Aminophylline Infusion Induced Excretion of Magnesium During Magnesium Loading Test in Critically Ill Patients

Document Type: Research Paper


1 Faculty of Pharmacy, and Neuroscience Research Centre, Kerman University of Medical Sciences, Kerman, Iran

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


      The aim of this study was to investigate the prevalence of Mg deficiency and effect of aminophylline infusion on urine magnesium concentration after magnesium loading test (MLT). To determine serum Mg, venous blood specimens were obtained just before the first MLT. Two MLTs were performed. The first one was done before starting aminophylline infusion and the 2nd one was done during aminophylline infusion. Urine samples were collected from the starting of Mg infusion in each phase. Although low serum Mg was present only in 2 patients, MLT showed Mg deficiency in 18 patients. MLT detected Mg deficiency in 13 out of 14 patients with normal serum Mg, in 2 out of 2 subjects with serum hypomagnesemia, and in 3 out of 5 cases with serum hypomagnesemia. There was no relationship between Mg retention, age and serum Mg concentrations. Aminophylline administration increased the 24-h urine Mg concentration by 29.3%.


1. Introduction

      Magnesium (Mg) is the fourth most abundant cation in the body and the second most prevalent intracellular cation. It serves as a cofactor for about 300 cellular enzymes [1, 2]. Magnesium is essential for virtually all hormonal reactions that occur in the body [3]. It plays an essential role in the function of the cell membrane sodium-potassium ATPase pump [4]. Hypomagnesemia may cause cardiac, neuromuscular and central nervous system dysfunction. It is also associated with imbalance of other electrolytes, such as K+ and Ca2+ [5].

     Since only 1% of total body Mg is in the extra cellular fluid, serum Mg concentration may not adequately reflect Mg status. Significant Mg deficiency may exist while plasma Mg level is normal. Thus normal serum Mg could constitute a serious underestimation of the severity of Mg deficit [6-8]. The simplest and possibly the most reliable test used in the assessment of functional magnesium deficiency is believed to be the magnesium loading test (MLT). MLT appears to be valid in critically ill patients. Surveys of serum Mg levels in hospitalized patients indicate a high incidence of hypomagne-saemia (presumably an underestimate of the true incidence of Mg deficiency), ranging from 11% to 47% in general patients [9-11] and 20% to 65% in patients admitted to intensive care units [11-13].

     The main uses of aminophylline (ethylene-diamine theophylline) in critically ill patients are bronchospasm treatment and weaning patients from the ventilator [14]. One of the electrolyte abnormalities associated with theophylline administration is hypomagne-saemia [15]. There is no report yet that has evaluated aminophylline effects on urine Mg concentration after MLT in the intensive care unit (ICU) patients. Due to the importance of Mg deficiency and widespread use of aminophylline in the ICU, we decided to evaluate Mg status and the interaction between aminophylline and Mg status. This study was conducted in the critically ill patients at Sina Hospital (Affiliated with Tehran University of Medical Sciences, Iran).


2. Materials and methods

     This study was a quasi-experimental survey on 21 cases who were admitted for at least 72 h in the intensive care unit (ICU). The study was approved by the human ethics committee of Tehran University of Medical Sciences. The exclusion criteria were impaired renal function (serum creatinine>1.5 mg/dl) and known cases of renal failure, heart rate nd MLT was performed. The MLT was performed as described earlier in detail [17]. MgSO4 (30 mmole; 7.5 g) was administered as a continuous intravenous infusion for an 8 h period [16,18] . Mean arterial blood pressure, electrocardiogram, pulse rate, respiratory rate and deep tendon reflexes were recorded to detect any sign of hypomagne-saemia. Urine samples were collected in plastic bottles acidified with 15 ml 10% HCl from the beginning of the infusion for 24 h [19]. The uptake of Mg was calculated from the Mg dose given intravenously and the amount excreted during the study time and was expressed in percent of the amount of Mg given [1, 17]. [(30 mmol Mg2+ infused - amount of Mg2+ excreted in urine) 100]/30 mmol Mg2+ infused Venous blood specimens were obtained before defined as normal distribution.


Figure 1. Patients’ serum Mg status just before the first MLT.

Table 1. 24- h Patients urine magnesium content with and without aminophylline.

Urine magnesium (mg)





Without aminophylline




T= -5.5

Df= 20

P < 0.0001

With aminophylline





3. Results

      Mean patients age was 50±21 years (10 male, 11 female). Magnesium uptake (retention) in patients ranged from 39 to 93% with a mean value of 68.4%±13.2. Based on MLT, 18 patients had definite Mg deficiency and only 3 patients had normal level. The Pearson correlation coefficient (r) showed no linear relationship between Mg retention, age (r=0.1, p=0.63) and serum Mg (r=0.01, p=0.94). There was no correlation betweenMg uptake and sex (Chi2=14.3, p=0.575). Serum Mg concentrations (just before first MLT) were high in 5 patients, low in 2 patients, and normal in 14 patients (Figure1).

    Mg deficiency (according to MLT) was greatly found in 13 patients whose serum Mg levels were normal, in all hypomagnesemic cases and in 3 hypermagnesemic ones (Figure 2).

     The mean serum theophylline concentration and clearance were 5.9±2.6 mg/l and 1.64±0.93 l/h, respectively. Aminophylline administration increased 24 h urine magnesium concentration from 2302±1065 mg to 2773±9910 mg (by 29.3%; Table 1). No correlation was found between serum theophylline level and increase in urine Mg concentration (r=0.26, p=0.255).


4. Discussion

      Mg deficiency may have clinical importance due to important functions of Mg in the body. However, Mg deficiency has not usually been considered in clinical practice due to the lack of relevant blood tests and because the symptoms are not often clear or specific. Serum Mg is generally agreed to be a poor indicator of tissue Mg. Many of the methods used to determine intracellular Mg concentration have been unreliable, difficult to replace and tedious. The MLT has been suggested to reflect Mg status of the patients [18].

     This study shows the importance of MLT in determining the true Mg status in the ICU admitted patients. In agreement with previous studies [18], Mg deficiency was highly prevalent in critically ill patients. MLT was able to detect Mg deficiency in 18 out of 21 critically ill patients whereas serum Mg levels indicated deficiency only in 2 of those patients. Sina Hospital MLT appears to reflect the true Mg status of patients better, it should be the test of choice when assessing Mg deficiency.

     Mg deficiency seems to be more common in our study population than others. According to our definition of Mg deficiency (  using the same definition ( in ICU admitted patients ), was 20-65%. According to the definition for Mg deficiency used by other authors [13, 17, 18] (< 70% Mg excretion of the total Mg given) all subjects in our study could be considered Mg deficient.

     Various factors such as protein-calori malnutrition, intravenous medication of Mg-free fluids, total parenteral nutrition and drugs such as loop diuretics, aminoglycosides and amphotericin B [22] put the patients in the ICU at risk for development of hypomagnesemia. We think the great prevalence of hypomagnesemia in our patients is due to not having standard enteral nutrition products and also not giving enough parenteral nutrion and supplements to the patients. In the present study furosemide infusion (1-2 mg/h) can not significantly increase magnesium excretion. This finding was noted in a study [16]. This study confirms that serum magnesium is not a reliable method to determine the magnesium status in critically ill patients.

     The main aim of this study was to evaluate the effects of aminophylline infusion on the 24 h urine Mg content. Theophylline may induce hypomagnesemia. Mild diuresis is produced by combined effects of theophylline on renal hemodynamics and on tubular reabsorbtion [23]. On the other hand, an increase in the level of intra-cellular cyclic AMP due to inhibition of phosphodiesteras-es by theophylline, results in hypomagnesemia [24]. Many previous studies of theophylline-associated metabolic disturbances have assessed the relation of toxic serum theophylline concentrations [15]. Most of them evaluated serum Mg levels after single dose theophylline administration. Nowadays, we know that serum Mg is not a reliable marker to diagnose hypomagnesemia. There is only one article that evaluated effects of theophylline on urine Mg excretion [25]. In this study, 10 asthmatic women were enrolled in the study, and 300 mg aminophylline (serum theophylline concentration was 8.5 mg/l) was infused in 10 min. and patients' urine samples were collected for 6 h. Aminophylline infusion increased total urinary excretion of Mg by 59% compared to control without alteration in serum Mg levels. Our study was novel and is different from Knutsen's [25] because we did MLT with and without aminophylline infusion. In our study aminophylline infusion (serum theophylline concentration was 5.9 mg/l) could increase urine Mg excretion by 29.3% compare to control. In our study, both serum theophylline concentration and Mg excretion were lower than that amounts in Knutsen study [25]. Although in both of them there were no correlation between serum theophylline and Mg excretion.


Figure 2. Percentage of Mg deficient patients according to MLT versus serum Mg level.

      We conclude that Mg deficiency is very common in our critically ill patients, specifically in patients who receive aminophylline.

[1]      Koivisto M, Valta P, Lingren L. Magnesium depletion in chronic terminal liver cirrhosis. Clin Transplant 2002; 16: 325-8.


[2]      Ronald EJ. Magnesium metabolism in health and disease. Disease Manth 1998; 34: 161-218.


[3]      Salem M, Munoz R, Chernow B. Hypomagnesemia in critical illness. Crit Care Clin 1991; 7: 225-52.


[4]      Arsenia MA. Magnesium and cardiovascular disease. Prog Cardiovasc Dis 1993; 35: 271-310.


[5]      Kingston ME, Al-Sibai MB, Skooge WC. Clinical manifestations of hypomagnesemia. Crit Care Med 1986; 14: 950-4.


[6]      Al-Ghamdi SM, Cameron EC, Sutton RA. Magnesium deficiency: Pathophysiologic and clinical overview. Am J Kidney Dis 1994; 24: 737-52.


[7]      Olerich MA, Rude RK. Should we supplement magnesium in critically ill patients? New Horiz 1994; 2: 186-92.


[8]       Lim P, Jacob E. Tissue magnesium level in chronic diarrhea. J Lab Clin Med 1972; 80: 313-31.

[9]      Whang R, Ryder KW. Frequency of hypomagnesemia and hypermagnesemia: requested vs routine. JAMA 1990; 263: 3063-4.


[10]   Wong ET, Rude RK, Singer FR, Shaw ST Jr. A high prevalence of hypomagnesemia and hyper-magnesemia in hospitalized patients. Am J Clin Pathol 1983; 79: 348-52.


[11]   Rubeiz GJ, Thill-Baharozian M, Hardie D, Carlson RW. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med 1993; 21: 203-9.


[12]   Reinhart RA, Desbiens NA. Hypomagnesemia in patients entering the ICU. Crit Care Med 1985;

13:  506-7.


[13]   Ryzen E, Wagers PW, Singer FR, Rude RK. Magneseium deficiency in medical ICU population. Crit Care Med 1985; 13: 19-21.


[14]   Kohls PR, Townsend PL, Markowsky SJ. Phar-macokinetics and dosing of theophylline. In:Rippe JM, (editor). Intensive care medicine, 2nd ed. New York; 1991. pp. 1748-53.


[15]   Flack JM, Ryder KW, Strickland D, Whang R. Metabolic correlates of theophylline therapy: A concentration-related phenomenon. Annals Pharmacother 1994; 28: 175-9.


[16]   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.


[17]   Gullestad L, Midtvedt K. The magnesium loading test: Reference values in healthy subjects. Scand J Clin Lab Invest 1994; 54: 23.


[18]   Gullestad L, Dolva L, Waage A, Falch D, Fagerthum H, Kjekshus J. Magnesium deficiency diagnosed by an intravenous loading test. Scand J Clin Lab Invest 1992; 52: 245-53.


[19]   Rob PM, Dick K, Bley N, Seyfert T, Brinckmann C, Hollriegel V, Friedrich HJ, Dibbelt L, Seelig MS. Can one really measure magnesium deficiency using the short-term magnesium loading test? J Inter Med 1999; 246: 373-8.


[20]   Papazachariou IM, Martinez-Isla A, Efthimior E, Williamson RC, Giris SI. Magnesium deficiency in patients with chronic pancreatitis identified by an intravenous loading test. Clinica Chimica Acta 2000; 302: 145-54.


[21]   Sohrevardi SM, Mojtahedzadeh M, Sadray S, Najafi A, Spence JD, Munoz C, Tavakoli H. The value of aminophylline dosing based on phar-macokinetic variables in the critically ill patients.J Medical Council IRI 2004; 22: 28-31.


[22]   Polderman KH, Bloemers FW, Peerdeman S, Girbes ARJ. Hypomagnesemia and hypophos-phatemia at admission in patients with severe head injury. Crit Care Med 2000; 28: 2022-5.


[23]   Pretzlaff RK, Vardis RJ, Pollack MM. Aminophylline in the treatment of fluid overload. Crit Care Med 1999; 27: 787-90.


[24]   Rayssiguier Y. Hypomagnesemia resulting from adrenaline infusion in ewes: Its relation to lipolysis. Horm Metab Res 1997; 9: 309-14.


[25]   Knutsen R, Bohmer T, Falch J. Intravenous theophylline-induced excretion of calcium, magnesium and sodium in patients with recurrent asthmatic attacks. Scand J Clin Lab Invest 1994; 54: 119-25.