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What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?
Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Egyptian Journal of Chest Diseases and Tuberculosis journal homepage: www.sciencedirect.com
What to use for bronchial asthma; nebulized or intravenous magnesium sulfate? Ibrahim Salah-Eldin Ibrahim ⇑, Reham Mohamed Elkolaly Chest Department, Faculty of Medicine, Tanta University, Tanta, Egypt
a r t i c l e
i n f o
Article history: Received 20 December 2016 Accepted 19 January 2017 Available online xxxx Keywords: Asthma Magnesium sulfate Nebulized
a b s t r a c t Background: Asthma is characterized by airways narrowing and airflow limitation. The conventional therapy for asthma exacerbation is usually efficient but sometimes patients not respond to it, consequently; other additive drugs may be used as magnesium sulfate(MgSO4) either intravenously or by nebulization. Objective: To compare the bronchodilator effect of MgSO4 via intravenous injection and nebulization in controlling asthma exacerbation. Methods: 40 patients with asthma exacerbation were equally and randomly enrolled in two groups. One group received nebulized MgSO4 (A), and the other group received intravenous MgSO4 (B). Results: Improvement was higher in group B than in group A but without significant change in PEFR also there was no high significant difference in the two group parameters after MgSO4 treatment. Complications were few and manageable in both groups. Conclusion: Intravenous MgSO4 is effective affordable and cheap drug for asthma exacerbation management with good response while nebulized MgSO4 didn’t give the aimed response in these patients. Ó 2017 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction Asthma is one of the common chronic airway diseases that leads to decrease of airflow and characterized by bronchial and bronchioles inflammation with airways smooth muscle contraction and increase mucous synthesis and secretion. Leading to recurrent wheeze, breathing difficulties and coughing either at night or/and early morning [1]. This airways narrowing is often reversible with or without treatment [2]. Asthma morbidity and mortality rates are high and are mostly related to acute exacerbations [3]. So severe asthma attacks must be treated rapidly and effectively to avoid its fatal consequences, to decrease triggering for further future exacerbation [4] and to prevent more decline in lung functions after these attacks [5]. Patients having asthma exacerbations usually need rapid treatment to relieve their suffering, so they use inhaled bronchodilators
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis. ⇑ Corresponding author at: Chest Department, Tanta University Hospitals, Elgharbyia, Tanta, Egypt. E-mail addresses: [email protected] (I.S.-E. Ibrahim), [email protected] (R.M. Elkolaly).
in form of b2 agonists (±anticholinergic) in addition to parental corticosteroids if they are admitted to hospitals [6]. And in spite of that; corticosteroids used in emergency department need a relatively longer time (6–8 h) to produce their antiinflammatory effect and control the acute attack [7], while inhaled b2 agonists give their adequate bronchodilator effect in only two thirds of treated patients and the rest of patients still suffer from the attack effect [6]. For that reason; physicians tried to use other additive drugs to give rapid bronchodilator effect to manage asthma early before patients deterioration. Magnesium sulfate (MgSO4) is the drug that was previously used as an additive line of treatment in many cases with acute severe asthma [8]. Magnesium sulfate was studied and supposed to reduce intracellular calcium influx via closure of calcium channels and inhibits calcium release from endoblasmic reticulum [9], it also inhibits inflammatory mediator release from mast cells and inhibits acetyl choline release from nerve endings, that leads finally to muscle relaxation [10]. Some physicians used magnesium via nebulization-especially in children-during severe asthma attacks to achieve bronchodilatation and to avoid the systemic side effects of the intravenous drug
http://dx.doi.org/10.1016/j.ejcdt.2017.01.005 0422-7638/Ó 2017 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
2
I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx
[11]. While others used it parentrally to give rapid action and relieve of the bronchoconstriction, but this may lead to some side effects like arrhythmia flushing, hypotension and renal intoxication in high doses [2]
Aim of the study To compare the bronchodilator effect of magnesium sulfate via intravenous route versus nebulization in patients with asthma exacerbation.
Patients and methods The study was conducted from March 2016 through July 2011 at Tanta University Hospital, Tanta, Egypt. This study was conducted on 40 patients with acute bronchial asthma exacerbation with the following inclusion criteria: – Patient with acute exacerbation of asthma according clinical assessment of asthma using GINA guidelines [12]. – Patient not controlled on conventional therapy for acute exacerbation. Exclusion criteria were as follow Patients with stable asthma, COPD, pneumonia, heart failure or renal insufficiency, in need for endotracheal intubation, inability to do peak flow meter, pregnant or breastfeeding mothers or had received oral, inhaled or parenteral bronchodilators in the past 6 h, or steroids in the past 12 h. All patients were subjected to history taking, clinical examination and PEF% (wright peak flow meter) and scoring was done according guidelines [13]. All patients received the conventional treatment of acute exacerbation as follow: – Supplemental oxygen to have O2 sat. greater than 90%. – Nebulization of 1 ml Farcolin respirator solutionÒ mixed with 9 ml saline for two sessions with interval of 15 min [Farcolin respirator solutionÒ: each 20 ml of Farcolin contains Salbutamol sulfate 0.121 gm. Made in Egypt, by: Pharco Pharmaceuticals – Alexandria]. – Intravenous Solu-CortefÒ 100 mg once [Solu-CortefÒ: vial contains powder of 100 mg Sodium hydrocortisone hemisuccinate dissolved with 2 ml solvent of sterile bacteriostatic water for IV injection. Manufactured by: Egyptian Int. Pharmaceutical Industries co. (e.i.p.i.co.) – Egypt. Under license of: Pfizer]. Patients were assisted clinically every 15 min. If the patient didn’t improve after one hour; he was randomly enrolled in one of the two groups that contained 20 patients in each group. Each patient was evaluated clinically for blood pressure (BP) and Fischl index that consists of seven items (pulse, respiratory rate (RR), pulsus paradoxicus (PP), PEF%, dyspnea, wheeze and accessory muscle use) and scored 0–1 for each [6]. These pre-treatment parameters were labeled (level zero) before MgSO4 treatment. Group A (nebulization group): four doses of nebulization solution with 15 min apart, each dose contained 1 ml MgSO4 mixed with 9 ml saline, to have isotonic mixture to avoid hyperosmolar broncho-constriction [14]. Group B (injection group): 2 g of MgSO4 diluted in 30 ml saline to have a 50 ml solution for slow intravenous injection along 20– 30 min [15].
Magnesium Sulfate USP2Ò 1 g/10 ml [Magnesium SulfateÒ: Sterile ampoule 10 ml. 100 mg/ml = 0.41 mMol/ml. Manufactured by: Egyptian int. Pharmaceutical industries co. (e.i.p.i.co.) – Egypt]. Patients were assisted after 30 min (level 1) then after 1 h (level 2) N.B.; Patients who deteriorated were re-evaluated for other management procedures. Statistical analysis All data were statistically analysed by the SPSS software for Windows (IBM SPSS Statistics 21.0). P value <0.05 was significant. Results Forty patients with acute asthma were enrolled in this study; they were divided into two groups. Group A consisted of 20 patients (12 female and 8 male) that received nebulized MgSO4 and group B that consisted of 20 patients (11 female and 9 male) who received intravenous MgSO4. There was no statistically significant difference between the two groups as regard age, pre-treatment pulse, BP, RR and PEFR, Fischl’s index) (Table 1). After 30 min of treatment; patients were re-evaluated (Table 2). These parameters improvement showed no significance difference between the two groups, but the improvement in group B was more than that in group A. Another re-evaluation was done after one hour as follow (Table 3) Which revealed improvement in group B than that in group A; but also without significant difference. The significance of changes in group A as regard pre-treatment, after 30 min and after one hour were as follow (Table 4). The significance of changes in group B as regard pre-treatment, after 30 min and after one hour were as follow (Table 5). As regard results in Tables 4 and 5; the clinical parameter in group A showed mild improvement after I hour as regard BP and pulse with less improvement in other parameters. But in group B; there was significant improvement in BP and RR after 30 min while the improvement was more significant in all parameters after I hour. There were minor complications that reported in 3 patients in group A including headache, flushing, hypotension and nausea. The adverse effects in group B were recorded in 5 patients; including nausea, vomiting, arrhythmia and hypotension (Table 6). Discussion Asthma is one of the chronic respiratory disorders that has repeated episodes of exacerbations that may be mild, moderate and even severe attack which may lead to hospital or ICU admission, intubation or even death [8]. Intravenous magnesium sulfate was used as a possible additive drug for asthma exacerbation management especially in severe attacks [16]. Magnesium is an important ion in cellular and tissue homeostasis including airways musculature via its role for different enzymes action [16]. MgSO4 helps smooth muscle relaxation via facilitating calcium ions influx to sarcoplasmic reticulum [17]. It also inhibits both acetyl choline and histamine release from nerve ending and mast cells respectively. Some authors suggest that it has a central sedative effect [17]. In that study; MgSO4 injection had marvelous response in most patients in intravenous group while patients in group A not revealed the desired effect that most physicians aim to in asthma attack management. In consistent with those results; Mohammed and his colleague [18] found in their systemic review that intravenous MgSO4 had
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
3
I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx Table 1 Base line parameters before treatment of both groups. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
153.500 157.750 1.385 0.174
10.144 9.244
31.450 31.150 0.254 0.801
3.591 3.884
108.800 108.100 0.193 0.848
12.353 10.533
386.250 355.000 1.131 0.265
87.688 87.102
4.450 4.050 1.125 1.000
1.099 1.146
Table 2 Measured parameters in both groups after 30 minutes of treatment. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
145.000 139.250 1.977 0.055
9.319 9.072
28.450 28.600 0.120 0.905
4.097 3.775
102.600 102.350 0.0773 0.939
10.625 9.821
415.750 386.500 1.076 0.289
88.113 83.840
2.850 2.800 0.131 0.897
1.424 0.951
Table 3 Measured parameters in both groups after one hour of treatment. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
139.500 131.000 3.594 <0.001
8.256 6.609
25.850 26.750 0.807 0.425
4.320 2.489
98.400 97.750 0.224 0.824
10.475 7.691
426.750 411.750 0.555 0.582
87.529 83.387
1.600 1.500 0.281 1.000
0.754 1.100
Table 4 Parameters at base line and after 30 minutes and one hour of treatment in group A.
BP Significance RR Significance Pulse Significance PEFR Significance Fischl’s index Significance
Pre-treatment & after 30 m.
After 30 m. & after 1 h.
Pre-treatment & after 1 h.
Between all
t
p
t
p
t
p
F
p
2.899 Yes 1.533 No 1.702 No 1.061 No 3.359 Yes
0.005
1.976 No 0.718 No 1.188 No 0.396 No 4.299 Yes
0.055
4.787 Yes 2.358 No 2.941 Yes 1.462 No 7.658 Yes
<0.001
11.574 Yes 2.879 No 4.377 Yes 1.138 No 29.469 Yes
<0.001
0.134 0.097 0.295 0.001
0.477 0.240 0.694 <0.001
0.024 0.005 0.152 <0.001
0.064 0.017 0.327 <0.001
Table 5 Parameters at base line and after 30 minutes and one hour of treatment in group B.
BP Significance RR Significance Pulse Significance PEFR Significance Fischl’s index Significance
Pre-treatment & after 30 m.
After 30 m. & after 1 h.
Pre-treatment & after 1 h.
Between all
t
p
t
p
t
p
F
p
6.388 Yes 2.106 Yes 1.786 No 1.165 No 4.957 Yes
<0.001
3.287 Yes 1.830 No 1.649 No 0.955 No 3.906 Yes
0.002
10.527 Yes 4.266 Yes 3.549 Yes 2.105 Yes 8.863 Yes
<0.001
53.246 Yes 8.242 Yes 6.054 Yes 2.249 No 39.459 Yes
<0.001
0.042 0.082 0.251 <0.001
significant effect in respiratory function improvement in asthmatic patients, while nebulized MgSO4 had a mild improving effect on asthmatics’ respiratory functions. Another similar study on 1754 patients; Shan and colleagues [11] who studied 25 clinical trials, revealed that clinical improvement in patients was highly significant in adults after intravenous
0.075 0.107 0.346 <0.001
<0.001 0.001 0.042 <0.001
<0.001 0.004 0.115 <0.001
MgSO4 and also was high in children in addition to decreased hospitalization, while improvement in lung functions after MgSO4 nebulization was in adults no in children. Goodacre et al. [19] in a double-blineded placebo-controlled trial studied 1109 asthmatic patients that enrolled in three groups; intravenous MgSO4, nebulized MgSO4, and control group. They
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
4
I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx
Table 6 Complication in both groups.
Hypotension Nausea Vomiting Arrhythmia Flushing Headache
Conflicts of interest
Group A (20 patients)
Group A (20 patients)
2 1 0 0 2 1
3 2 1 1 0 0
(10%) (5%)
(10%) (5%)
(15%) (10%) (5%) (5%)
revealed that intravenous MgSO4 had a limited role in acute asthma management, while nebulized MgSO4 has no role in its management similar to that in placebo group. In a study by Albuali [20]; he found that intravenous MgSO4 is a good and safe adjunct drug that can be added to conventional bronchodilators for acute and severe asthma attack treatment in children. In contrary to that study; MAGNETIC trial results; concluded that after an hour of nebulized MgSO4 for patients with severe asthma attack; they were significantly improved either adults or children in comparison to control group [21]. Blitz et al. [8] in their study found that; usage of nebulized MgSO4 in addition to B2 agonist is more beneficial in acute asthma treatment than intravenous MgSO4. In a study performed by Abdelnabi and his colleagues [22] to study the effect of nebulized MgSO4 in treatment of asthma exacerbation; they found that MgSO4 not produce significant effect except when added to nebulized salbutamol to give the desired bronchodilator effect. Badawy et al. [14] concluded in their studies on pregnant asthmatic women during exacerbation that adding nebulized MgSO4 to salbutamol nebulization leads to marked improvement in lung functions. As regard complications; most studies revealed no complications [8] while few authers faced some complications like nausea, vomiting, flushing, thirst, hypotension, drowsiness, confusion [1,17,19,23] and rarely loss of deep tendon reflexes, muscle weakness, respiratory depression and cardiac arrhythmias, which can lead to coma and cardiac arrest that may occur due to toxicity [24]. This study has a number of potential limitations. Firstly, the study included few number of patients in each group and more patients were required to be studied. Secondly; different drug concentrations may be needed to be tried to study different drug effect on asthma management. Thirdly; duration of hospitalization didn’t be taken in consideration during follow up period and after treatment. Conclusion MgSO4 is available, cheap, effective and mostly safe drug that used since years in the treatment of acute asthma exacerbation when conventional inhaler treatment produced no effect in controlling the attack. Intravenous MgSO4 use in those patients during exacerbation is beneficial with improvement in clinical state of the patient without evident improvement in PEFR, in contrary to nebulized MgSO4 that showed little improvement in studied patients. Support
No. References [1] W.F.S. Sellers, Inhaled and intravenous treatment in acute severe and lifethreatening asthma, Br. J. Anaesth. 110 (2) (2013) 183–190. [2] K.M. Kew, L. Kirtchuk, C.I. Michell, Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department, Cochrane Database Syst. Rev. 5 (2014), CD010909. [3] T.A. Bradshaw, S.P. Matusiewicz, G.K. Crompton, J.A. Innes, A.P. Greening, Intravenous magnesium sulphate provides no additive benefit to standard management in acute asthma, Respir. Med. 102 (1) (2008) 143–149. [4] M.K. Miller, J.H. Lee, D.P. Miller, l.S.E. Wenze, Recent asthma exacerbations: a key predictor of future exacerbations, Respirat. Med. 101 (3) (2007) 481–489. [5] P. Lange, J. Parner, J. Vestbo, P. Schnohr, G. Jensen, A 15-year follow-up study of ventilatory function in adults with asthma, N. Engl. J. Med. 339 (17) (1998) 1194–1200. [6] M.A. Fischl, A. Pitchenik, L.B. Gardner, An index predicting relapse and need for hospitalization in patients with acute bronchial asthma, N. Engl. J. Med. 305 (14) (1981) 783–789. [7] M.S. Sherman Verceles, C. Avelino, Systemic steroids for the treatment of acute asthma: where do we stand? Clinical, Pulmonary Medicine. 13 (6) (2006) 315– 320. [8] M. Blitz, S. Blitz, R. Hughes, B. Diner, R. Beasley, J. Knopp, et al., Aerosolized magnesium sulfate for acute asthma: a systematic review, Chest 128 (1) (2005) 337–344. [9] K.I. Gourgoulianis, G. Chatziparasidis, A. Chatziefthimiou, P.A. Molyvdas, Magnesium as a relaxing factor of airway smooth muscles, J. Aerosol Med. 14 (3) (2001) 301–307. [10] C. Gontijo-Amaral, M.A. Ribeiro, L.S. Gontijo, A. Condino-Neto, J.D. Ribeiro, Oral magnesium supplementation in asthmatic children: a double-blind randomized placebo-controlled trial, Eur. J. Clin. Nutr. 61 (1) (2007) 54–60. [11] Z. Shan, Y. Rong, W. Yang, D. Wang, P. Yao, J. Xie, et al., Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis, Respir. Med. 107 (3) (2013) 321–330. [12] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: www.ginasthma.org. [13] C.J. Gore, A.J. Crockett, D.G. Pederson, M.L. Booth, A. Bauman, N. Owen, Spirometric standards for healthy adult lifetime nonsmokers in Australia, Eur. Respirat. J. 8 (5) (1995) 773–782. [14] M.S.H. Badawy, M.A.I. Hassanin, The value of magnesium sulfate nebulization in treatment of acute bronchial asthma during pregnancy, Egypt. J. Chest Dis. Tuberculosis 63 (2014) 285–289. [15] R.A. Silverman, H. Osborn, J. Runge, E.J. Gallagher, W. Chiang, J. Feldman, et al., IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial, Chest 122 (2) (2002) 489–497. [16] B.H. Rowe, J.A. Bretzlaff, C. Bourdon, G.W. Bota, C.A. Camargo Jr., Magnesium sulfate for treating exacerbations of acute asthma in the emergency department, Cochrane Database Syst. Rev. 2 (2000), CD001490. [17] H.S. Mangat, G.A. D’Souza, M.S. Jacob, Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma: a clinical trial, Eur. Respirat. J. 12 (2) (1998) 341–344. [18] S. Mohammed, S. Goodacre, Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis, Emerg. Med. J.: EMJ. 24 (12) (2007) 823–830. [19] S. Goodacre, J. Cohen, M. Bradburn, A. Gray, J. Benger, T. Coats, et al., Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial, Lancet Respirat. Med. 1 (4) (2013) 293–300. [20] W.H. Albuali, The use of intravenous and inhaled magnesium sulphate in management of children with bronchial asthma, J. Matern. Fetal Neonatal. Med. 27 (17) (2014) 1809–1815. [21] C. Powell, R. Kolamunnage-Dona, J. Lowe, A. Boland, S. Petrou, I. Doull, et al., Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial, Lancet Respirat. Med. 1 (4) (2013) 301– 308. [22] E.A. Abdelnabi, M.M. Kamel, A.E. Ali, Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma, Egypt. J. Chest Dis. Tuberculosis 61 (2012) 29–34. [23] A.A. Piotrowski, J.S. Kalus, Magnesium for treatment and prevention of atrial tachyarrhythmias, Pharmacotherapy 24 (2004) 879–895. [24] G.K.N.L.D. Monem, Use of magnesium sulfate in asthma in childhood, Pediatr. Ann. 25 (3) (1996) 139–144.
No.
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
Contents lists available at ScienceDirect
Egyptian Journal of Chest Diseases and Tuberculosis journal homepage: www.sciencedirect.com
What to use for bronchial asthma; nebulized or intravenous magnesium sulfate? Ibrahim Salah-Eldin Ibrahim ⇑, Reham Mohamed Elkolaly Chest Department, Faculty of Medicine, Tanta University, Tanta, Egypt
a r t i c l e
i n f o
Article history: Received 20 December 2016 Accepted 19 January 2017 Available online xxxx Keywords: Asthma Magnesium sulfate Nebulized
a b s t r a c t Background: Asthma is characterized by airways narrowing and airflow limitation. The conventional therapy for asthma exacerbation is usually efficient but sometimes patients not respond to it, consequently; other additive drugs may be used as magnesium sulfate(MgSO4) either intravenously or by nebulization. Objective: To compare the bronchodilator effect of MgSO4 via intravenous injection and nebulization in controlling asthma exacerbation. Methods: 40 patients with asthma exacerbation were equally and randomly enrolled in two groups. One group received nebulized MgSO4 (A), and the other group received intravenous MgSO4 (B). Results: Improvement was higher in group B than in group A but without significant change in PEFR also there was no high significant difference in the two group parameters after MgSO4 treatment. Complications were few and manageable in both groups. Conclusion: Intravenous MgSO4 is effective affordable and cheap drug for asthma exacerbation management with good response while nebulized MgSO4 didn’t give the aimed response in these patients. Ó 2017 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction Asthma is one of the common chronic airway diseases that leads to decrease of airflow and characterized by bronchial and bronchioles inflammation with airways smooth muscle contraction and increase mucous synthesis and secretion. Leading to recurrent wheeze, breathing difficulties and coughing either at night or/and early morning [1]. This airways narrowing is often reversible with or without treatment [2]. Asthma morbidity and mortality rates are high and are mostly related to acute exacerbations [3]. So severe asthma attacks must be treated rapidly and effectively to avoid its fatal consequences, to decrease triggering for further future exacerbation [4] and to prevent more decline in lung functions after these attacks [5]. Patients having asthma exacerbations usually need rapid treatment to relieve their suffering, so they use inhaled bronchodilators
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis. ⇑ Corresponding author at: Chest Department, Tanta University Hospitals, Elgharbyia, Tanta, Egypt. E-mail addresses: [email protected] (I.S.-E. Ibrahim), [email protected] (R.M. Elkolaly).
in form of b2 agonists (±anticholinergic) in addition to parental corticosteroids if they are admitted to hospitals [6]. And in spite of that; corticosteroids used in emergency department need a relatively longer time (6–8 h) to produce their antiinflammatory effect and control the acute attack [7], while inhaled b2 agonists give their adequate bronchodilator effect in only two thirds of treated patients and the rest of patients still suffer from the attack effect [6]. For that reason; physicians tried to use other additive drugs to give rapid bronchodilator effect to manage asthma early before patients deterioration. Magnesium sulfate (MgSO4) is the drug that was previously used as an additive line of treatment in many cases with acute severe asthma [8]. Magnesium sulfate was studied and supposed to reduce intracellular calcium influx via closure of calcium channels and inhibits calcium release from endoblasmic reticulum [9], it also inhibits inflammatory mediator release from mast cells and inhibits acetyl choline release from nerve endings, that leads finally to muscle relaxation [10]. Some physicians used magnesium via nebulization-especially in children-during severe asthma attacks to achieve bronchodilatation and to avoid the systemic side effects of the intravenous drug
http://dx.doi.org/10.1016/j.ejcdt.2017.01.005 0422-7638/Ó 2017 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
2
I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx
[11]. While others used it parentrally to give rapid action and relieve of the bronchoconstriction, but this may lead to some side effects like arrhythmia flushing, hypotension and renal intoxication in high doses [2]
Aim of the study To compare the bronchodilator effect of magnesium sulfate via intravenous route versus nebulization in patients with asthma exacerbation.
Patients and methods The study was conducted from March 2016 through July 2011 at Tanta University Hospital, Tanta, Egypt. This study was conducted on 40 patients with acute bronchial asthma exacerbation with the following inclusion criteria: – Patient with acute exacerbation of asthma according clinical assessment of asthma using GINA guidelines [12]. – Patient not controlled on conventional therapy for acute exacerbation. Exclusion criteria were as follow Patients with stable asthma, COPD, pneumonia, heart failure or renal insufficiency, in need for endotracheal intubation, inability to do peak flow meter, pregnant or breastfeeding mothers or had received oral, inhaled or parenteral bronchodilators in the past 6 h, or steroids in the past 12 h. All patients were subjected to history taking, clinical examination and PEF% (wright peak flow meter) and scoring was done according guidelines [13]. All patients received the conventional treatment of acute exacerbation as follow: – Supplemental oxygen to have O2 sat. greater than 90%. – Nebulization of 1 ml Farcolin respirator solutionÒ mixed with 9 ml saline for two sessions with interval of 15 min [Farcolin respirator solutionÒ: each 20 ml of Farcolin contains Salbutamol sulfate 0.121 gm. Made in Egypt, by: Pharco Pharmaceuticals – Alexandria]. – Intravenous Solu-CortefÒ 100 mg once [Solu-CortefÒ: vial contains powder of 100 mg Sodium hydrocortisone hemisuccinate dissolved with 2 ml solvent of sterile bacteriostatic water for IV injection. Manufactured by: Egyptian Int. Pharmaceutical Industries co. (e.i.p.i.co.) – Egypt. Under license of: Pfizer]. Patients were assisted clinically every 15 min. If the patient didn’t improve after one hour; he was randomly enrolled in one of the two groups that contained 20 patients in each group. Each patient was evaluated clinically for blood pressure (BP) and Fischl index that consists of seven items (pulse, respiratory rate (RR), pulsus paradoxicus (PP), PEF%, dyspnea, wheeze and accessory muscle use) and scored 0–1 for each [6]. These pre-treatment parameters were labeled (level zero) before MgSO4 treatment. Group A (nebulization group): four doses of nebulization solution with 15 min apart, each dose contained 1 ml MgSO4 mixed with 9 ml saline, to have isotonic mixture to avoid hyperosmolar broncho-constriction [14]. Group B (injection group): 2 g of MgSO4 diluted in 30 ml saline to have a 50 ml solution for slow intravenous injection along 20– 30 min [15].
Magnesium Sulfate USP2Ò 1 g/10 ml [Magnesium SulfateÒ: Sterile ampoule 10 ml. 100 mg/ml = 0.41 mMol/ml. Manufactured by: Egyptian int. Pharmaceutical industries co. (e.i.p.i.co.) – Egypt]. Patients were assisted after 30 min (level 1) then after 1 h (level 2) N.B.; Patients who deteriorated were re-evaluated for other management procedures. Statistical analysis All data were statistically analysed by the SPSS software for Windows (IBM SPSS Statistics 21.0). P value <0.05 was significant. Results Forty patients with acute asthma were enrolled in this study; they were divided into two groups. Group A consisted of 20 patients (12 female and 8 male) that received nebulized MgSO4 and group B that consisted of 20 patients (11 female and 9 male) who received intravenous MgSO4. There was no statistically significant difference between the two groups as regard age, pre-treatment pulse, BP, RR and PEFR, Fischl’s index) (Table 1). After 30 min of treatment; patients were re-evaluated (Table 2). These parameters improvement showed no significance difference between the two groups, but the improvement in group B was more than that in group A. Another re-evaluation was done after one hour as follow (Table 3) Which revealed improvement in group B than that in group A; but also without significant difference. The significance of changes in group A as regard pre-treatment, after 30 min and after one hour were as follow (Table 4). The significance of changes in group B as regard pre-treatment, after 30 min and after one hour were as follow (Table 5). As regard results in Tables 4 and 5; the clinical parameter in group A showed mild improvement after I hour as regard BP and pulse with less improvement in other parameters. But in group B; there was significant improvement in BP and RR after 30 min while the improvement was more significant in all parameters after I hour. There were minor complications that reported in 3 patients in group A including headache, flushing, hypotension and nausea. The adverse effects in group B were recorded in 5 patients; including nausea, vomiting, arrhythmia and hypotension (Table 6). Discussion Asthma is one of the chronic respiratory disorders that has repeated episodes of exacerbations that may be mild, moderate and even severe attack which may lead to hospital or ICU admission, intubation or even death [8]. Intravenous magnesium sulfate was used as a possible additive drug for asthma exacerbation management especially in severe attacks [16]. Magnesium is an important ion in cellular and tissue homeostasis including airways musculature via its role for different enzymes action [16]. MgSO4 helps smooth muscle relaxation via facilitating calcium ions influx to sarcoplasmic reticulum [17]. It also inhibits both acetyl choline and histamine release from nerve ending and mast cells respectively. Some authors suggest that it has a central sedative effect [17]. In that study; MgSO4 injection had marvelous response in most patients in intravenous group while patients in group A not revealed the desired effect that most physicians aim to in asthma attack management. In consistent with those results; Mohammed and his colleague [18] found in their systemic review that intravenous MgSO4 had
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
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I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx Table 1 Base line parameters before treatment of both groups. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
153.500 157.750 1.385 0.174
10.144 9.244
31.450 31.150 0.254 0.801
3.591 3.884
108.800 108.100 0.193 0.848
12.353 10.533
386.250 355.000 1.131 0.265
87.688 87.102
4.450 4.050 1.125 1.000
1.099 1.146
Table 2 Measured parameters in both groups after 30 minutes of treatment. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
145.000 139.250 1.977 0.055
9.319 9.072
28.450 28.600 0.120 0.905
4.097 3.775
102.600 102.350 0.0773 0.939
10.625 9.821
415.750 386.500 1.076 0.289
88.113 83.840
2.850 2.800 0.131 0.897
1.424 0.951
Table 3 Measured parameters in both groups after one hour of treatment. BP
Group A Group B t p
RR
Pulse
PEFR
Fischl’s index
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
139.500 131.000 3.594 <0.001
8.256 6.609
25.850 26.750 0.807 0.425
4.320 2.489
98.400 97.750 0.224 0.824
10.475 7.691
426.750 411.750 0.555 0.582
87.529 83.387
1.600 1.500 0.281 1.000
0.754 1.100
Table 4 Parameters at base line and after 30 minutes and one hour of treatment in group A.
BP Significance RR Significance Pulse Significance PEFR Significance Fischl’s index Significance
Pre-treatment & after 30 m.
After 30 m. & after 1 h.
Pre-treatment & after 1 h.
Between all
t
p
t
p
t
p
F
p
2.899 Yes 1.533 No 1.702 No 1.061 No 3.359 Yes
0.005
1.976 No 0.718 No 1.188 No 0.396 No 4.299 Yes
0.055
4.787 Yes 2.358 No 2.941 Yes 1.462 No 7.658 Yes
<0.001
11.574 Yes 2.879 No 4.377 Yes 1.138 No 29.469 Yes
<0.001
0.134 0.097 0.295 0.001
0.477 0.240 0.694 <0.001
0.024 0.005 0.152 <0.001
0.064 0.017 0.327 <0.001
Table 5 Parameters at base line and after 30 minutes and one hour of treatment in group B.
BP Significance RR Significance Pulse Significance PEFR Significance Fischl’s index Significance
Pre-treatment & after 30 m.
After 30 m. & after 1 h.
Pre-treatment & after 1 h.
Between all
t
p
t
p
t
p
F
p
6.388 Yes 2.106 Yes 1.786 No 1.165 No 4.957 Yes
<0.001
3.287 Yes 1.830 No 1.649 No 0.955 No 3.906 Yes
0.002
10.527 Yes 4.266 Yes 3.549 Yes 2.105 Yes 8.863 Yes
<0.001
53.246 Yes 8.242 Yes 6.054 Yes 2.249 No 39.459 Yes
<0.001
0.042 0.082 0.251 <0.001
significant effect in respiratory function improvement in asthmatic patients, while nebulized MgSO4 had a mild improving effect on asthmatics’ respiratory functions. Another similar study on 1754 patients; Shan and colleagues [11] who studied 25 clinical trials, revealed that clinical improvement in patients was highly significant in adults after intravenous
0.075 0.107 0.346 <0.001
<0.001 0.001 0.042 <0.001
<0.001 0.004 0.115 <0.001
MgSO4 and also was high in children in addition to decreased hospitalization, while improvement in lung functions after MgSO4 nebulization was in adults no in children. Goodacre et al. [19] in a double-blineded placebo-controlled trial studied 1109 asthmatic patients that enrolled in three groups; intravenous MgSO4, nebulized MgSO4, and control group. They
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005
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I.S.-E. Ibrahim, R.M. Elkolaly / Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx
Table 6 Complication in both groups.
Hypotension Nausea Vomiting Arrhythmia Flushing Headache
Conflicts of interest
Group A (20 patients)
Group A (20 patients)
2 1 0 0 2 1
3 2 1 1 0 0
(10%) (5%)
(10%) (5%)
(15%) (10%) (5%) (5%)
revealed that intravenous MgSO4 had a limited role in acute asthma management, while nebulized MgSO4 has no role in its management similar to that in placebo group. In a study by Albuali [20]; he found that intravenous MgSO4 is a good and safe adjunct drug that can be added to conventional bronchodilators for acute and severe asthma attack treatment in children. In contrary to that study; MAGNETIC trial results; concluded that after an hour of nebulized MgSO4 for patients with severe asthma attack; they were significantly improved either adults or children in comparison to control group [21]. Blitz et al. [8] in their study found that; usage of nebulized MgSO4 in addition to B2 agonist is more beneficial in acute asthma treatment than intravenous MgSO4. In a study performed by Abdelnabi and his colleagues [22] to study the effect of nebulized MgSO4 in treatment of asthma exacerbation; they found that MgSO4 not produce significant effect except when added to nebulized salbutamol to give the desired bronchodilator effect. Badawy et al. [14] concluded in their studies on pregnant asthmatic women during exacerbation that adding nebulized MgSO4 to salbutamol nebulization leads to marked improvement in lung functions. As regard complications; most studies revealed no complications [8] while few authers faced some complications like nausea, vomiting, flushing, thirst, hypotension, drowsiness, confusion [1,17,19,23] and rarely loss of deep tendon reflexes, muscle weakness, respiratory depression and cardiac arrhythmias, which can lead to coma and cardiac arrest that may occur due to toxicity [24]. This study has a number of potential limitations. Firstly, the study included few number of patients in each group and more patients were required to be studied. Secondly; different drug concentrations may be needed to be tried to study different drug effect on asthma management. Thirdly; duration of hospitalization didn’t be taken in consideration during follow up period and after treatment. Conclusion MgSO4 is available, cheap, effective and mostly safe drug that used since years in the treatment of acute asthma exacerbation when conventional inhaler treatment produced no effect in controlling the attack. Intravenous MgSO4 use in those patients during exacerbation is beneficial with improvement in clinical state of the patient without evident improvement in PEFR, in contrary to nebulized MgSO4 that showed little improvement in studied patients. Support
No. References [1] W.F.S. Sellers, Inhaled and intravenous treatment in acute severe and lifethreatening asthma, Br. J. Anaesth. 110 (2) (2013) 183–190. [2] K.M. Kew, L. Kirtchuk, C.I. Michell, Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department, Cochrane Database Syst. Rev. 5 (2014), CD010909. [3] T.A. Bradshaw, S.P. Matusiewicz, G.K. Crompton, J.A. Innes, A.P. Greening, Intravenous magnesium sulphate provides no additive benefit to standard management in acute asthma, Respir. Med. 102 (1) (2008) 143–149. [4] M.K. Miller, J.H. Lee, D.P. Miller, l.S.E. Wenze, Recent asthma exacerbations: a key predictor of future exacerbations, Respirat. Med. 101 (3) (2007) 481–489. [5] P. Lange, J. Parner, J. Vestbo, P. Schnohr, G. Jensen, A 15-year follow-up study of ventilatory function in adults with asthma, N. Engl. J. Med. 339 (17) (1998) 1194–1200. [6] M.A. Fischl, A. Pitchenik, L.B. Gardner, An index predicting relapse and need for hospitalization in patients with acute bronchial asthma, N. Engl. J. Med. 305 (14) (1981) 783–789. [7] M.S. Sherman Verceles, C. Avelino, Systemic steroids for the treatment of acute asthma: where do we stand? Clinical, Pulmonary Medicine. 13 (6) (2006) 315– 320. [8] M. Blitz, S. Blitz, R. Hughes, B. Diner, R. Beasley, J. Knopp, et al., Aerosolized magnesium sulfate for acute asthma: a systematic review, Chest 128 (1) (2005) 337–344. [9] K.I. Gourgoulianis, G. Chatziparasidis, A. Chatziefthimiou, P.A. Molyvdas, Magnesium as a relaxing factor of airway smooth muscles, J. Aerosol Med. 14 (3) (2001) 301–307. [10] C. Gontijo-Amaral, M.A. Ribeiro, L.S. Gontijo, A. Condino-Neto, J.D. Ribeiro, Oral magnesium supplementation in asthmatic children: a double-blind randomized placebo-controlled trial, Eur. J. Clin. Nutr. 61 (1) (2007) 54–60. [11] Z. Shan, Y. Rong, W. Yang, D. Wang, P. Yao, J. Xie, et al., Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis, Respir. Med. 107 (3) (2013) 321–330. [12] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: www.ginasthma.org. [13] C.J. Gore, A.J. Crockett, D.G. Pederson, M.L. Booth, A. Bauman, N. Owen, Spirometric standards for healthy adult lifetime nonsmokers in Australia, Eur. Respirat. J. 8 (5) (1995) 773–782. [14] M.S.H. Badawy, M.A.I. Hassanin, The value of magnesium sulfate nebulization in treatment of acute bronchial asthma during pregnancy, Egypt. J. Chest Dis. Tuberculosis 63 (2014) 285–289. [15] R.A. Silverman, H. Osborn, J. Runge, E.J. Gallagher, W. Chiang, J. Feldman, et al., IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial, Chest 122 (2) (2002) 489–497. [16] B.H. Rowe, J.A. Bretzlaff, C. Bourdon, G.W. Bota, C.A. Camargo Jr., Magnesium sulfate for treating exacerbations of acute asthma in the emergency department, Cochrane Database Syst. Rev. 2 (2000), CD001490. [17] H.S. Mangat, G.A. D’Souza, M.S. Jacob, Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma: a clinical trial, Eur. Respirat. J. 12 (2) (1998) 341–344. [18] S. Mohammed, S. Goodacre, Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis, Emerg. Med. J.: EMJ. 24 (12) (2007) 823–830. [19] S. Goodacre, J. Cohen, M. Bradburn, A. Gray, J. Benger, T. Coats, et al., Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial, Lancet Respirat. Med. 1 (4) (2013) 293–300. [20] W.H. Albuali, The use of intravenous and inhaled magnesium sulphate in management of children with bronchial asthma, J. Matern. Fetal Neonatal. Med. 27 (17) (2014) 1809–1815. [21] C. Powell, R. Kolamunnage-Dona, J. Lowe, A. Boland, S. Petrou, I. Doull, et al., Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial, Lancet Respirat. Med. 1 (4) (2013) 301– 308. [22] E.A. Abdelnabi, M.M. Kamel, A.E. Ali, Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma, Egypt. J. Chest Dis. Tuberculosis 61 (2012) 29–34. [23] A.A. Piotrowski, J.S. Kalus, Magnesium for treatment and prevention of atrial tachyarrhythmias, Pharmacotherapy 24 (2004) 879–895. [24] G.K.N.L.D. Monem, Use of magnesium sulfate in asthma in childhood, Pediatr. Ann. 25 (3) (1996) 139–144.
No.
Please cite this article in press as: I.-S.E. Ibrahim, R.M. Elkolaly, What to use for bronchial asthma; nebulized or intravenous magnesium sulfate?, Egypt. J. Chest Dis. Tuberc. (2017), http://dx.doi.org/10.1016/j.ejcdt.2017.01.005