment. We also found a reduced risk of admission to the ED with the use of MgSO4, consistent with the improved lung function, although this risk was lower than that found in other trials [26], probably due to the lower dose of b2agonist used. Other studies have used higher dose of MgSO4 (up to 1.5 g) [24] but smaller doses may be sufficient to observe improvement as we have shown. If we had decided to admit patients only with post-BD FEV1 < 50%p, we may have also observed a significant reduction in the risk of hospitalization due to MgSO4 (RR 0.19, 95% CI 0.047e0.782). Several known pharmacological properties of MgSO4 may explain the observed improvement over that produced by systemic steroids and a combination of bronchodilators; however, the exact mechanisms involved are unclear. It may be due to additional smooth muscle relaxation and interference with the release of acetylcholine or it may be through mast cell stabilization, blocking the release of histamine or possibly by an anti-inflammatory effect reducing the neutrophil burst [4]. We also do not know if inhaled MgSO4 affects the deposition of nebulized bronchodilators or if other types of interactions are involved in the observed effect when bronchodilators and MgSO4 are mixed for nebulization. 5. Conclusions This study suggests that nebulized albuterol and ipratropium bromide diluted with MgSO4 solution improves lung function and oxygen saturation and reduces the rate of ED admissions compared to the standard dilution with isotonic saline.
4. Discussion
Acknowledgments
The study shows that adding inhaled MgSO4 to the standard treatment for severe asthma crisis with a significant impact on quality of life produces a greater improvement in symptoms and lung function determined by post-BD FEV1%p as well as oxygenation (SpO2). Treatment also reduced the risk of emergency hospitalization in a group of patients with severe asthma crisis. Additional treatments for severe asthma crisis are always helpful and MgSO4 may be one of them. GINA recommends its use as first-line treatment: in 296 patients analyzed in a meta-analysis, there was a median difference found in FEV1 (l) of 0.17 l (95% CI 0.51e0.86 l) in favor of MgSO4, without impacting on the reduction of ED admissions (RR 0.69, 95% CI 0.42e1.12) [21]. The first systematic review was done in the year 2000 [7] and this was subsequently reviewed in the year 2005 [21], creating doubt as to the beneficial effect of MgSO4 or classifying the effect as weak [8,21]. Although inhaled MgSO4 has been shown to inhibit bronchial hyperresponsiveness in asthmatic patients due to sodium metasulfite [3], four clinical trials have not recommended the use of MgSO4 [22e25], whereas two other studies favor its use [14,26]. Previous studies reported a variety of MgSO4 and albuterol dosages that make it difficult to compare [14,22e26]
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