Introduction

        Asthma is one of the commonest diseases in the United Kingdom affecting approximately 5.1 million people (7.8% of the adult population) and is responsible for approximately 4 deaths per day (1,2,3). The management of asthma is mainly with nebulised ß2 agonists, ipratropium bromide and with oral or intravenous steroids. Intravenous salbutamol, aminophylline, intubation and ventilation may be required for patients with severe or life threatening asthma. In the past decade there has been recognition that intravenous magnesium has a use in patients who present with acute severe asthma. This has been reflected in recent asthma guidelines both in the United Kingdom (4,5) and across the Atlantic Ocean (6).
 

Objectives

         My objective was to determine if nebulised magnesium has an effect in acute asthma and whether it should be used in addition or instead of some of the currently recommended agents. .

Applied Physiology

    
       Magnesium is the second commonest intracellular cation in human cells (7). It has a wide variety of actions of relevance to airway bronchodilatation. It has an important role in inhibition of vascular (8) and bronchial (9) smooth muscle contraction. It achieves this effect by competition with calcium entry through voltage dependent channels on the cell membranes (10,11). It facilitates calcium uptake into the sarcoplasmic reticulum, inhibiting inward current and calcium release (12).
It inhibits acetylcholine release from cholingeric nerve terminals and histamine release from mast cells (13). Magnesium also stimulates nitric oxide formation and prostacyclin synthesis (14). Low dietary intake of magnesium has been associated with wheezing, airway hyper-reactivity and impairment of FEV1 (15). It has been known since 1938 that magnesium is helpful in the treatment of asthma (16). There has been much work on the effect of intravenous magnesium on asthma resulting in two meta-analysis (17,18). Magnesium may augment the effect of ß2 agonists by regulating components of the ß receptor adenylate cyclase complex (19). This has been proven experimentally in smooth muscle (20,21)..

         
Method

      Search Strategy A literature search to find studies about the use of nebulised magnesium in asthma was performed using the Dialog Datastar interface. An advanced search using Medline then EMBASE databases was used as well as an easy search (see Appendix 2). The Cochrane database was searched, and then Google and PubMed search engines were also used to check for any additional papers. The journals Chest, Thorax, Journal of Accident and Emergency Medicine/Emergency Medical Journal, Annals of Emergency Medicine and Academic Emergency Medicine from 1990 to 2005 were hand searched for papers, letters or abstracts published from scientific meetings with reference to use of nebulised magnesium in asthma. The references of the all papers found were then examined to find any additional papers not already found in the initial search. The corresponding authors of the principal papers and correspondence letters (23-38) as well as other experts in this topic were contacted (22) by email or posted mail..

Search Results

      Search Results(see Appendix 1)
The Medline search yielded 19 papers, 7 of which were relevant and of sufficient quality to include, 3 Russian papers were excluded as only an abstract was available in English and they were only indirectly relevant by demonstrating ability to inhibit bronchoconstriction by chemicals in an experimental setting.
One additional relevant paper was found on both the EMBASE and easy searches. Seven papers were found by searching the references, 2 of these were in abstract format only. Two additional abstracts were found on hand searching and the unpublished systematic review was found after a response from writing to the principal authors. .

Search Summary

      The search yielded 11 prospective studies directly investigating use of nebulised magnesium sulphate as a bronchodilator in asthma patients and one systematic review. Seven papers involved an adult population, 3 paediatric and 1 paper did not specify the age of patients. These form the focus of the review. There was an additional 6 studies found demonstrating the ability of magnesium to inhibit bronchoconstriction caused by other agents such as histamine, methacholine, AMP and metabisulfite..

Hughes

     Hughes et al (23) This was a randomised double blind placebo controlled trial with 52 adult patients presenting acutely to 2 emergency departments in New Zealand. They chose to study a group of adult patients with acute severe asthma, entry criteria was a peak flow <50% predicted after 2.5mg nebulised salbutamol. The randomisation process was valid and successful; the magnesium and saline groups had similar clinical and demographic features. The patients, investigators and healthcare workers were effectively blind as the syringes were unmarked. The authors have accounted for all the patients who entered the trial, six were excluded, four on the basis of COPD and two with pneumonia. Twenty-eight patients had 3 nebulisations with 2.5mg salbutamol and 151mg magnesium sulphate at 30 minutes intervals, with the 24 controls having 3 nebulisations with 2.5mls of normal saline and 2.5mg salbutamol. All patients received 100mg intravenous hydrocortisone. FEV1 was measured at 30, 60 and 90 minutes from the time of the first nebulisation and the difference was greatest at 90 minutes. The treatment effect was significant with a difference of 0.37 L between the mean FEV1 of the groups with p=0.003. The relative risk of admission was 0.61 (95%CI 0.37-0.99), p=0.04. Five patients discharged in the magnesium group had a FEV1<50% predicted, compared to one in the normal saline group. The greatest improvement in FEV1 was seen in the patients with FEV1 <30% with life threatening asthma. There was no difference between the groups in change of blood pressure or heart rate and no clinically significant adverse events were recorded. The strengths of this study were that it targeted the group of acute asthmatic patients most likely to benefit from the intervention in an accident and emergency department clinical setting. Isotonic magnesium sulphate solution was used to avoid adverse bronchoconstriction that is associated with the use of hypotonic or hypertonic solutions (24,25). Weakness of the study is that isotonic magnesium was compared to Salbutamol alone but the recommended treatment guidelines for severe acute asthma include nebulised Salbutamol and Ipratropium (26). The study was limited as it was small, a larger study would have been more precise with narrower confidence intervals..

Mahagan

     Mahagan et al (27) This was a randomised double blind controlled trial with 62 children between 5-17 years presenting to an emergency department in the USA with mild/moderate asthma, peak flows 45-75% predicted. A relatively low dose of isotonic magnesium sulphate solution was given with albuterol and compared with albuterol and saline, both groups also received 2mg/Kg prednisolone. There was a statistically significant difference in FEV1 at 10 minutes between the magnesium group 1.41±0.53Land saline group 1.13±0.34L, p=0.03. There was a sustained improvement in magnesium group although the difference was no longer statistically significant at 20 minutes, magnesium group 1.44±0.62L and saline group 1.18±0.33L, p=0.06. 2 patients were admitted from the magnesium group and 1 from the saline group. This was in an urban environment were 97% of the children were Afro-American. Patients were only followed up for 20 minutes after the therapy. It was well designed although had several limitations e.g. its size and the exclusion of the severe asthmatic patients..

Nannini

     Nannini et al (28) This was a multi-centred randomised controlled trial with 35 adult patients presenting acutely to 4 emergency departments in Argentina. They did not discuss how their patients were randomised, but the baseline demographics and clinical parameters were similar. Patients recruited had acute severe asthma with mean average PEF of 198 L/min for the magnesium group, 195 L/min for the control group and had a similar average percentage predicted PEF, 38% for both groups. All patients were accounted for, three patients enrolled more than once but only the results from the initial visit was used. The blinding was effective as identical vials were used. None of the patients were able to distinguish the magnesium sulphate solution and none complained of any adverse effects.
The intervention group had a mixture of nebulised isotonic 225mg magnesium sulphate with 2.5mg salbutamol, PEFR was measured at 10 and 20 minutes. There was no statistically significant difference between the absolute values of PEF between the magnesium and saline groups although there was a difference between the % increase in PEF. The confidence intervals were relatively wide indicating poor precision due to the small sample size. .

Mangat

     Mangat et al (29) This was a randomised double blind controlled trial with 33 adult patients in an acute emergency department in India. They also chose to study an acute group of patients with PEF <300L/min and Fischl index was used as an outcome measure of asthma severity.
 

The author describes the study as randomised double blinded though he gives no information on how this was done, but the two groups of patients were demographically and clinically similar at the start of the trial. All the patients were accounted for at its conclusion with no missing data or drop outs. One patient in each group developed transient hypotension that resolved spontaneously, two patients developed fine tremors of the hand and an additional one developed palpitations.
Patients in the magnesium group received 4 nebulisations of 95mg magnesium sulphate 20 minutes apart and the control group received 4 nebulisations of 2.5mg salbutamol. PEF and Fischl index were measured at 20, 40, 60, 90 and 120 minutes. All patients received 100mg intravenous hydrocortisone. Final PEF increased by 35% in the magnesium group and 42% in the salbutamol group. The study was limited by its size and broad confidence intervals. This study showed that nebulised magnesium has a bronchodilatory effect in asthma similar to salbutamol but does not indicate how it should supplement the current agents..

Meral

     Meral et al (30) This was a prospective controlled trial with 40 children aged 8-13 years presenting to a paediatric allergy department in Turkey. There was no description of randomisation or blinding although the two groups had similar baseline characteristics. The patients included in the magnesium and saline groups had mean PEFR of 59.77% and 66.60% of predicted values respectively after one hour. The authors have included moderate as well as severe asthmatics as PEFR <75% predicted was used.
In this study magnesium was compared with oses of both were used. PEFR and respiratory scores were measured at 5, 15, 30, 60, 180 and 360 minutes.
 

The ratio of increase in PEFR % and ratio of decrease of respiratory scores were maximal in the magnesium group at 1 hour 42.63% (±20.21) and 79.97%(±19.18) respectively. Although these changes were statistically significant, improvements were greater in the salbutamol group at all the times of testing. Patients were followed up for 6 hours, the effect of the salbutamol was sustained but the effects of the magnesium was short term with ratio of increase in PEFR % 14.54% (±23.42) and ratio of decrease of respiratory score % of 30.80%(±34.79) at 6 hours.

Bessmertny

     Bessmertny et al. (31) This was a prospective randomised double blind placebo controlled trial with 74 adult patients presenting acutely to an emergency department in New York, USA. They studied mild, moderate and severe asthmatics with peak flow 40- 80% predicted. Randomisation was effectively performed by a third party using a computer generated random table into two groups with similar baseline characteristics, mean PEFR of the control and magnesium groups was 52% and 50% of predicted values respectively. Healthcare workers, study personnel and patients were blind to treatment although some patients complained of a bitter taste and burning in the throat. There were three patients in each group who were withdrawn due to inability to perform spirometry or previous participation. Power calculations were performed prospectively to calculate sample size.
Patients received 3 ions of 2.5mg albuterol at 20 minutes intervals followed by either 384mg of isotonic magnesium sulphate or isotonic normal saline. The study showed that the mean FEV1 was no greater in the magnesium group, but actually showed more improvement in the normal saline group after 25 minutes of the study. This study failed to demonstrate benefit in the magnesium group because the more severe life threatening asthmatics were excluded and both groups were treated with a relatively high dose of 7.5mg nebulised salbutamol..

Hill

     Hill et al. (32) This was a prospective randomised controlled trial with 20 patients with mild/moderate stable asthma with a mean FEV1 of 66.7% being compared with 20 nonsmoking patients without asthma in a non-acute setting in the UK. One asthmatic patient dropped out after developing bronchoconstriction after the maximum dose of magnesium.
The patients were given nebulisations with 0, 90, 135, 180, 360mg magnesium dissolved in 3mls of normal saline on 5 different mornings, measurements of Sgaw, FEV1, FVC, Vmax25 and PEF were made at 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 minutes post-nebulisation. The results demonstrated no significant bronchodilator effect, indeed a bronchoconstrictive effect when 360mg magnesium sulphate was given. This study used hypertonic and hypotonic magnesium sulphate solution resulting in adverse bronchoconstriction. Beasley et al (30), describes how osmolality, acidity, preservatives as well as bacterial contamination can all result in adverse reactions to nebuliser solutions. The patients studied had very mild disease and mild bronchospasm so a significant bronchodilatory effect was more difficult to demonstrate..

Plaisance

     Plaisance et al. (Abstract) (34) This was a randomised double blind controlled pre-hospital trial with 84 patients presenting with acute exacerbations of asthma in Paris, France. The patients were divided into 2 groups: mild with a Fischl index <4 and severe with Fischl index > 4. The mild group were treated with 0.5mg subcutaneous terbutaline and 20mg intravenous dexamethasone, the severe group an additional 0.5mg/h intravenous salbutamol initially and 0.5mg subcutaneous terbutaline at 20 minutes. Both groups were then randomised to receive either magnesium sulphate or normal saline. 5mls of inhaled 15% MgSO4 (750mg) was given to both mild and severe groups initially, the severe group received an additional dose at 20 minutes and the control group received 5mls normal saline instead.
The magnesium group had a relatively lower Fischl score after treatment than the placebo group, more marked in the severe asthmatics. The difference in the severe asthmatic group between the magnesium and placebo was statistically significant at 40 minutes (p<0.05)..
 

Randall

     Randall et al. (Abstract) (35) This was a prospective cross over study from America, 9 asthmatic patients were given treatment with albuterol 0.5ml with 2g magnesium sulphate or albuterol 0.5ml with 2.5mls normal saline on consecutive mornings. There was no significant difference in percentage changes of FEV1 post-nebulisation.
A hypertonic solution of magnesium was used that may have resulted in sub-optimal bronchodilatation. This study is limited by its small size and the non-acute presentation of the mildly asthmatic patients included..

Clark

     Clark et al. (Abstract) (36) This was a prospective randomised double blind placebo controlled study with 22 children with acute presentation in America. The children received 3 treatments of either nebulised magnesium sulphate (3.8mg/Kg/dose, maximum dose 200mg) with albuterol (0.03mL/Kg/dose, maximum dose 1mL) or normal saline with albuterol at 30 minutes intervals. They do not give any explanation for using isotonic solution, it must be assumed that the osmolality was not taken into account.
The magnesium group had lower PEFR, this difference was statistically significantly after the third treatment, p<0.05..

Aggarwai

     Aggarwai et al. (Abstract) (37) This study was published as an abstract so not much information is included. There is no information on how the patients were randomised to the treatment or control groups. Minimal information has been given about the patients, demographics and asthma severity only. The authors describe the solution as isotonic but do not give any information about osmolality or percentage.
 

Salbutamol 0.5mg with magnesium sulphate 500mg was compared to salbutamol 0.5mg alone, given 3 times at 20 minutes intervals. The outcome measure was increase in PEFR at 15, 60, 75 and 120 minutes. There was no difference in the increase in PEFR at any time interval and no difference in admission rates although no numerical results were included in the abstract..
 

Rowe

     Rowe et al. (38) This is a meta-analysis of 6 randomised controlled trials (23, 27-31) with a total of 296 patients. They used the Cochrane approach in which all the studies were rated B in concealment allocation due to the lack of information given regarding blinding and randomisation. Using the Jadad scale, Meral et al. (28) scored 1 and the other trials scored 3. They have also included subgroup analyses. The results were limited by the heterogeneity of both treatment and outcome measures.
The meta-analysis subgroup analysis demonstrated the effect of magnesium sulphate on pulmonary function was greatest in the severe group and in the adult groups. The results also demonstrated that relative risk of admission was only statistically significant for the adult severe group..
 

Discussion

Outcome Measurement
FEV1 Versus PEFR
I note that 6 of the studies (23,27,31,32,35,36) used FEV1 as the pulmonary function test and the other 5 used peak expiratory flow (28-30,34,37). The FEV1 is regarded as the most reproducible pulmonary function parameter and is linearly related to severity of airways disease (39).

Admission
Five of the studies also measured admission as an outcome measure (23,27-29,37). Using the formulas below, relative risk reduction/increase was calculated for the 4 studies that gave sufficient data. ARR= CER– EER ARI= CER–EER RRR = ARR/CER RRI =ARR/CER NNT = 100/ARR (when ARR expressed as %)

Doses and Types of Therapeutic Agents
Nebulised Magnesium and ß2 Agonist or Nebulised Saline and ß2 Agonist
Six of the studies compared a mixture of nebulised magnesium and ß2 agonist with nebulised saline and ß2 agonist as control although they all compared different doses of magnesium and used different doses as ß2 agonist as the adjunct (23,27,28,31,35,36). Table 4 demonstrates that a relatively higher dose of ß2 agonist was used by Hughes et al. (23) and Mahagan et al.(27).
 

 Nebulised Magnesium or Nebulised Salbutamol
Two studies compared nebulised magnesium with nebulised salbutamol directly (Mangat et al. [29] and Meral et al. [30]). Mangat used relatively higher doses of both magnesium (380mg) and salbutamol (10mg) as this study had a more severe group of asthmatics. Meral used a relatively higher dose of magnesium (138mg) in relation to salbutamol (2.5mg), with a higher magnesium/salbutamol ratio (55.2) in comparison to Mangat (38).
Aggarwai et al. (37) was the only study that compared a nebulised salbutamol and magnesium mixture with salbutamol alone. Plaisance et al. (34) compared nebulised magnesium with nebulised saline and transcutaneous and intravenous ß2 agonists were given to both groups.

Steroids
Four of the studies used steroids as part of the treatment. Hughes et al. (23) and Mangat et al. (29) used 100mg intravenous hydrocortisone for all patients. Mahagan et al. (27) used 2mg/Kg prednisolone for all patients and Plaisance et al. (34) used 20mg intravenous dexamethasone for all patients. Bessmertney et al. (31) used 2mg/Kg intravenous hydrocortisone for only one patient who failed to respond to the third dose of albuterol. Steroids should have been included as part of optimal management as recommended for moderate and severe asthmatics (4).

Magnesium- Amount and Concentration
The studies used different amounts of magnesium sulphate and a variety of concentrations. Most of the studies attempted to use isotonic solutions, Hughes et al. (23), Nannini et al. (28), Mangat et al. (29), Meral et al. (30) and Clark et al. (36), Aggarwai et al. (37) did not describe the concentration of solution used but Plaisance et al. (34) and Randall E et al. (35) used hypertonic solutions. Bessmertney et al. (31) reported that they had calculated an isotonic solution of magnesium sulphate, the 64mg/ml of magnesium sulphate does not correspond to a concentration of 260mmol/L given, but a calculated concentration of 531.7mmol/L, which is in fact hypertonic. All the patients in Hill et al’s. (32) study received hypertonic magnesium solutions as the magnesium was dissolved in normal s aline.
 

Adverse Effects
None of the patients in the 11 studies had any serious side effects noted. The inhaled route would be associated with fewer side effects than may result from systemic intravenous therapy such as flushing, sedation, hypotension and nausea.

Setting
Nine of the studies involved patients presenting with acute clinical exacerbations of asthma (23,27-30,34,36,37). Two of the studies were experimental with non-acute patients, Hill et al. (32) and Randall et al (35).
There were a number of other studies which showed the effect of magnesium in a non-acute experimental setting using histamine/methacholine challenge (40-45). .
 

Conclusions

        Six of the prospective studies demonstrated a significant beneficial effect of using nebulised magnesium in asthma. These studies used patients with greater severity of asthma. It has been shown that intravenous magnesium is of most benefit in the refractory asthmatics not responsive to initial nebulised ß2 agonists with ipratropium and it appears that nebulised magnesium may have a similar role. Five studies showed no significant benefit from using nebulised magnesium although there were weaknesses in the methodology of these studies such as the severity of the asthma and the concentration of magnesium sulphate solutions used. Due to publication bias there is likely to be more negative unpublished studies. The effect of magnesium was greater when used with ß2 agonist. Magnesium may have an additive effect with salbutamol’s bronchodilator effect by increasing the affinity of agonist to ß2 receptors, (32-34) other mechanisms include potentiation of the ß agonist effects on magnesium requiring enzymes, e.g. adenyl cyclase or sodium-potassium ATPase (46).
On the basis of the current evidence available it would not be advisable to use nebulised magnesium as all of the reviewed studies were relatively small, It could possibly be used in addition to nebulised ipratropium, or as an alternative to intravenous magnesium, as it has less systemic adverse effects. A larger multi-centre study specifically looking at patients with severe asthma exacerbations comparing this to a control on optimal current therapy, including nebulised salbutamol, ipratropium, systemic corticosteroids and intravenous magnesium is needed. In addition to shortterm pulmonary function and intubation other long-term valid outcome measures should be used such as length of hospital/intensive care admission and relapse. A large study has not been done as nebulised magnesium would not be better than currently used intravenous magnesium in severe asthmatics as air entry is poor and the reported adverse effects of intravenous magnesium are minimal. The case for this recommendation has not yet been proven.

Abbreviations as they appear in the text and
illustrations.

AMP Adenosine monophosphate
ARR Absolute risk reduction
ARI Absolute risk increase
ATPase Adenosine triphosphatase
ß beta
CER Control event rate
CI Confidence intervals
COPD Chronic obstructive pulmonary disease
EER Experimental event rate
e.g. for example
FEV1 Forced expiratory volume in one second
FVC Forced vital capacity
iv intravenous
Kg Kilograms
L/min Litres per minute
L Litres
mg Milligrams
MgSO4 Magnesium sulphate
Mg Magnesium
mins minutes
mmol/L millimols per litre
mls millilitres
neb nebuliser
NHS National Health Service
NNH Number needed to harm
NNT Number needed to treat
PEF Peak expiratory flow
PEFR Peak expiratory flow rate
p probability
PD20FEV1 the dose of histamine which produced a
20% decrease in control
FEV1
RCT Randomised controlled trial
RRR Relative risk reduction
RRI Relative risk increase
Sd standard deviation
Sgaw specific airways conductance
UK United Kingdom
< less than
> greater than
% Percentage

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Search 1:

 

Search 2:

Appendix 1

An advanced search was done using the Dialogue Datastar,
the NHS core content provider using the Medline and then
the EMBASE databases.
Medline 1951 to date
1 exp.asthma.w..de
2 magnesium.w.de or magnesium-sulphate.w.de or
magnesium-compounds.w.de
3 [nebulizers and vaporizers.w.de] or aerosols.w..de or
powders.w.de
4 review-academic or biography or case reports or journal
article or letter or review-literature or meta-analysis or
multi-centre-study or randomised controlled trial or review
or review of reported cases or review tutorial or clinical
trial$ or comment or congresses or controlled clinical trial
or editorial or evaluation-studies or guideline or historical
article
1 and 2 and 3 and 4 (See search 1)
An Easy search was done on Dialogue Datastar using
magnesium and nebuli$ and asthma with the following
search engines.
Medline – 1966 to date (MEZZ)
EMBASE – 1974 to date (EMZZ)
King Fund – 1979 to date (KFND)
CINAHL ® 1982 to date (NAHL)
Allied + Complementary Medicine 1985 to date (AMED)
British Nursing Index (1994 to date) (BNID)
DH-DATA: Health Administration + Medical Toxicology
(DHZZ)
(See search 2)
The Cochrane database was searched using
Asthma and magnesium and nebulised, 1 systemic review
was found.

Other Topics:

Review Article # 1-  Traumatic Dental Injuries: Review of Hard Tissue Fractures Treatment Guidelines