Electrolyte abnormalities are common in hospitalized patients. Critically ill patients in an intensive care unit (ICU) are predisposed to magnesium deficiency because they have a high magnesium consumption, reduced magnesium intake, reduced magnesium absorption or pharmacologically induced urinary magnesium loss [1,2]. The prevalence of hypomagnesaemia varies according the population studied and the method used to identify it [1,3-5].
Only 1% of total body magnesium is found in the extracellular compartment whereas 60% is in the bones and 39% in the tissues. In spite of the fact that only 1% of the total body magnesium is represented by measurement of the magnesium concentration in plasma, measurement of the extracellular magnesium concentration is the most common method to evaluate magnesium metabolism clinically, because the extracellular compartment can easily be sampled.
Measurement of intracellular magnesium concentrations in erythrocytes, lymphocytes, sublingual epithelial cells and bones is invasive and technically complicated. Moreover, extracellular magnesium concentrations do not correlate well with intracellular magnesium concentrations .
There are studies which have tried to evaluate the clinical significance of low magnesium concentrations in critically illness. Rubeiz and colleagues  showed that hypomagnesaemia detected at the time of admission for acutely ill medical patients is associated with an increased mortality rate for ward and medical ICU patients and that time to death was shorter for patients with hypomagnesaemia than for those with normal magnesium plasma concentrations. Frankel and colleagues  suggest that there is a correlation between high mortality rates and hypomagnesaemia in the ICU.
The magnesium loading test has been demonstrated in various studies to be a sensitive and reliable test to assess magnesium status in critically ill patients [8-11].
The purpose of this investigation was to evaluate intracellular erythrocyte, total plasma, extracellular ionized and urinary magnesium concentrations and urinary magnesium retention by an intravenous (i.v.) magnesium loading test in order to investigate, whether intracellular, extracellular and urinary magnesium concentrations predict magnesium retention as measured by a magnesium loading test.
Materials and methods
Patients and healthy subjects
The procedures were performed in accordance with the Helsinki Declaration of 1964 and after Ethics Committee approval by the medical faculty of the Georg-August-University of Goettingen. One-hundred-and-three patients (36 females, 67 males) in a surgical ICU and 41 healthy volunteers (13 females, 28 males) took part in the study. Age was not matched between subjects and controls. Simplified acute physiology score (SAPS II) was evaluated in ICU patients as a measure of severity of illness. Age, height, weight and body mass index (BMI) are described in Table 1. Primary diagnoses of the patients were polytrauma (n = 48) and respiratory insufficiency (n = 55). Furosemide was given in 67 (65%) patients.
Inclusion criteria for the patients taking part in the study were length of ICU stay more than 4 days and age over 18 yr. Exclusion criteria were: plasma creatinine ≥ 0.11 mmol L−1; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 80U L−1; ileus, gastrointestinal tumour, peritonitis, gastroenteritis or diarrhoea; ventricular dysrhythmia; pregnancy or lactation; large loss of fluid by gastric tube or drainage.
Inclusion criteria for the healthy control group were age over 18 yr and no ongoing medical treatment. Exclusion criteria were: recent hospitalization; plasma creatinine ≥ 0.11 mmol L−1; AST or ALT > 80 U L−1; ileus, gastrointestinal tumour, peritonitis, gastroenteritis or diarrhoea; ventricular dysrhythmia; pregnancy or lactation. Patients and healthy subjects with atrial dysrhythmia were not excluded from the study.
Three millilitres of blood were obtained from arterial (ICU patients) or venous (healthy subjects) catheters for the measurement of total plasma and ionized extracellular magnesium concentrations and intracellular erythrocyte magnesium concentration. A tourniquet was not used. After the withdrawal of blood, ionized magnesium concentrations were measured using a Novastat profile ultra (NOVA Biomedical, Waltham, USA). Blood was also drawn into 1 mL Eppendorf cups and centrifuged for 2 min at 10 000 rpm (Eppendorf Centrifuge 5415). Plasma was removed using a pipette. Plasma and erythrocyte fractions were frozen at −20°C.
The magnesium loading test was performed as previously described by Ryzen and colleagues . On the day preceding the test, urine collection was commenced for 24 h in order to evaluate the baseline urinary magnesium excretion before magnesium loading.
After the baseline 24 h urine was completed the patients and healthy subjects were all given 0.1 mmol kg−1 lean body weight i.v. magnesium hydrogen aspartate in 5% glucose over 4 h. This dose was chosen so as not to greatly exceed the renal tubular maximum of magnesium reabsorption. The magnesium loading test started at 08.00 h. Twenty-four hour urine samples were again collected from the start of the infusion. The amount of collected urine was measured, hydrochloric acid 25% was added to a hydrogen ion concentration of 10−5 mol L−1 and frozen at −20°C.
For the analyses of magnesium concentrations in plasma, erythrocytes and urine, samples were thawed and treated as follows. Plasma was diluted 1:50 with strontium chloride, erythrocytes were diluted 1:1 with 0.1 N sulphuric acid and urine was diluted 1:7 with distilled water. Magnesium concentrations of plasma, erythrocytes and urine were analysed using an atomic absorption spectrophotometer (Perkin-Elmer, Zeeman 5100). The retention of magnesium following the magnesium loading test was calculated as follows:
where Mg1 is the baseline urinary magnesium excretion before magnesium loading (mmol) and Mg0 is the urinary magnesium excretion following magnesium loading (mmol).
Mean and standard deviations (SD) were calculated for patient characteristics data stratified by gender. Patient characteristics data were compared using the t-test for independent samples. Total plasma, ionized extracellular and intracellular magnesium concentration, urinary magnesium excretion before magnesium loading and magnesium retention of both groups were compared by an one-factor analysis with the factor group and covariable age.
In order to predict the results of the magnesium loading test, firstly, magnesium retention was compared for patients and controls adjusting for gender, age and BMI by analysis of covariance. Subsequently, relevant factors determining magnesium retention - defined as P < 0.01 - were identified by multiple regression using gender, age, BMI, and intracellular, total plasma, ionized extracellular and urinary magnesium concentrations as independent variables. These variables were used because the literature has shown an influence of these variables on magnesium measurements. Analyses were performed using the statistical package Statistica '99 Edition.
Population descriptors for the study and the control groups are shown in Table 1. Total plasma, ionized extracellular and urinary magnesium excretion before magnesium loading were not different between patients and controls, whereas intracellular magnesium concentration (P < 0.01) and magnesium retention (P < 0.001) were significantly increased in ICU patients in comparison with healthy subjects (Table 2).
There was a significant influence of the factor ‘group’ (patients/controls) on magnesium retention (P < 0.001). Gender, age and BMI had no effect on magnesium. Multiple regression was performed for patients and healthy subjects. Total plasma magnesium concentration was the only parameter that had a significant predictive property regarding magnesium retention in intensive care patients (P < 0.01) but was poorly correlated with magnesium retention (r = 0.36, r2 = 0.13) (Table 3). However, only 10% of the magnesium retention data were explained by the total plasma magnesium concentration. Age, BMI, intracellular and ionized magnesium concentrations and urinary magnesium excretion did not contribute significantly to the prediction of magnesium retention in ICU patients. In healthy subjects, however, none of the evaluated variables had a significant influence on magnesium retention.
Magnesium plays an essential role in both extracellular and intracellular metabolism [5,13]. Magnesium deficiency results primarily from gastrointestinalor urinary magnesium losses, but malnutrition and decreased magnesium intake may hasten the development of magnesium depletion [14,15]. Subsequently, patients on an ICU are predisposed to magnesium depletion because of magnesium loss by diuretics, inadequate magnesium intake and a high magnesium turnover due to a hypermetabolic state.
The incidence of magnesium deficiency in hospitalized patients is common, but frequently present with normal plasma magnesium concentrations [5,11]. This can be explained by the fact that the human body contains 1000 mmol (24 g) magnesium of which 60% is present in bone and 39% in skeletal muscle and other tissues like heart and liver while only 1% is found in the extracellular compartment . Accordingly, no single determination is available to accurately assess magnesium metabolism, and magnesium concentrations in different compartments have been shown not to correlate .
Determination of the total plasma and ionized magnesium blood concentrations has become the simplest and most useful approach for evaluation of magnesium metabolism [17,18]. Methods for the measurement of intracellular magnesium concentration in sublingual, myocardial, hepatic cells and bone are complicated and invasive so are not used in routine clinical chemistry laboratories. Determination of intracellular magnesium concentrations has shown marked variation because reticulocytes undergo changes in membrane lipid composition and ion transport properties during the maturation process, leading to an increase in intracellular free magnesium concentrations upon maturation .
The kidney plays a major role in regulation of magnesium metabolism. Variations in magnesium intake are paralleled by changes in excretion of magnesium . The magnesium loading test has been found to be a sensitive and reliable tool for the evaluation of magnesium metabolism because normo- and hypomagnesaemic subjects retain significantly greater amounts of i.v. administered magnesium than healthy subjects and because, in patients who were restudied following parenteral magnesium repletion, retention of magnesium load has returned to normal [5,9,11,12,15].
Ryzen and colleagues  investigated 6 hypo- and 18 normomagnesaemic alcoholic patients in comparison with 16 normal subjects. In patients who were restudied following parenteral magnesium repletion, retention of the magnesium load had returned to normal. The authors concluded that increased retention of a magnesium load is a more sensitive index of magnesium deficiency than the magnesium serum concentration and suggested that magnesium loading should be used more frequently as a clinical tool in the evaluation of normomagnesaemic magnesium deficiency.
Gullestad and colleagues  investigated 661 hospitalized patients with medical conditions assumed to interfere with magnesium uptake and excretion. A group of 30 patients without any known predisposition for magnesium deficiency and a group of 27 healthy volunteers recruited from the medical staff served as controls. A significantly higher magnesium retention was observed in the patients. The mean serum magnesium concentration among the patient groups was similar to the control group except for the alcoholics, hypertensives and young healthy controls who had significantly reduced levels.
It is interesting that the magnesium retention of the healthy volunteers in our study was higher than the magnesium retention of the control group of Gullestad and colleagues .
The ICU patients had a higher intracellular magnesium concentration than the healthy subjects despite an increased magnesium retention. This is in accordance with the findings of Gullestad and colleagues  who demonstrated an increased serum magnesium concentration in critically ill patients compared with healthy subjects. One reason for this might be a higher turnover of magnesium because of an increased demand for magnesium by critically ill patients. Although ICU patients did not significantly excrete more magnesium than healthy subjects, magnesium retention was increased, which also may be influenced by the furosemide given. Although furosemide is known to increase urinary magnesium excretion which is reflected in magnesium depletion, in this study magnesium excretion was not significantly different in critically ill patients and controls.
Magnesium retention has been shown to significantly correlate with age . In this study, age was not matched between subjects and controls but age was included as an independent variable in multiple regression in order to predict magnesium retention. Moreover, age was included as a covariable comparing the measures of magnesium retention. As many of the patients studied were older than the reference group, age could be a confounding factor for the interpretation of the magnesium retention data, but multivariate analysis showed that age was not a main contributor to increased magnesium retention.
It is known that magnesium levels may change between arterial and venous sampling because pH changes across tissue beds may be important in determining the magnesium value . In order to minimize this effect on the magnesium concentration, no tourniquet was used in this study.
The poor correlation between magnesium retention and other measures of magnesium demonstrate the need for further studies to clarify whether magnesium retention or a combination of measures of hypomagnesaemia is the best predictor of clinical outcome for critically ill patients in an ICU.
The results show that only total plasma magnesium concentration significantly predicted magnesium retention in ICU patients. However, only a small proportion of magnesium retention could be explained by the total plasma magnesium concentration. These findings may be explained by the fact that only 1% of the total body magnesium is found in the extracellular compartment. In case of a latent or early magnesium deficiency, there is a movement of magnesium out of intracellular compartments such as soft tissue and bone into extracellular fluid causing a movement of magnesium from intracellular to extracellular compartments and after this back into intracellular compartments in order to act as an intracellular enzymatic cofactor. The results confirm former studies which demonstrated that there is no correlation between erythrocyte magnesium concentration and other intracellular magnesium concentrations such as soft tissue and bone .
Rubeiz and colleagues  showed that patients with hypomagnesaemia in a medical ICU who died experienced a more rapidly deteriorating course than non-surviving normomagnesaemic patients. A possible explanation is that hypomagnesaemia may reflect an underlying metabolic disturbance that may predispose patients to an earlier and more severe decompensation of homeostatic mechanisms. Hypomagnesaemia was not the primary cause of death but the presence of hypomagnesaemia in acutely ill patients identified a group of patients with increased mortality rate that is independent of the severity of illness. Animal studies suggest that magnesium deficiency is associated with increased oxidative stress, supporting the hypothesis that magnesium deficiency reduces the threshold antioxidant capacity.
Further studies are needed to explore the relationships between clinical outcome, magnesium concentration and retention, particularly with reference to the magnesium loading test. The fact that total plasma magnesium concentration was not able to predict magnesium retention in healthy subjects may be caused by only 10% of the variability in magnesium retention being attributable to the plasma magnesium concentration.
Total plasma magnesium concentration was the only parameter that was significantly correlated with magnesium retention and predicted magnesium retention in ICU patients using the magnesium loading test. The other intracellular and extracellular magnesium concentrations did not. However, only 10% of the variability in magnesium retention was attributed to the total plasma magnesium concentration. Further studies are needed to clarify whether magnesium retention or a combination of measures of hypomagnesaemia is the best predictor of clinical outcome in critically ill patients on an ICU.
The authors gratefully acknowledge Matthias Schmidt and the nurses of the ICU 0112 and 0113 for their assistance in providing the samples from the patients, Heribert Tölke and Michael Joneleit for their generous assistance in providing the samples from healthy subjects and Bettina Kulle for her assistance in statistical data analysis.
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