Review article

The role of magnesium sulfate in the intensive care unit

Yunes Panahi1[*],2, Mojtaba Mojtahedzadeh2,3, Atabak Najafi4, Mohammad Reza Ghaini5, Mohammad Abdollahi6, Mohammad Sharifzadeh6, Arezoo Ahmadi4, Seyyed Mahdi Rajaee1, Amirhossein Sahebkar7

1Clinical Pharmacy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran

2Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

3Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran

4Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

5Department of Neurosurgery and Neurology, Sina Hospital, Tehran University, Iran

6Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

7Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

EXCLI J 2017;16:Doc464



Magnesium (Mg) has been developed as a drug with various clinical uses. Mg is a key cation in physiological processes, and the homeostasis of this cation is crucial for the normal function of body organs. Magnesium sulfate (MgSO4) is a mineral pharmaceutical preparation of magnesium that is used as a neuroprotective agent. One rationale for the frequent use of MgSO4 in critical care is the high incidence of hypomagnesaemia in intensive care unit (ICU) patients. Correction of hypomagnesaemia along with the neuroprotective properties of MgSO4 has generated a wide application for MgSO4 in ICU.

Keywords: magnesium sulfate, intensive care unit, neuroprotection, ICU


Magnesium (Mg) is one of the most abundant cations in the body, and is also a drug with numerous clinical applications. The body usually contains up to 28 g of Mg (Wacker and Parisi, 1968[161]). Most of the Mg is present as an intracellular cation. Of total Mg in the body, 53 % accumulates in bones, 27 % in muscular tissues, 19 % in soft tissues, 0.5 % in red blood cells, and 0.3 % in blood serum (Facchinetti et al., 1991[40]). Half of this Mg is available as free ion and not bound to albumin or anions (Jahnen-Dechent and Ketteler, 2012[68]). Increase or decrease in serum Mg level is associated with impaired body hemostasis and disorders of different organs (Kingston et al., 1986[80]). Hypomagnesaemia is described as serum Mg levels below 1.7 mg/dL, while hypermagnesaemia occurs when the total serum Mg level is higher than 2.6 mg/dL (Kingston et al., 1986[80]; Soesan et al., 2000[147]).

Physiological Roles of Mg

Magnesium is a vital element that is directly or indirectly involved in the physiological processes (Aikawa, 1980[5]). Magnesium is an essential co-factor for the enzymatic reactions (Aikawa, 1980[5]). This element is particularly involved in the storage and transfer of the energy (Noronha and Matuschak, 2002[118]; Reinhart, 1988[124]). Also, Mg regulates glycolysis-related enzymes (Fawcett et al., 1999[41]). Mg activates a lot of enzymatic systems that are essentially necessary in the metabolism of energy. Magnesium is a calcium antagonist that acts via regulating intracellular calcium availability (Romani, 2011[127]). Calcium metabolism and transportation has crucial roles in cardiac function, muscular contraction, blood pressure regulation and neuronal activity (Akhtar et al., 2011[7]; Noronha and Matuschak, 2002[118]).

Influx and efflux of Mg plays an important role in different transcellular transports (Kolte et al., 2014[84]). Magnesium deficiency induces a systemic stress to respond during activation of neuroendocrine pathways (Mazur et al., 2007[101]); it has been implicated in the pathophysiology of several diseases and reported to be related to increased mortality in ICU patients (Zafar et al., 2014[172]). A defect in any part of the transcellular transports may lead to different diseases such as pre-eclampsia, Parkinson's disease, atrial fibrillation and anoxic brain injury (Kolte et al., 2014[84]). Magnesium has analgesic properties that are due to N-methyl-D-aspartate (NMDA) receptor blocking action (Akhtar et al., 2011[7]). Other physiological roles of Mg include: (1) establishing the electrical potential across cell membranes; (2) involvement in intermediary metabolism; (3) involvement in protein and nucleic acid synthesis; (4) exerting depressant effect at the synapse as Mg affects channels on the cardiac and smooth muscles; (5) cell cycle regulation; (6) mitochondrial functions control; (7) maintaining stability of cell membranes, and (8) supporting cytoskeletal integrity (Aikawa, 1980[5]; Dubé and Granry, 2003[34]; Fawcett et al., 1999[41]; Golf et al., 1993[46]; Gordon, 1963[50]; Mubagwa et al., 2007[111]; Nadler and Rude, 1995[115]; Simpson and Knox, 2004[142]; Volpe and Vezu, 1993[159]; Wacker and Parisi, 1968[161]; White and Hartzell, 1989[167]).

Magnesium Deficiency in ICU

One of the key reasons for the wide use of Mg in critical care is the high prevalence of hypomagnesaemia in ICU patients (Noronha and Matuschak, 2002[118]; Tong and Rude, 2005[153]). Around 90 % of ICU patients under surgery and 65 % of ICU patients under drug therapy commonly experience hypomagnesaemia (Koch et al., 2002[82]). Hypomagnesaemia is correlated with poor prognosis and high mortality rate in critically ill patients (Dabbagh et al., 2006[30]).

Noronha and Matuschak in 2009 described major causes of Mg deficiency in ICU patient as: (1) reduction of intestinal absorption of Mg, (2) increased loss of Mgbyrenal route, and (3) compartmental redistribution (Noronha and Matuschak, 2002[118]). The most common gastrointestinal (GI) diseases with Mg loss include intestinal malabsorption syndromes, inadequate Mg intake, re-feeding syndrome, chronic diarrhea, short bowel syndrome, fistulae in the intestinal and biliary system, and acute pancreatitis (Booth et al., 1963[17]; Edmondson et al., 1952[35]; Gordon, 1963[50]; Hall and Joffe, 1973[57]; Martin et al., 2009[99]). Long-term use of Proton Pump Inhibitors (PPIs) has also been reported to block intestinal absorption of Mg. The mechanism of this action is an increase in the intestinal lumen PH that proceeds to the reduction of TRPM 6/7 channel affinity for Mg (Thongon and Krishnamra, 2011[151]; William et al., 2014[170]).

Intravenous Mg supplementation rapidly increases serum Mg level following long-term use of PPIs and subsequent hypomagnesaemia. PPIs affect intestinal epithelial cell locally. Oral Mg is not effective in PPI's induced hypomagnesaemia. Discontinuation of PPI use will resultsin quick normalization of serum Mg levels (Mackay and Bladon, 2010[96]; William and Danziger, 2016[169]).

Renal excretion is an important cause of Mg loss in ICU patients. Interstitial nephropathy, post-obstructive diuresis, acute tubular necrosis (diuretic phase), post-renal transplantation and drug-induced Mg wasting (Aminoglycosides, Amphotericin B, Cisplatin, Colony-stimulating factor therapy, Cyclosporine A, Loop and thiazide diuretics, Pentamidine) are reasons for renal Mg loss (Barton et al., 1984[10], 1987[11]; Hellman et al., 1962[61]; Jones et al., 1966[73]; Kingston et al., 1986[80]; Knochel, 1977[81]; Lim and Jacob, 1972[91]; Martin et al., 2009[99]; Noronha and Matuschak, 2002[118]; Shah et al., 1990[137]; Shah and Kirschenbaum, 1991[138]; von Vigier et al., 2000[160]).

Causes of Mg loss due to redistribution of Mg and endocrine disorders include acute respiratory alkalosis, administration of epinephrine, alcoholic ketoacidosis, blood transfusion, diabetic ketoacidosis, hyperaldosteronism, hyperparathyroidism, hyperthyroidism, hungry bone syndrome, and syndrome of inappropriate antidiuretic hormone (al-Ghamdi et al., 1994[8]; Aziz et al., 1996[9]; England et al., 1992[38]; Martin et al., 2009[99]; McLellan et al., 1984[104]; Shane and Flink, 1991[140]; Whyte et al., 1987[168]). Other causes include cardiopulmonary bypass, hypophosphatemia (chronic alcoholism), hypercalcemia/hypercalciuria, excessive sweating and severe burns (al-Ghamdi et al., 1994[8]; Kingston et al., 1986[80]; Martin et al., 2009[99]; Weglicki and Phillips, 1992[165]).

Clinical Manifestations of Hypomagnesaemia in the ICU

The symptoms of hypomagnesaemia start when serum Mg levels fall below 1.2 mg/dL (Kingston et al., 1986[80]). These symptoms affect different body organs and depend on the rate of deficiency of ionized Mg (Brenner and Rector, 1991[19]). However, most cases of hypomagnesaemia in intensive care are asymptomatic (Soesan et al., 2000[147]). Clinical manifestations of hypomagnesaemia in ICU patients include muscle cramps, tremor, weakness, hyperreflexia, positive Trousseau or Chvostek sign, carpopedal spasm, tetany, nystagmus, vertigo, aphasia, hemiparesis, delirium, choreoathetosis, supraventricular arrhythmias, ventricular arrhythmias, torsades de pointes, electrolyte disturbance (hypocalcemia, hypokalemia, or both), hypertension, coronary vasospasms, and bronchial airway constriction. Severe hypomagnesaemia may cause generalized tonic-clonic seizures (Burch and Giles, 1977[22]; Iseri et al., 1989[67]; Ralston et al., 1989[123]; Ryzen et al., 1985[131]; Tzivoni et al., 1988[155]; Wacker, 1962[162]; Watanabe and Dreifus, 1972[164]).

Magnesium Sulfate in ICU

Numerous roles for magnesium in critical care medicine have been suggested (Noronha and Matuschak, 2002[118]). Deficiency of Mg is common in hospitalized patients, and is frequently reported in admitted ICU patients (Koch et al., 2002[82]; Ryzen et al., 1985[131]). Management of patients in ICU is somehow complicated and depends on the conditions of every patient (Honarmand et al., 2012[63]). It has been suggested to employ an established protocol as a base to define a moderate dose of Mg that is safe over the years in ICU (Hebert et al., 1997[60]).

In 1906, for the first time, magnesium sulfate (MgSO4) was used to prevent eclamptic seizures in Germany (Horn, 1906[64]). Magnesium is replaced intravenously with MgSO4 when hypomagnesaemia is severe (Ryzen et al., 1985[131]). MgSO4 is the essential preparation of intravenous Mg. Magnesium sulfate, usually known as Epsom salt, is an ordinary mineral pharmaceutical preparation of Mg that is used both externally and internally. Both Mg and sulfate absorb through the skin to recover blood levels (Noronha and Matuschak, 2002[118]; Ignatavicius and Workman, 2015[66]). A number of authors have described Mg as “the forgotten electrolyte” (Elin, 1994[37]; Gonzalez et al., 2013[48]). Hypomagnesaemia is a significant but underdiagnosed electrolyte imbalance (Gonzalez et al., 2013[48]). MgSO4 has been used during the 20th century for eclamptic seizures' prevention (Lazard, 1925[89]; Pritchard, 1955[121]), and continues to be used widely.

Numerous mechanisms of action have been suggested for magnesium including (1) vasodilatory action, (2) blood-brain barrier (BBB) protection, (3) reduction of cerebral edema, and (4) central anticonvulsant action (Aali et al., 2007[1]).

Clinical Application of Magnesium Sulfate in ICU

Acute asthma

Asthma has been described as a chronic inflammatory disorder of the airways with an increase of bronchial responsiveness to a variety of stimuli. It is often reversible, either spontaneously or with treatment (Bateman et al., 2008[12]).

Standard treatments for asthma crisis include bronchodilators (short-acting), agonists of β2-receptors, inhaled ipratropium bromide, corticosteroids, anticholinergic drugs and general managements (Bateman et al., 2008[12]). Researchers have suggested MgSO4 as a treatment option for patients who are resistant to standard therapy (Bateman et al., 2008[12]; Gontijo-Amaral et al., 2007[47]; Jones and Goodacre, 2009[74]; Kew et al., 2014[77]). Life-threatening conditions like severe asthma attacks require intensive medical care. The beneficial effects of MgSO4 have been shown in children and adult patients with severe asthma in the ICU (Boonyavorakul et al., 2000[16]; Daengsuwan and Watanatham, 2016[31]; Griffiths and Kew, 2016[52]; Kew et al., 2014[77]; Kokturk et al., 2005[83]; Rowe, 2013[128]; Rowe and Camargo, 2008[129]; Rower et al., 2017[130]; Singh et al., 2008[143]).

Mechanisms of Mg action for the management of severe asthma include: (1) reduction of intracellular calcium level (blockade of calcium entry, calcium release and activation of Na+-Ca2+ pumps), (2) muscle relaxation (inhibition of myosin and calcium interaction), (3) reduction of inflammatory mediators (inhibition of degranulation of mast cells and T-cells stabilization), (4) depression of the irritability of muscle fibers, and (5) inhibition of prostacyclin and nitric oxide synthesis. These mechanisms lead to a reduction in the severity of asthma (Gontijo-Amaral et al., 2007[47]; Rowe, 2013[128]).

MgSO4 is used via intravenous and inhalation routes for the management of acute asthma (Shan et al., 2013[139]). Use of MgSO4 through intravenous route in adult and children patients improves respiratory function (Boonyavorakul et al., 2000[16]; Daengsuwan and Watanatham, 2016[31]; Griffiths and Kew, 2016[52]; Kew et al., 2014[77]; Kokturk et al., 2005[83]; Rowe, 2013[128]; Rowe and Camargo, 2008[129]; Rower et al., 2017[130]; Singh et al., 2008[143]). In some countries, the intravenous form of MgSO4 is broadly used as an adjunctive therapy for severe acute asthma, especially in patients not responding to initial treatments (British Thoracic Society Scottish Intercollegiate Guidelines, 2008[20]; Jones and Goodacre, 2009[74]). Unlike adults, in children MgSO4 has a significant effect on hospital admission (Ciarallo et al., 2000[28], 1996[29]; Gurkan et al., 1999[55]; Porter et al., 2001[120]; Scarfone et al., 2000[133]). The impact of MgSO4 on forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR) were assessed in different clinical trials (Bessmertny et al., 2002[13]; Bloch et al., 1995[15]; Boonyavorakul et al., 2000[16]; Devi et al., 1997[32]; Gallegos-Solorzano et al., 2010[43]; Green and Rothrock, 1992[51]; Hughes et al., 2003[65]; Mahajan et al., 2004[97]; Silverman et al., 2002[141]; Tiffany et al., 1993[152]). In children, brief infusion and maximum weight-based dosage of MgSO4 have been suggested for the management of severely ill asthmatic patients in the ICU (Egelund et al., 2013[36]; Liu et al., 2016[94]). Up to 2.5 gram of Mg loading dose with β-agonist and corticosteroid (methylprednisolone, hydrocortisone, and dexamethasone) were reported to be efficacious in the management of asthma (British Thoracic Society Scottish Intercollegiate Guidelines, 2008[20]). Ipratropium, aminophylline, theophylline and ephedrine are additional drugs in the management of acute asthma (Bloch et al., 1995[15]; Devi et al., 1997[32]; Green and Rothrock, 1992[51]; Singh et al., 2008[143]; Tiffany et al., 1993[152]). However, in contrast to intravenous MgSO4, the effect of the inhaled form remains controversial. Up to 500 mg MgSO4 for each dose of nebulization has been used in several clinical trials (Aggarwal et al., 2006[3]; Ahmed et al., 2013[4]; Bessmertny et al., 2002[13]; Chande and Skoner, 1992[24]; Gallegos-Solorzano et al., 2010[43]; Gandia et al., 2012[44]; Hill et al., 1997[62]; Hughes et al., 2003[65]; Kokturk et al., 2005[83]; Mangat et al., 1998[98]; Nannini and Hofer, 1997[116]; Nannini et al., 2000[117]; Rolla et al., 1987[126]; Zandsteeg et al., 2009[173]). Respiratory functions and hospital admission were assesed in all studies and, similar to intravenous MgSO4 therapy, β-agonists and corticosteroids were used in all patients (Aggarwal et al., 2006[3]; Ahmed et al., 2013[4]; Chande and Skoner, 1992[24]; Gandia et al., 2012[44]; Hill et al., 1997[62]; Mangat et al., 1998[98]; Nannini and Hofer, 1997[116]; Nannini et al., 2000[117]; Rolla et al., 1987[126]; Zandsteeg et al., 2009[173]). In one study, nebulized MgSO4 was compared to nebulized salbutamol (Mangat et al., 1998[98]). The authors showed that there is no significant difference between the bronchodilatory effect of nebulized MgSO4 and salbutamol in the management of acute asthma (Gonzalez et al., 2013[48]). In 2016, Ling and colleagues reported that nebulized MgSO4 is not useful to improve pulmonary function or reduce the number of patients admitted to the hospital in adults with acute asthma (Ling et al., 2016[92]). In children, treatment with nebulized magnesium sulfate showed no significant effect on respiratory function or hospital admission and further treatment (Su et al., 2016[149]). Adverse events have been occasionally reported in the clinical trials, but the most common adverse reactions with MgSO4 are cardiac arrhythmia, confusion, drowsiness, flushing, hypotension, loss of deep tendon reflexes, muscle weakness, nausea, respiratory depression, thirst, and vomiting. Rarely, administration of MgSO4 can lead to cardiac arrest and coma (Martindale and Westcott, 2008[100]).

Magnesium sulfate as a neuroprotective agent

MgSO4 has been well documented to be beneficial in the management of nervous system injuries especially in the ICU. These injuries include stroke, aneurysmal subarachnoid hemorrhage (ASAH), and traumatic brain injuries (Afshari et al., 2013[2]; Akdemir et al., 2009[6]; Bradford et al., 2013[18]; Chan et al., 2005[23]; Chen et al., 2015[25]; Chen and Carter, 2011[27]; Dabbagh et al., 2006[30]; Dorhout Mees et al., 2012[33]; Friedlich et al., 2009[42]; Gao et al., 2013[45]; Gonzalez-Garcia et al., 2012[49]; Hassan et al., 2012[58]; James et al., 2009[69]; Jiang et al., 2017[71]; Johnson et al., 1993[72]; Kahraman et al., 2003[75]; Kidwell et al., 2009[79]; Kumar et al., 2015[85]; Lamers et al., 2003[87]; Lampl et al., 2001[88]; Mirrahimi et al., 2015[107]; Mousavi et al., 2004[109], 2010[110]; Muir and Lees, 1995[112]; Muir et al., 2004[113]; Muroi et al., 2008[114]; Rahimi-Bashar et al., 2017[122]; Rinosl et al., 2013[125]; Saver et al., 2015[132]; Selvaraj and Syed, 2014[136]; Singh et al., 2012[144]; Sleeswijk et al., 2008[146]; Stippler et al., 2006[148]; van den Bergh et al., 2005[156]; van Norden et al., 2005[157]; Veyna et al., 2002[158]; Wang et al., 2012[163]; Westermaier et al., 2010[166]; Wong et al., 2010[171]; Zafar et al., 2014[172]; Zhao et al., 2016[174]; Zhu et al., 2004[175]).

MgSO4 and Aneurysmal Subarachnoid Hemorrhage (ASAH)

Several studies have been performed on the efficacy and dosage of MgSO4 in ASAH in the last two decades (Afshari et al., 2013[2]; Akdemir et al., 2009[6]; Bradford et al., 2013[18]; Chen et al., 2015[25]; Chen and Carter, 2011[27]; Dabbagh et al., 2006[30]; Dorhout Mees et al., 2012[33]; Hassan et al., 2012[58]; Jiang et al., 2017[71]; Kahraman et al., 2003[75]; Kidwell et al., 2009[79]; Kumar et al., 2015[85]; Mousavi et al., 2010[110]; Muir and Lees, 1995[112]; Muir et al., 2004[113]; Muroi et al., 2008[114]; Saver et al., 2015[132]; Selvaraj and Syed, 2014[136]; Singh et al., 2012[144]; Sleeswijk et al., 2008[146]; Stippler et al., 2006[148]; van den Bergh et al., 2005[156]; van Norden et al., 2005[157]; Veyna et al., 2002[158]; Wang et al., 2012[163]; Westermaier et al., 2010[166]; Wong et al., 2010[171]; Zafar et al., 2014[172]; Zhao et al., 2016[174]; Zhu et al., 2004[175]). Different doses of MgSO4 have been suggested for neuroprotection. Veyna and colleagues used MgSO4 in 20 ASAH patients and showed that high dose of Mg is safe and efficient and can maintain serum Mg levels in the range of 4-5.5 mg/dL. Their study was focused on vasospasm, middle cerebral artery (MCA) velocity and Glasgow Outcome Scale (GOS). The findings showed better outcome in patients with ASAH 90 days post-hemorrhage, but they did not find a significant difference in GOS between the control and treatment groups (Veyna et al., 2002[158]). Also, van Norden et al. (2005[157]) showed that treatment with MgSO4 at a dose of 64 mmol/day will result in 1-2 mmol/L of serum Mg level without any side effect. Studies by Van der Bergh and colleagues (2005[156]) revealed that MgSO4 delays cerebral ischemia. They used Rankin score to measure outcomes in the patients. Stippler reported the efficacy of Mg in the management of SAH and improving the Rankin score. The mechanism of Mg efficacy in SAH was suggested to involve a significant reduction in vasospasm (Stippler et al., 2006[148]). High dose of MgSO4 was also suggested to be prophylactic and associated with better outcomes in SAH patients (Muroi et al., 2008[114]). MgSO4 can increase ischemic tolerance in the nervous system at the time of hypo-perfusion, attenuate vasospasm and decrease outcomes in patients with ASAH (Bradford et al., 2013[18]; Chen and Carter, 2011[27]; Westermaier et al., 2010[166]). Despite these findings on the beneficial role of MgSO4 in ASAH, in three studies authors did not suggest this drug for ASAH or did not find any efficacy in the patients (Akdemir et al., 2009[6]; Dorhout Mees et al., 2012[33]; Wong et al., 2010[171]). Friedlich et al. (2009[42]) reported that MgSO4 at a dose of 0.6 g/hour has a prophylactic effect on cerebral vasospasm in the first 72 hours in a patient with ASAH. Overall, MgSO4 seems to be beneficial in the management of ASAH.

MgSO4 and stroke

The use of MgSO4 24 hours post-stroke shows a significant decrease in the infarct volume based on the findings of MRI (Kidwell et al., 2009[79]). Saver and colleagues performed a study on 1700 stroke patients in 2015 (Saver et al., 2015[132]). In their study, GCS, NIHSS and Barthel index were improved in the treatment group receiving MgSO4 compared with the control group (Veyna et al., 2002[158]). Singh et al. (2012[144]) showed neuroprotective properties of Mg in the stroke patients that received intravenous MgSO4 in comparison to the control group. Afshari and colleagues showed a significant effect of MgSO4 in decreasing the length of hospital stay in stroke patients (Afshari et al., 2013[2]). The significant effect of Mg on Barthel index, the length of hospital stays and recovery in 30 days post-stroke in the patients was reported by Lampl and colleagues (2001[88]). It was also suggested that one gram of MgSO4 daily decreases mortality rate in the non-cardiac ICU patients (Dabbagh et al., 2006[30]). Concurrent use of MgSO4 and nimesulide, and MgSO4 alone, has been reported to reduce the infarct volume in an animal model of stroke (Wang et al., 2012[163]; Zhu et al., 2004[175]).

Effect of MgSO4 on biomarkers in different neuropathies has been assessed in several studies (Bharosay et al., 2012[14]; Chan et al., 2005[23]; Friedlich et al., 2009[42]; Gao et al., 2013[45]; Gonzalez-Garcia et al., 2012[49]; Hassan et al., 2012[58]; James et al., 2009[69]; Johnson et al., 1993[72]; Lamers et al., 2003[87]; Mirrahimi et al., 2015[107]; Rahimi-Bashar et al., 2017[122]; Rinosl et al., 2013[125]). MgSO4 was shown to decrease S100B levels with little side effects (Hassan et al., 2012[58]). The increase of biomarkers like S100B and S-SNE has been reported with serum Mg levels below 1.2 mmol/L, and is associated with poor outcomes and a higher rate of mortality in patients with stroke (James et al., 2009[69]; Mirrahimi et al., 2015[107]). The decrease of these biomarkers may be correlated with an increase of Barthel index (James et al., 2009[69]). S100B has more sensitivity and specify than S-NSE (Gonzalez-Garcia et al., 2012[49]; Lamers et al., 2003[87]). Increase in S100B levels is associated with an increase in infarct size and NIH stroke score (Jauch et al., 2006[70]; Mizukoshi et al., 2013[108]). Increase in serum NSE levels has also been reported to be associated with an increase in post-stroke disability (Bharosay et al., 2012[14]).

Gao and colleagues reported that 5 to 10 mmol/L of intravenous MgSO4 decreases inflammatory biomarkers such as nitric oxide, prostaglandin E2, interleukin 1β and tumor necrosis factor-α (Gao et al., 2013[45]). Concurrent use of neuroprotective agents and thrombolytic therapy is a promising treatment for acute ischemic stroke (Chen et al., 2002[26]; Ovbiagele et al., 2003[119]).

Mg and Traumatic brain injuries (TBI)

TBI is an important health problem with high a mortality and morbidity rate (Maas et al., 2008[95]). Studies on animal models have shown that Mg can increase the survival of neurons in cerebral ischemia and traumatic brain injury (Schanne et al., 1993[134]; Sirin et al., 1998[145]).

Numerous studies have reported that Mg plays an important role in the prevention and treatment of central nervous system (CNS) injuries. Magnesium protects neurons from ischemic injuries and supports neuronal survival following TBI with different mechanisms such as: (1) blocking NMDA channels, (2) inhibition of presynaptic excitatory neurotransmitters, (3) inhibition of voltage-gated calcium channels, and (4) potentiation of presynaptic adenosine. Moreover, Mg can relax vascular smooth muscles and enhance cerebral blood flow. Serum total and ionized Mg levels are reduced after head injuries (McIntosh, 1993[103]; Memon et al., 2009[105]). The entrance of Mg into the CNS is dependent on the integrity of the BBB. In animal models, traumatic head injuries will facilitate entrance of Mg into the CNS for at least 24 hours (Habgood et al., 2007[56]; Heath and Vink, 1998[59]). The permeability of BBB in personal traumatic head injuries is not always present (Miller and D'Ambrosio, 2007[106]).

MgSO4 in other patients admitted to the ICU

The beneficial effect of MgSO4 in ICU patients was described and assessed by researchers using different assessment methods (SOFA score, GCS, Rankin score, RASS score, APACHE score, NIH stroke scores, Barthel index, infarction volume, sepsis, tissue oxygenation index, mechanical ventilation and intubation requirement, length of hospital and ICU stay, and mortality) (Afshari et al., 2013[2]; Chen et al., 2015[25]; Dabbagh et al., 2006[30]; Jiang et al., 2017[71]; Kidwell et al., 2009[79]; Kumar et al., 2015[85]; Mousavi et al., 2010[110]; Muir and Lees, 1995[112]; Saver et al., 2015[132]; Singh et al., 2012[144]; Wang et al., 2012[163]; Zafar et al., 2014[172]; Zhao et al., 2016[174]; Zhu et al., 2004[175]).

The neuroprotective effect of MgSO4 in diffuse axonal injury has been shown by Zhao et al. (2016[174]). The intervention group in the referred study showed higher Glasgow coma scale (GCS) and lower serum neuron-specific enolase level (S-NSE), but the length of ICU stay and mortality did not differ between control and intervention groups (Habgood et al., 2007[56]). The presence of hypomagnesaemia in 374 ICU patients was reported by Chen and colleagues. Their results showed that hypomagnesaemia was correlated with increased length of ICU stay, SOFA score and mortality rate (Chen et al., 2015[25]). The mortality rate in the ICU patients with hypomagnesaemia was reported as 74 % in comparison with 36 % in patients with normal serum Mg levels (Zafar et al., 2014[172]).

Hypomagnesaemia had a higher incidence in the alcoholic patients and patients with diabetes mellitus, sepsis, hepatic cirrhosis and chronic kidney disease. Higher need to mechanical ventilation, increase in the length of mechanical ventilation, increase in the risk of sepsis, higher APACHE score, decrease in NIHS score, decrease in serum albumin level and hypokalemia were also reported in these patients (Jiang et al., 2017[71]; Kumar et al., 2015[85]; Mousavi et al., 2004[109], 2010[110]; Muir and Lees, 1995[112]). MgSO4 cannot improve the strength of respiratory muscles in the critically ill patients under mechanical ventilation (Johnson et al., 1993[72]). Serum Mg level is a key factor determining the outcome of the patients in ICU (Rahimi-Bashar et al., 2017[122]). The normal level of serum Mg was associated with shorter time under mechanical ventilation and intubation and decreased ICU stay (Lampl et al., 2001[88]).

In patients admitted to the ICU after major abdominal surgery, serum Mg level should be checked daily because two-thirds of patients after abdominal surgery are diagnosed with hypomagnesaemia (Selvaraj and Syed, 2014[136]). As stated earlier, hypomagnesaemia is widely observed in the ICU, thus Mg replenishment should be considered in patients admitted to the ICU. For this reason, MgSO4 is an important drug in the ICU. MgSO4 can increase brain tissue oxygenation index by 34 % after cerebral artery occlusion (Chan et al., 2005[23]).

Electrolyte imbalance following hypomagnesaemia has been reported by researchers in the ICU (Buckley et al., 2010[21]; Elin, 1994[37]; Faber et al., 1994[39]; Gonzalez et al., 2013[48]; Sedlacek et al., 2006[135]). Hypomagnesaemia can lead to a 2-3-fold increased mortality in ICU, and is one of the main causes of hypokalemia and hypocalcemia. It is also associated with hyponatremia and hypophosphatemia (Elin, 1994[37]; Gonzalez et al., 2013[48]; Sedlacek et al., 2006[135]). Mg has a major role in the transport of potassium, and simultaneous correction of hypomagnaesemia and hypokalemia is mandatory (Sedlacek et al., 2006[135]). Gupta et al. (2009[54]) showed that in a critically ill patient, administration of potassium and calcium is not sufficient to correct hypocalcemia and hypokalemia. Correction of hypomagnesaemia and control of Mg level in serum is highly recommended in patients with hypocalcemia and hypokalemia (Gupta et al., 2009[54]).

Magnesium sulfate was suggested by some authors to be efficacious in cardiac operations such as atrial fibrillation (AF), coronary artery bypass surgery and heart valve surgeries (Gu et al., 2012[53]; Lee et al., 2016[90]; Lip, 2016[93]; Mazurek and Lip, 2017[102]; Talkachova et al., 2016[150]; Treggiari-Venzi et al., 2000[154]). Low serum Mg level and older age have been reported as risk factors for AF (Treggiari-Venzi et al., 2000[154]). Atrial fibrillation is also one of the risk factors for ischemic stroke (Talkachova et al., 2016[150]). The role of MgSO4 for the management of AF is controversial. Use of intravenous MgSO4 without any other drugs in 16 patients was able to return heart rhythm to normal sinus rhythm after atrial fibrillation crisis (Sleeswijk et al., 2008[146]). Kaplan et al. reported that MgSO4 alone is not useful in the management of AF (Kaplan et al., 2003[76]). Concurrent use of MgSO4 with amiodarone in a post-operative patient with thorax surgery was reported to be beneficial for the prophylaxis against AF (Khalil et al., 2012[78]). In subjects with coronary bypass surgeries, MgSO4 was reported to reduce the risk of AF by 36 percent (Gu et al., 2012[53]). Administration of intravenous MgSO4, pre-operatively, post-operatively and during the heart valve surgery, decreased the risk of AF (Laiq et al., 2013[86]).


Despite the controversial views on the effects of MgSO4 as a neuroprotective agent, current evidence suggests that MgSO4 is an important part of the management of ICU patients (Table 1(Tab. 1)). (References in Table 1: Kaplan et al., 2003[76]; Khalil et al., 2012[78]; Laiq et al., 2013[86]; Sleeswijk et al., 2008[146]; Treggiari-Venzi et al., 2000[154]; Akdemir et al., 2009[6]; Hassan et al., 2012[58]; Dorhout Mees et al., 2012[33]; Muroi et al., 2008[114]; van Norden et al., 2005[157]; Stippler et al., 2006[148]; van den Bergh et al., 2005[156]; Veyna et al., 2002[158]; Westermaier et al., 2010[166]; Wong et al., 2010[171]; Chan et al., 2005[23]; Zhao et al., 2016[174]; Afshari et al., 2013[2]; Lampl et al., 2001[88]; Muir et al., 2004[113]; Mirrahimi et al., 2015[107]; Muir and Lees, 1995[112]; Saver et al., 2015[132]; Singh et al., 2012[144]; Singh et al., 2008[143]; Boonyavorakul et al., 2000[16]; Green and Rothrock, 1992[51]; Silverman et al., 2002[141]; Porter et al., 2001[120]; Scarfone et al., 2000[133]; Ciarallo et al., 1996[29]; Ciarallo et al., 2000[28]; Gurkan et al., 1999[55]; Devi et al., 1997[32]; Bloch et al., 1995[15]; Tiffany et al., 1993[152].) Magnesium sulfate is essential to correct hypomagnesaemia and can decrease mortality rate, decrease the length of ICU stay, and is associated with reduced outcomes in patients admitted to the ICU. Because of the high prevalence of hypomagnesaemia and necessity of intravenous MgSO4 therapy in the ICU, serum Mg levels should be checked on a daily basis.

Conflict of interests

The authors have no competing interests to declare.



1. Aali BS, Khazaeli P, Ghasemi F. Ionized and total magnesium concentration in patients with severe preeclampsia-eclampsia undergoing magnesium sulfate therapy. J Obstet Gynaecol Res. 2007;33:138-43.
2. Afshari D, Moradian N, Rezaei M. Evaluation of the intravenous magnesium sulfate effect in clinical improvement of patients with acute ischemic stroke. Clin Neurol Neurosurg. 2013;115:400-4.
3. Aggarwal P, Sharad S, Handa R, Dwiwedi SN, Irshad M. Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study. Emerg Med J. 2006;23:358-62.
4. Ahmed S, Sutradhar SR, Miah AH, Bari MA, Hasan MJ, Alam MK, et al. Comparison of salbutamol with normal saline and salbutamol with magnesium sulphate in the treatment of severe acute asthma. Mymensingh Med J. 2013;22:1-7.
5. Aikawa JK. Magnesium: Its biological significance. Boca Raton, FL: CRC Press, 1980.
6. Akdemir H, Kulakszoğlu EO, Tucer B, Menkü A, Postalc L, Günald Ö. Magnesium sulfate therapy for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurg Quart. 2009;19:35-9.
7. Akhtar MI, Ullah H, Hamid M. Magnesium, a drug of diverse use. J Pak Med Assoc. 2011;61:1220-5.
8. al-Ghamdi SM, Cameron EC, Sutton RA. Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis. 1994;24:737-52.
9. Aziz S, Haigh WG, Van Norman GA, Kenny RJ, Kenny MA. Blood ionized magnesium concentrations during cardiopulmonary bypass and their correlation with other circulating cations. J Card Surg. 1996;11:341-7.
10. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med. 1984;77:471-4.
11. Barton CH, Vaziri ND, Martin DC, Choi S, Alikhani S. Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine. Am J Med. 1987;83:693-9.
12. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31:143-78.
13. Bessmertny O, DiGregorio RV, Cohen H, Becker E, Looney D, Golden J, et al. A randomized clinical trial of nebulized magnesium sulfate in addition to albuterol in the treatment of acute mild-to-moderate asthma exacerbations in adults. Ann Emerg Med. 2002;39:585-91.
14. Bharosay A, Bharosay VV, Varma M, Saxena K, Sodani A, Saxena R. Correlation of brain biomarker Neuron Specific Enolase (NSE) with degree of disability and neurological worsening in cerebrovascular stroke. Indian J Clin Biochem. 2012;27:186-90.
15. Bloch H, Silverman R, Mancherje N, Grant S, Jagminas L, Scharf SM. Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma. Chest. 1995;107:1576-81.
16. Boonyavorakul C, Thakkinstian A, Charoenpan P. Intravenous magnesium sulfate in acute severe asthma. Respirology. 2000;5:221-5.
17. Booth CC, Babouris N, Hanna S, Macintyre I. Incidence of hypomagnesaemia in intestinal malabsorption. Br Med J. 1963;2:141-4.
18. Bradford CM, Finfer S, O'Connor A, Yarad E, Firth R, McCallister R, et al. A randomised controlled trial of induced hypermagnesaemia following aneurysmal subarachnoid haemorrhage. Crit Care Resusc. 2013;15:119-25.
19. Brenner BM, Rector FC. The kidney. Philadelphia, PA: W.B. Saunders, 1991.
20. British Thoracic Society Scottish Intercollegiate Guidelines N. British Guideline on the Management of Asthma. Thorax. 2008;63(Suppl 4):iv1-121.
21. Buckley MS, Leblanc JM, Cawley MJ. Electrolyte disturbances associated with commonly prescribed medications in the intensive care unit. Crit Care Med. 2010;38:S253-64.
22. Burch GE, Giles TD. The importance of magnesium deficiency in cardiovascular disease. Am Heart J. 1977;94:649-57.
23. Chan MT, Boet R, Ng SC, Poon WS, Gin T. Magnesium sulfate for brain protection during temporary cerebral artery occlusion. Acta Neurochir Suppl. 2005;95:107-11.
24. Chande VT, Skoner DP. A trial of nebulized magnesium sulfate to reverse bronchospasm in asthmatic patients. Ann Emerg Med. 1992;21:1111-5.
25. Chen M, Sun R, Hu B. [The influence of serum magnesium level on the prognosis of critically ill patients]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015;27:213-7.
26. Chen SD, Lee JM, Yang DI, Nassief A, Hsu CY. Combination therapy for ischemic stroke: potential of neuroprotectants plus thrombolytics. Am J Cardiovasc Drugs. 2002;2:303-13.
27. Chen T, Carter BS. Role of magnesium sulfate in aneurysmal subarachnoid hemorrhage management: A meta-analysis of controlled clinical trials. Asian J Neurosurg. 2011;6:26-31.
28. Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med. 2000;154:979-83.
29. Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr. 1996;129:809-14.
30. Dabbagh OC, Aldawood AS, Arabi YM, Lone NA, Brits R, Pillay M. Magnesium supplementation and the potential association with mortality rates among critically ill non-cardiac patients. Saudi Med J. 2006;27:821-5.
31. Daengsuwan T, Watanatham S. A comparative pilot study of the efficacy and safety of nebulized magnesium sulfate and intravenous magnesium sulfate in children with severe acute asthma. Asian Pac J Allergy Immunol. 2016, epub ahead of print.
32. Devi PR, Kumar L, Singhi SC, Prasad R, Singh M. Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy. Indian Pediatr. 1997;34:389-97.
33. Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, et al. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380:44-9.
34. Dubé L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anesth. 2003;50:732-46.
35. Edmondson HA, Berne CJ, Homann RE Jr, Wertman M. Calcium, potassium, magnesium and amylase disturbances in acute pancreatitis. Am J Med. 1952;12:34-42.
36. Egelund TA, Wassil SK, Edwards EM, Linden S, Irazuzta JE. High-dose magnesium sulfate infusion protocol for status asthmaticus: a safety and pharmacokinetics cohort study. Intensive Care Med. 2013;39:117-22.
37. Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am J Clin Pathol. 1994;102:616-22.
38. England MR, Gordon G, Salem M, Chernow B. Magnesium administration and dysrhythmias after cardiac surgery. A placebo-controlled, double-blind, randomized trial. JAMA. 1992;268:2395-402.
39. Faber MD, Kupin WL, Heilig CW, Narins RG. Common fluid-electrolyte and acid-base problems in the intensive care unit: selected issues. Semin Nephrol. 1994;14:8-22.
40. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31:298-301.
41. Fawcett WJ, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br J Anaesth. 1999;83:302-20.
42. Friedlich D, Agner C, Boulos AS, Mesfin F, Feustel P, Bernardini GL, et al. Retrospective analysis of parenteral magnesium sulfate administration in decreased incidence of clinical and neuroradiological cerebral vasospasm: a single center experience. Neurol Res. 2009;31:621-5.
43. Gallegos-Solorzano MC, Perez-Padilla R, Hernandez-Zenteno RJ. Usefulness of inhaled magnesium sulfate in the coadjuvant management of severe asthma crisis in an emergency department. Pulm Pharmacol Ther. 2010;23:432-7.
44. Gandia F, Guenard H, Sriha B, Tabka Z, Rouatbi S. Inhaled magnesium sulphate in the treatment of bronchial hyperresponsiveness. Magnes Res. 2012;25:168-76.
45. Gao F, Ding B, Zhou L, Gao X, Guo H, Xu H. Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-kappaB pathway. J Surg Res. 2013;184:944-50.
46. Golf S, Dralle D, Leonardo V. Magnesium 1993. London: Libbey, 1993.
47. Gontijo-Amaral C, Ribeiro MA, Gontijo LS, Condino-Neto A, Ribeiro JD. Oral magnesium supplementation in asthmatic children: a double-blind randomized placebo-controlled trial. Eur J Clin Nutr. 2007;61:54-60.
48. Gonzalez W, Altieri PI, Alvarado S, Banchs HL, Escobales N, Crespo M, et al. Magnesium: the forgotten electrolyte. Bol Asoc Med P R. 2013;105:17-20.
49. Gonzalez-Garcia S, Gonzalez-Quevedo A, Fernandez-Concepcion O, Pena-Sanchez M, Menendez-Sainz C, Hernandez-Diaz Z, et al. Short-term prognostic value of serum neuron specific enolase and S100B in acute stroke patients. Clin Biochem. 2012;45:1302-7.
50. Gordon DT. The assessment and management of tetanus. Thesis. Aberdeen: University of Aberdeen, 1963.
51. Green SM, Rothrock SG. Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization. Ann Emerg Med. 1992;21:260-5.
52. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev. 2016;4:CD011050.
53. Gu WJ, Wu ZJ, Wang PF, Aung LH, Yin RX. Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. Trials. 2012;13:41.
54. Gupta S, Sodhi S, Kaur J, Yamini J. Improvement in electrolyte imbalance in critically ill patient after magnesium supplementation - A case report. Indian J Clin Biochem. 2009;24:208-10.
55. Gurkan F, Haspolat K, Bosnak M, Dikici B, Derman O, Ece A. Intravenous magnesium sulphate in the management of moderate to severe acute asthmatic children nonresponding to conventional therapy. Eur J Emerg Med. 1999;6:201-5.
56. Habgood MD, Bye N, Dziegielewska KM, Ek CJ, Lane MA, Potter A, et al. Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur J Neurosci. 2007;25:231-8.
57. Hall RC, Joffe JR. Hypomagnesemia. Physical and psychiatric symptoms. JAMA. 1973;224:1749-51.
58. Hassan T, Nassar M, Elhadi SM, Radi WK. Effect of magnesium sulfate therapy on patients with aneurysmal subarachnoid hemorrhage using serum S100B protein as a prognostic marker. Neurosurg Rev. 2012;35:421-7.
59. Heath DL, Vink R. Neuroprotective effects of MgSO4 and MgCl2 in closed head injury: a comparative phosphorus NMR study. J Neurotrauma. 1998;15:183-9.
60. Hebert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P. Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med. 1997;25:749-55.
61. Hellman ES, Tschudy DP, Bartter FC. Abnormal electrolyte and water metabolism in acute intermittent porphyria. The transient inappropriate secretion of antidiuretic hormone. Am J Med. 1962;32:734-6.
62. Hill J, Lewis S, Britton J. Studies of the effects of inhaled magnesium on airway reactivity to histamine and adenosine monophosphate in asthmatic subjects. Clin Exp Allergy. 1997;27:546-51.
63. Honarmand H, Abdollahi M, Ahmadi A, Javadi MR, Khoshayand MR, Tabeefar H, et al. Randomized trial of the effect of intravenous paracetamol on inflammatory biomarkers and outcome in febrile critically ill adults. Daru. 2012;20:12.
64. Horn E. To tilfaelde af eclampsia gravidarum behandlet med suflas magnesicus injiceret: zygmarens subarachnoidalium. Medicinsk Rev (Bergen). 1906;32:264-72.
65. Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial. Lancet. 2003;361:2114-7.
66. Ignatavicius DD, Workman ML. Medical-surgical nursing: patient-centered collaborative care. Philadelphia, PA: Saunders, 2015.
67. Iseri LT, Allen BJ, Brodsky MA. Magnesium therapy of cardiac arrhythmias in critical-care medicine. Magnesium. 1989;8:299-306.
68. Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J. 2012;5:i3-i14.
69. James ML, Blessing R, Phillips-Bute BG, Bennett E, Laskowitz DT. S100B and brain natriuretic peptide predict functional neurological outcome after intracerebral haemorrhage. Biomarkers. 2009;14:388-94.
70. Jauch EC, Lindsell C, Broderick J, Fagan SC, Tilley BC, Levine SR. Association of serial biochemical markers with acute ischemic stroke: the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator stroke study. Stroke. 2006;37:2508-13.
71. Jiang P, Lv Q, Lai T, Xu F. Does hypomagnesemia impact on the outcome of patients admitted to the intensive care unit? a systematic review and meta-analysis. Shock. 2017;47:288-95.
72. Johnson D, Gallagher C, Cavanaugh M, Yip R, Mayers I. The lack of effect of routine magnesium administration on respiratory function in mechanically ventilated patients. Chest. 1993;104:536-41.
73. Jones JE, Desper PC, Shane SR, Flink EB. Magnesium metabolism in hyperthyroidism and hypothyroidism. J Clin Invest. 1966;45:891-900.
74. Jones LA, Goodacre S. Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emerg Med J. 2009;26:783-5.
75. Kahraman S, Ozgurtas T, Kayali H, Atabey C, Kutluay T, Timurkaynak E. Monitoring of serum ionized magnesium in neurosurgical intensive care unit: preliminary results. Clin Chim Acta. 2003;334:211-5.
76. Kaplan M, Kut MS, Icer UA, Demirtas MM. Intravenous magnesium sulfate prophylaxis for atrial fibrillation after coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125:344-52.
77. Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014:CD010909.
78. Khalil MA, Al-Agaty AE, Ali WG, Abdel Azeem MS. A comparative study between amiodarone and magnesium sulfate as antiarrhythmic agents for prophylaxis against atrial fibrillation following lobectomy. J Anesth. 2012;27:56-61.
79. Kidwell CS, Lees KR, Muir KW, Chen C, Davis SM, De Silva DA, et al. Results of the MRI substudy of the intravenous magnesium efficacy in stroke trial. Stroke. 2009;40:1704-9.
80. Kingston ME, Al-Siba'i MB, Skooge WC. Clinical manifestations of hypomagnesemia. Crit Care Med. 1986;14:950-4.
81. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med. 1977;137:203-20.
82. Koch SM, Warters RD, Mehlhorn U. The simultaneous measurement of ionized and total calcium and ionized and total magnesium in intensive care unit patients. J Crit Care. 2002;17:203-5.
83. Kokturk N, Turktas H, Kara P, Mullaoglu S, Yilmaz F, Karamercan A. A randomized clinical trial of magnesium sulphate as a vehicle for nebulized salbutamol in the treatment of moderate to severe asthma attacks. Pulm Pharmacol Ther. 2005;18:416-21.
84. Kolte D, Vijayaraghavan K, Khera S, Sica DA, Frishman WH. Role of magnesium in cardiovascular diseases. Cardiol Rev. 2014;22:182-92.
85. Kumar S, Honmode A, Jain S, Bhagat V. Does magnesium matter in patients of medical intensive care unit: a study in rural central India. Indian J Crit Care Med. 2015;19:379-83.
86. Laiq N, Anwar Khan R, Malik A, Ahmad H. Intravenous magnesium prevents atrial fibrillation after valvular heart surgery. J Med Sci (Peshawar). 2013;21:77-80.
87. Lamers KJ, Vos P, Verbeek MM, Rosmalen F, van Geel WJ, van Engelen BG. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res Bull. 2003;61:261-4.
88. Lampl Y, Gilad R, Geva D, Eshel Y, Sadeh M. Intravenous administration of magnesium sulfate in acute stroke: a randomized double-blind study. Clin Neuropharmacol. 2001;24:11-5.
89. Lazard EM. A preliminary report on the intravenous use of magnesium sulphate in puerperal eclampsia. Am J Obstet Gynecol. 1925;9:178-88.
90. Lee TM, Ivers NM, Bhatia S, Butt DA, Dorian P, Jaakkimainen L, et al. Improving stroke prevention therapy for patients with atrial fibrillation in primary care: protocol for a pragmatic, cluster-randomized trial. Implement Sci. 2016;11:159.
91. Lim P, Jacob E. Magnesium deficiency in liver cirrhosis. Q J Med. 1972;41:291-300.
92. Ling ZG, Wu YB, Kong JL, Tang ZM, Liu W, Chen YQ. Lack of efficacy of nebulized magnesium sulfate in treating adult asthma: A meta-analysis of randomized controlled trials. Pulm Pharmacol Ther. 2016;41:40-7.
93. Lip GYH. Optimizing stroke prevention in elderly patients with atrial fibrillation. J Thromb Haemost. 2016;14:2121-3.
94. Liu X, Yu T, Rower JE, Campbell SC, Sherwin CM, Johnson MD. Optimizing the use of intravenous magnesium sulfate for acute asthma treatment in children. Pediatr Pulmonol. 2016;51:1414-21.
95. Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7:728-41.
96. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM. 2010;103:387-95.
97. Mahajan P, Haritos D, Rosenberg N, Thomas R. Comparison of nebulized magnesium sulfate plus albuterol to nebulized albuterol plus saline in children with acute exacerbations of mild to moderate asthma. J Emerg Med. 2004;27:21-5.
98. Mangat HS, D'Souza GA, Jacob MS. Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma: a clinical trial. Eur Respir J. 1998;12:341-4.
99. Martin KJ, Gonzalez EA, Slatopolsky E. Clinical consequences and management of hypomagnesemia. J Am Soc Nephrol. 2009;20:2291-5.
100. Martindale W, Westcott WW. The extra pharmacopia of unofficial drugs and chemical and pharmaceutical preparations. London: Pharmaceutical, 2008.
101. Mazur A, Maier JAM, Rock E, Gueux E, Nowacki W, Rayssiguier Y. Magnesium and the inflammatory response: Potential physiopathological implications. Arch Biochem Biophys. 2007;458:48-56.
102. Mazurek M, Lip GY. To occlude or not? Left atrial appendage occlusion for stroke prevention in atrial fibrillation. Heart. 2017;103:93-5.
103. McIntosh TK. Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: a review. J Neurotrauma. 1993;10:215-61.
104. McLellan BA, Reid SR, Lane PL. Massive blood transfusion causing hypomagnesemia. Crit Care Med. 1984;12:146-7.
105. Memon ZI, Altura BT, Benjamin JL, Cracco RQ, Altura BM. Predictive value of serum ionized but not total magnesium levels in head injuries. Scandinavian J Clin Lab Invest. 2009;55:671-7.
106. Miller JW, D'Ambrosio R. When basic research doesn't translate to the bedside--lessons from the magnesium brain trauma study. Epilepsy Curr. 2007;7:133-5.
107. Mirrahimi B, Mortazavi A, Nouri M, Ketabchi E, Amirjamshidi A, Ashouri A, et al. Effect of magnesium on functional outcome and paraclinical parameters of patients undergoing supratentorial craniotomy for brain tumors: a randomized controlled trial. Acta Neurochir (Wien). 2015;157:985-91.
108. Mizukoshi G, Katsura K-i, Katayama Y. Urinary 8-hydroxy-2′-deoxyguanosine and serum S100βin acute cardioembolic stroke patients. Neurol Res. 2013;27:644-6.
109. Mousavi SA, Ziaei J, Saadatnia M. Magnesium sulfate in acute stroke: a randomized double-blind clinical trial. J Res Med Sci. 2004;9:158-61.
110. Mousavi SAJ, Salimi S, Rezai M. Serum magnesium level impact on the outcome of patients admitted to the intensive care unit. Tanaffos. 2010;9(4):28-33.
111. Mubagwa K, Gwanyanya A, Zakharov S, Macianskiene R. Regulation of cation channels in cardiac and smooth muscle cells by intracellular magnesium. Arch Biochem Biophys. 2007;458:73-89.
112. Muir KW, Lees KR. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Stroke. 1995;26:1183-8.
113. Muir KW, Lees KR, Ford I, Davis S. Intravenous magnesium efficacy in stroke study. I. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004;363:439-45.
114. Muroi C, Terzic A, Fortunati M, Yonekawa Y, Keller E. Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial. Surg Neurol. 2008;69:33-9.
115. Nadler JL, Rude RK. Disorders of magnesium metabolism. Endocrinol Metab Clin North Am. 1995;24:623-41.
116. Nannini LJ Jr, Hofer D. Effect of inhaled magnesium sulfate on sodium metabisulfite-induced bronchoconstriction in asthma. Chest. 1997;111:858-61.
117. Nannini LJ Jr, Pendino JC, Corna RA, Mannarino S, Quispe R. Magnesium sulfate as a vehicle for nebulized salbutamol in acute asthma. Am J Med. 2000;108:193-7.
118. Noronha JL, Matuschak GM. Magnesium in critical illness: metabolism, assessment, and treatment. Intensive Care Med. 2002;28:667-79.
119. Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Curr Treat Options Cardiovasc Med. 2003;5:441-9.
120. Porter RS, Nester, Braitman LE, Geary U, Dalsey WC. Intravenous magnesium is ineffective in adult asthma, a randomized trial. Eur J Emerg Med. 2001;8:9-15.
121. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Obstet Gynecol Survey. 1955;10:494-507.
122. Rahimi-Bashar F, Ansari O, Jarahzadeh M. Total serum magnesium level in ICU in-patients under mechanical ventilation. J Biol Today's World. 2017;5(1):25-9.
123. Ralston MA, Murnane MR, Kelley RE, Altschuld RA, Unverferth DV, Leier CV. Magnesium content of serum, circulating mononuclear cells, skeletal muscle, and myocardium in congestive heart failure. Circulation. 1989;80:573-80.
124. Reinhart RA. Magnesium metabolism. A review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med. 1988;148:2415-20.
125. Rinosl H, Skhirtladze K, Felli A, Ankersmit HJ, Dworschak M. The neuroprotective effect of magnesium sulphate during iatrogenically-induced ventricular fibrillation. Magnes Res. 2013;26:109-19.
126. Rolla G, Bucca C, Bugiani M, Arossa W, Spinaci S. Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects. Allergy. 1987;42:186-8.
127. Romani AM. Cellular magnesium homeostasis. Arch Biochem Biophys. 2011;512:1-23.
128. Rowe BH. Intravenous and inhaled MgSO4 for acute asthma. Lancet Respir Med. 2013;1:276-7.
129. Rowe BH, Camargo CA Jr. The role of magnesium sulfate in the acute and chronic management of asthma. Curr Opin Pulm Med. 2008;14:70-6.
130. Rower JE, Liu X, Yu T, Mundorff M, Sherwin CM, Johnson MD. Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma. Eur J Clin Pharmacol. 2017;73:325-31.
131. Ryzen E, Wagers PW, Singer FR, Rude RK. Magnesium deficiency in a medical ICU population. Crit Care Med. 1985;13:19-21.
132. Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med. 2015;372:528-36.
133. Scarfone RJ, Loiselle JM, Joffe MD, Mull CC, Stiller S, Thompson K, et al. A randomized trial of magnesium in the emergency department treatment of children with asthma. Ann Emerg Med. 2000;36:572-8.
134. Schanne FA, Gupta RK, Stanton PK. 31P-NMR study of transient ischemia in rat hippocampal slices in vitro. Biochim Biophys Acta. 1993;1158:257-63.
135. Sedlacek M, Schoolwerth AC, Remillard BD. Electrolyte disturbances in the intensive care unit. Semin Dial. 2006;19:496-501.
136. Selvaraj T, Syed AA. Serum magnesium in postoperative patients admitted to the intensive care unit. Eur J Intern Med. 2014;25:e48-9.
137. Shah GM, Alvarado P, Kirschenbaum MA. Symptomatic hypocalcemia and hypomagnesemia with renal magnesium wasting associated with pentamidine therapy in a patient with AIDS. Am J Med. 1990;89:380-2.
138. Shah GM, Kirschenbaum MA. Renal magnesium wasting associated with therapeutic agents. Miner Electrolyte Metab. 1991;17:58-64.
139. Shan Z, Rong Y, Yang W, Wang D, Yao P, Xie J, et al. Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis. Respir Med. 2013;107:321-30.
140. Shane SR, Flink EB. Magnesium deficiency in alcohol addiction and withdrawal. Magnes Trace Elem. 1991;10:263-8.
141. Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, et al. IV Magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002;122:489-97.
142. Simpson KR, Knox GE. Obstetrical accidents involving intravenous magnesium sulfate: recommendations to promote patient safety. MCN Am J Matern Child Nurs. 2004;29:161-9;quiz 170-1.
143. Singh AK, Gaur S, Kumar R. A randomized controlled trial of intravenous magnesium sulphate as an adjunct to standard therapy in acute severe asthma. Iran J Allergy Asthma Immunol. 2008;7:221-9.
144. Singh H, Jalodia S, Gupta MS, Talapatra P, Gupta V, Singh I. Role of magnesium sulfate in neuroprotection in acute ischemic stroke. Ann Indian Acad Neurol. 2012;15:177-80.
145. Sirin BH, Coskun E, Yilik L, Ortac R, Sirin H, Tetik C. Neuroprotective effects of preischemia subcutaneous magnesium sulfate in transient cerebral ischemia. Eur J Cardiothorac Surg. 1998;14:82-8.
146. Sleeswijk ME, Tulleken JE, Van Noord T, Meertens JH, Ligtenberg JJ, Zijlstra JG. Efficacy of magnesium-amiodarone step-up scheme in critically ill patients with new-onset atrial fibrillation: a prospective observational study. J Intensive Care Med. 2008;23:61-6.
147. Soesan MDM, Sanders PGT, Kesecioglu MDPJ, Sanders PR, Huijgen PHJ, Mairuhu BWM. Magnesium levels in critically ill patients. Am J Clin Pathol. 2000;114:688-95.
148. Stippler M, Crago E, Levy EI, Kerr ME, Yonas H, Horowitz MB, et al. Magnesium infusion for vasospasm prophylaxis after subarachnoid hemorrhage. J Neurosurg. 2006;105:723-9.
149. Su Z, Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: a systematic review and meta-analysis. Pediatr Emerg Care. 2016;epub ahead of print.
150. Talkachova A, Jaakkola J, Mustonen P, Kiviniemi T, Hartikainen JEK, Palomäki A, et al. Stroke as the first manifestation of atrial fibrillation. Plos One. 2016;11:e0168010.
151. Thongon N, Krishnamra N. Omeprazole decreases magnesium transport across Caco-2 monolayers. World J Gastroenterol. 2011;17:1574-83.
152. Tiffany BR, Berk WA, Todd IK, White SR. Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest. 1993;104:831-4.
153. Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med. 2005;20:3-17.
154. Treggiari-Venzi MM, Waeber JL, Perneger TV, Suter PM, Adamec R, Romand JA. Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery. Br J Anaesth. 2000;85:690-5.
155. Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation. 1988;77:392-7.
156. van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005;36:1011-5.
157. van Norden AG, van den Bergh WM, Rinkel GJ. Dose evaluation for long-term magnesium treatment in aneurysmal subarachnoid haemorrhage. J Clin Pharm Ther. 2005;30:439-42.
158. Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, et al. Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2002;96:510-4.
159. Volpe P, Vezu L. Intracellular magnesium and inositol 1,4,5-trisphosphate receptor: molecular mechanisms of interaction, physiology and pharmacology. Magnes Res. 1993;6:267-74.
160. von Vigier RO, Truttmann AC, Zindler-Schmocker K, Bettinelli A, Aebischer CC, Wermuth B, et al. Aminoglycosides and renal magnesium homeostasis in humans. Nephrol Dial Transplant. 2000;15:822-6.
161. Wacker WE, Parisi AF. Magnesium metabolism. N Engl J Med. 1968;278:658-63.
162. Wacker WEC. Normocalcemic magnesium deficiency tetany. Jama. 1962;180:161.
163. Wang LC, Huang CY, Wang HK, Wu MH, Tsai KJ. Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia. J Neurotrauma. 2012;29:1518-29.
164. Watanabe Y, Dreifus LS. Electrophysiological effects of magnesium and its interactions with potassium. Cardiovasc Res. 1972;6:79-88.
165. Weglicki WB, Phillips TM. Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis. Am J Physiol. 1992;263:R734-7.
166. Westermaier T, Stetter C, Vince GH, Pham M, Tejon JP, Eriskat J, et al. Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, clinical study. Crit Care Med. 2010;38:1284-90.
167. White RE, Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochem Pharmacol. 1989;38:859-67.
168. Whyte KF, Addis GJ, Whitesmith R, Reid JL. Adrenergic control of plasma magnesium in man. Clin Sci (Lond). 1987;72:135-8.
169. William JH, Danziger J. Magnesium deficiency and proton-pump inhibitor use: a clinical review. J Clin Pharmacol. 2016;56:660-8.
170. William JH, Nelson R, Hayman N, Mukamal KJ, Danziger J. Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology (Carlton). 2014;19:798-801.
171. Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, et al. Plasma magnesium concentrations and clinical outcomes in aneurysmal subarachnoid hemorrhage patients: post hoc analysis of intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage trial. Stroke. 2010;41:1841-4.
172. Zafar MS, Wani JI, Karim R, Mir MM, Koul PA. Significance of serum magnesium levels in critically ill-patients. Int J Appl Basic Med Res. 2014;4:34-7.
173. Zandsteeg AM, Hirmann P, Pasma HR, Yska JP, ten Brinke A. Effect of MgSO(4) on FEV(1) in stable severe asthma patients with chronic airflow limitation. Magnes Res. 2009;22:256-61.
174. Zhao L, Wang W, Zhong J, Li Y, Cheng Y, Su Z, et al. The effects of magnesium sulfate therapy after severe diffuse axonal injury. Ther Clin Risk Manag. 2016;12:1481-6.
175. Zhu HD, Martin R, Meloni B, Oltvolgyi C, Moore S, Majda B, et al. Magnesium sulfate fails to reduce infarct volume following transient focal cerebral ischemia in rats. Neurosci Res. 2004;49:347-53.

Table 1: Summary of clinical studies evaluating the role of magnesium sulfate (MgSO4) in critically ill patients

[*] Corresponding Author:

Yunes Panahi, Clinical Pharmacy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran, eMail: