Uploaded on January 30, 2002
Summary: Disorders of electrolyte homeostasis are known at many diseases and clinical situations. They have serious consequences for the cell. Mg-deficiency is followed by a K-deficiency, which cannot be equalized by K alone: a refractory hypokalemia always needs additional Mg supply for its restitution. From K, Mg-deficiency a Na/Ca-overload of the cell with aggravating consequences will follow: impaired activity and vitality with electric instability. Mg, which is responsible for development of a Ca-overload is also able to restore electrolyte homeostasis by sufficient supply competitively. The pathophysiologic relations for development of a cellular imbalance and its restitution concern the Na/K-pump, the Ca-pump and the Na/Ca-exchange. The clinical applications of Mg therefore are manifold: recovery under diuretic treatment, coronary heart disease, arrhythmias, perioperative electrolyte therapy, transcellular shifts, coronary dilatation and so on.
Electrolyte homeostasis - what does it mean? As we know, the electrolytes sodium, potassium, magnesium and calcium with their corresponding anions: chloride, phosphate and bicarbonate are represented within and without the cells at very different concentrations.
For those electrolytes a transcellular concentration difference exists with varying gradients between the. intra- and extracellular space - for example, here at the myocardium. Naturally there is a tendency for concentration differences to an equilibrium. It is a characteristic sign of life, however, that the cell shows a continuous effort against this tendency to maintain those given gradients with an expense of energy in the form of a dynamic electrolyte homeostasis. From the concentration gradients an electric voltage of the cell results, which we call the electric potential and which is calculable according to Nernst’s equation:
||In CE / CI|
|Table 1. Transcellular electrolyte gradients|
If the maintenance of the electrolyte gradients under electrolyte homeostasis is disturbed - for whatever reasons - then it has serious consequences for the cell:
Only within a certain limit and time will this be tolerable for the cell. Whenever the limits of injury are exceeded and the injury is irreversible, cellular death will be imminent. Then necrosis will develop, which later will be repaired by scarred tissue. Deleterious consequences for the heart than will be an insufficiency of the heart after a myocardial infarction or a rupture.
Imbalances of electrolyte homeostasis are known in many diseases or clinical situations, especially in patients with coronary heart disease, arrhythmias and angina pectoris, patients with acute myocardial infarction, with heart valve disease, hypertension and congestive heart failure, patients, treated with diuretics or cardiac glycosides, patients after reanimation or under intensive care. But trauma, polytrauma or surgical intervention also will impair the electrolyte homeostasis especially postoperatively. Many factors predisposing to electrolyte imbalance arise in open heart surgery with extracorporeal circulation. Patients suffering from burns need intensive electrolyte therapy. Furthermore, electrolyte imbalances must be presumed under excessive and long lasting stress, in latent tetany, cramps in the legs and diabetes. In the third trimester of pregnancy magnesium deficiency burdens the electrolyte situation. Chronic misuse of alcohol is another well known reason. A very wide field is the influence of hormonal disregulation on electrolyte homeostasis.
Electrolyte imbalances mainly concern the potassium gradient. High potassium gradients are characteristic for cells with high metabolic activity. Skeletal muscles and myocardium belong to these. Consequently, those tissues are affected first of all. Together with potassium the other predominantly intracellular cation magnesium is also involved, because potassium and magnesium deficiency mostly appear together. An isolated potassium deficiency is possible but it will remain a rarity. Lasting over a longer time, magnesium deficiency will always be followed by potassium deficiency secondarily and because potassium and magnesium are the most important intracellular cations, potassium and magnesium deficiency first of all is a deficiency of the cell.
Table 2. Disturbed electrolyte homeostasis known at:
For a long time it was not clear that with magnesium deficiency potassium will also be affected, because this combination must seem very paradoxical. Previously when those connections were not recognized, surprise was expressed, that an existing potassium deficiency could not be equalized by potassium substitution. This situation then was called 'a refractory potassium dose with refractory hypokalemia refractory potassium deficiency,' but it was dismissed as a curious event. Later on it was shown that increasing potassium supply aggravated the hypokalemic situation more and more. Today fortunately it is known, that increasing potassium supply will stimulate aldosterone secretion, so that renal excretion will increase too.
It is difficult to recognize electrolyte status according to serum values. Only about 2 per cent of the total body potassium (3600 mmol) is situated in the extracellular space and accessible there to measurement from plasma or serum. The situation for magnesium is much worse: only about 1 per cent from the total body magnesium (1000 mmol) is accessible in the extracellular space. Therefore it is uncertain whether the intracellular space with its much higher concentrations is provided with sufficient potassium and magnesium.
If a deficiency develops slowly, from insufficient supply, increased loss or higher demand, the organism will be able to maintain the serum concentrations at the same level for a longer time at the lower normal range. This will occur at the expense of the remaining electrolyte stores, which are mainly muscle, bone and liver. In this situation it is difficult to understand that serum levels, which are still within the normal range, will not indicate a potassium or magnesium deficit.
Serum magnesium will not usually be measured, because magnesium is not routinely measured. But in both cases magnesium deficiency cannot be recognized, unless deficiency symptoms point to an electrolyte deficiency or imbalance. Such symptoms may be: convulsions and cramps of the muscles or cardiac arrhythmias.
For a long time it has been known, that under cellular potassium magnesium deficiency a calcium overload of the cell will take place.
This alternating behaviour of magnesium to calcium is called calcium antagonism and relates back to the fundamental research of Hans Selye in Montreal and his counterpart Albrecht Fleckenstein in Freiburg.
Another very essential experience in this field was that cellular calcium overload can be reversed again with sufficient magnesium competitively. Magnesium therefore is called the physiologic calcium antagonist according to this mutual relation between calcium and magnesium.
Concomitantly to the calcium overload the cell additionally will be swamped by sodium, whereas potassium together with magnesium leaves the cell. Summarising, a magnesium deficiency is followed by a cellular potassium deficiency, which again causes a sodium and calcium over load of the cell. Then the electrolyte homeostasis between intra- and extracellular space is disturbed maximally: a total electrolyte imbalance now dominates.
Table 3. Refractory hypokalemia. 75 year old man, muscle weakness, diarrhoea, irregular heartbeat, diabetes, congestive heart failure after AMI
|On admission||+40 mmol KCl i.v.||+30 mmol MgSO4 i.v.|
|Muscle-K||33||.6||34||.5||45||.3 mmol/100g dw|
|Muscle-Mg||3||.67||3||.62||4||.26 mmol/100g dw|
|Muscle-Na||37||.4||37||.5||13||.2 mmol/100g dw|
|Daily: 53 mmol K+||(Whang 1985)|
Those changes have been confirmed experimentally and in clinical practice.1
A very characteristic example may be the case of a 75 year old patient suffering from congestive heart failure after myocardial infarction and from diabetes. Additionally he had diarrhoea and cardiac arrhythmias. He was also treated with diuretics. These anamnestic data must suggest a potassium-magnesium deficiency for many reasons. The cellular potassium and magnesium values, representatively measured at samples from muscle biopsies, are very deficient. Muscle sodium is very high, although serum potassium and magnesium are still within the normal range and do not suggest any deficiency.
For the first time the patient received 40 mmol potassium chloride intravenously. The serum potassium value did rise as expected, while serum magnesium remained unchanged. Also muscle potassium and magnesium did not change according to a biopsy 12 h later. This is a typical case for a refractory potassium deficiency. On the following day the patient received 30 mmol magnesium sulfate intravenously and again 12 h later the muscle biopsy showed an increase to normal potassium and magnesium values in the muscle, while the elevated muscle sodium now was decreased considerably, This example not only shows the close connections between potassium and magnesium, it also shows very convincingly the key role of magnesium for successful potassium substitution, which would have been impossible with potassium alone. With potassium chloride alone only a cosmetic correction of serum potassium was obtained, which was without any influence at the cellular potassium deficit and therefore it was without any sense. How can we understand this according to modern pathophysiologic relations?
The sodium/potassium pump at the cellular membrane maintains a high cellular potassium concentration by active transport against a considerable gradient. The pump is activated by magnesium. Under magnesium deficiency the pump function is impaired, because the membrane ATpase, the enzyme responsible, now shows reduced activity, The energy substrate for the transport activity of the sodium/potassium pump is represented by ATP in form of its magnesium complex. This ATP-Mg++ complex is split by the ATPase delivering the transport energy and therefore it is said that the ATPase is directing the sodium/potassium pump.
Magnesium deficiency, however means impaired effectivity of the sodium/potassium pump, whereby insufficient potassium can be pumped into the cell, although the potassium supply may be great enough. Therefore the paradoxical seeming statement can be understood, that magnesium deficiency will be the cause for potassium deficiency, Furthermore, under magnesium deficiency there is not enough energy substrate available for the sodium/potassium pump. The cell membrane now shows increased permeablilty and the gradients, especially the potassium gradient, cannot be maintained. Potassium leaves the cell and in compensation an influx of sodium and hydrogen ions will take place passively. Also, magnesium leaves the cell, if not enough ATP is present for forming the ATP-Mg complex and calcium influx will follow.
There are two possibilities for elimination of calcium out of the cell, but unfortunately both are impaired by magnesium deficiency: this is the calcium pump and the sodium/calcium exchange. After muscle contraction calcium ions will be transported back again from the cytosol to the stores of the sarcoplasmatic reticulum by the calcium pump. The concentration gradient at this action exceeds several decades and needs an high expense of energy: one ATP for two calcium ions. The calcium transport-ATPase there is magnesium dependent, but will be directed by calcium. The ionic compensation takes place presumably by one magnesium and two potassium ions.
The other possibility is sodium/calcium exchange. During the action potential calcium influx takes place along the slow calcium channels into the cell and induces the contraction procedure. The calcium influx will be compensated again by an exchange of three sodium ions into the cell. The energy for the exchange originates from the high extracellular sodium concentration, but the three sodium-ions must be removed again out of the cell by the sodium/potassium pump. For three sodium ions one ATP is necessary and finally for removing one calcium out of the cell by sodium/calcium exchange, one ATP is necessary.3
If the performance of the sodium/potassium pump is impaired, cellular sodium will increase and inhibit sodium/calcium exchange. This is due to ATP deficiency, ischemia, myocardial reperfusion, potassium and magnesium deficiency, hypothermia or an overdose of cardiac glycosides. In all cases the two impaired pumps together with the sodium/calcium exchange will lead to an accumulation of calcium within the cell, called calcium overload. Magnesium inhibits sodium/calcium exchange only with very high unphysiological concentrations, but it has an important influence on it. Increased extra- as well as intracellular magnesium is able to inhibit competitively the slow calcium-influx through the calcium channels of the sarcolemmal membrane in the myocardial cell. But decreased intra- as well as extracellular magnesium allows an increased calcium influx. This will burden the sodium/calcium exchange and also the energy demand of the sodium/potassium pump.
Whenever according to the described mechanisms the electrolyte homeostasis is disturbed and an electrolyte imbalance of the cell has taken place, deleterious consequences will follow:
Under all these conditions of increased energy consumption and disturbed perfusion, the way directly leads to ischemia of the concerning cells. Additionally the pump function of the heart is injured by ectopic beats and tachycardia. Therefore it can be concluded that magnesium deficiency, the subsequent potassium deficiency and calcium overload, cardiac ischemia and arrhythmias, moreover, will intensify themselves, forming a proceeding multifactorial vicious circle.
Recovery from electrolyte imbalance
The logic consequence to break up this fatal circle of a general electrolyte imbalance is to transport potassium and magnesium into the cell:
The example of the patient shown before could demonstrate, that the recovery of the electrolyte homeostasis is only possible with potassium and magnesium together. But it should not take place under urgent acute conditions, because the reactivation of the sodium/potassium pump as well as the reduction of the calcium overload needs some time.
Table 4. Mg-deficiency under diuretic therapy: balance only after Mg-supply
|n=12||On admission||+40 mmol KCl i.v.||+30 mmol MgSO4 i.v.|
|Muscle-K||39||.5||36||.0||42||.3 mmol/100 g dw|
|Muscle-Mg||3||.89||3||.53||4||.05 mmol/100 g dw|
This is shown by a Swedish study on 12 patients under diuretic therapy, who had developed a potassium-magnesium deficiency in spite of regular oral potassium substitution, obviously from the low values of muscle potassium and magnesium. The serum values are still within the normal range and do not reflect the actual existing cellular deficit. But the number of ventricular ectopic beats, about 200 per hour on average, should point out suspicion to the disturbed electrolyte situation.4
With supply of 40 mmol potassium chloride intravenously the serum levels did rise, but the supply was unsuccessuful, because an elevation of the cellular potassium in the muscle could not be realized. Only with subsequent or simultaneous additional magnesium supply after 12 h could normalization of muscle potassium and magnesium be obtained. It is consistent with the described pathophysiologic relations, that also the arrhythmias, induced by diuretics decrease essentially from 205 to 57 per hour.
The logic consequence. however. for any antiarrhythmic therapy therefore should be to normalize first of all the electrolyte status as well as the electric potentials at the cell membrane, before the ionic currents at the cell membrane are influenced by very effective membrane drugs such as antiarrhythmic drugs. Possibly several disappointing results of antiarrhythmic therapy studies in the past are related to the fact that not enough attention was paid to the electrolyte balance.
Very interestingly the same success as with potassium and magnesium supply can be obtained with magnesium supply alone. This case of a 75 year old woman with simultaneous potassium and magnesium deficiency according to a corresponding Anamnesis shows, that the cellular restitution of potassium and magnesium in the muscle is possible by mobilizing the present potassium stocks, after 30 mmol magnesium was given. The following potassium supply improves the situation additionally. Simultaneously the stepwise decrease of the high cellular sodium in the muscle can be demonstrated in agreement with the recovery of all the other transcellular gradients.1
All these examples show convincingly that magnesium alone plays a leading part for development of an electrolyte imbalance as well as for the recovery of electrolyte homeostasis. With respect to the fact that the electrolyte balance cannot happen suddenly, potassium and magnesium should be given as soon as possible. This will appply to all patients whose anamnesis suggests a magnesium deficiency or who show typical symptoms of it. All patients who are treated with diuretics, cardiac glycosides or cyclosporin need a regular potassium-magnesium supply.
Table 5. Refractory hypokalemia: 75-year old woman, increasing weakness, irregular heartbeat, diuretics, congestive heart failure
|On admission||+30 mmol MgSO4 i.v.||+40 mmol KCl i.v.|
|Muscle-K||38||.6||44||.5||47||.4 mmol/100 g dw|
|Muscle-Mg||3||.93||4||.04||4||.43 mmol/100 g dw|
|Muscle-Na||26||.5||18||.8||13||.1 mmol/100 g dw|
|daily: 27 mmol K||(Whang 1985)|
The electrolyte therapy in patients, who have to undergo surgery should begin preoperatively, so that an electrolyte balance without cellular deficits can be presumed at the beginning of the operation. It is very important to recognize an electrolyte imbalance in surgical patients and to equalize it, because many suffer from a potassium-magnesium deficiency as a result to their previous illness, for example diabetes, hypertension, coronary heart disease, cardiac valve disease, increased alcohol consumption or bad condition. The preoperative recovery of electrolyte homeostasis is very important, because the subsequent stress and trauma as well as duration or severity of the operation will induce additional transcellular electrolyte movements and loss of potassium and magnesium by increased secretion of catecholamines. The same follows from regional ischemia, hypoxidosis, acidosis and finally also the activation of the renin-angiotensin-aldosterone system with increased aldosterone secretion by renal hypoperfusion. In contrast to sodium or water, there exists no specific retention mechanism for potassium or magnesium. The increased renal excretion of potassium and magnesium by hyperaldosteronism will also continue if considerable depletion did occur in the organism. This deleterious fact can be corrected by aldosterone antagonists or specifically by adequate potassium and magnesium supply.
In the postoperative period it is no less important to maintain the potassium-magnesium homeostasis, because the patient in this period is very seriously ill. The catabolic phase, where potassium and magnesium are liberated from dying cells should change as soon as possible to the anabolic phase, where much potassium and magnesium will be necessary for generating new cells. Therefore also in the postoperative period will be an increased demand for potassium and magnesium supply. 5,6
Table 6. Surgical electrolyte therapy
For completeness also the changes by electrolyte shifts under acidosis and alkalosis must be mentioned. Under acidosis hydrogen ions enter the cell and potassium and free magnesium leave the cell. The hyperkalemia achieved will stimulate aldosterone secretion, which will increase renal excretion of potassium and magnesium. Lactate acidosis under ischemia or ketoacidosis under diabetes will potentiate cellular potassium magnesium efflux and aldosterone-induced renal excretion. It is very important to restore the electrolyte imbalance by potassium and magnesium supply, if the underlying cause of acidosis cannot be removed.
Under alkalosis hydrogen ions leave the cell and in compensation to this potassium and magnesium ions enter into the cell: hypokalemia will exist. If alkalosis is corrected causally, a potassium increase will take place, while for the correction of an acidosis a supply of potassium and magnesium will be necessary for recovery of electrolyte homeostasis.
Table 8. Papillary muscle-K and -Mg at mitral valve replacement with ECC
|KCl (n=10)||K, Mg (n=11)|
|Pap. muscle-K||62||.4||83||.9 mmol/kg ww|
|Pap. muscle-Mg||4||.9||9||.5 mmol/kg ww|
|Von Bormann 1983|
From an example shown before, it is evident that muscle cells take benefit from homeostasis. But it is important to know that the muscles need much more time for magnesium uptake, than myocardium or liver. Those organs show a tenfold higher magnesium uptake, which was shown by the magnesium isotope studies in our laboratory.
Therefore it was very interesting to examine whether the results in muscle can also be confirmed myocardium. This succeeded with direct measurement in the living heart additionally under maximal surgical conditions of extracorporeal circulation (ECC) with the highest known electrolyte turnover. In mitral valve replacement it is possible to take specimens from papillary muscles, which belong to the support apparatus of the mitral leaflets.8
Comparing two patient groups with that indication, which were substituted with potassium chloride on the one side or with potassium and magnesium together on the other side, this group shows better potassium and magnesium values in the papillary muscle.
Thus it is obvious directly in the heart, that potassium-magnesium substitution is superior also for an optimal electrolyte balance. According to high transcellular potassium gradients at the heart thanks to magnesium, the electric stability of the cell will also be maintained with a high resting membrane potential and will cause fewer reperfusion- and postoperative arrhythmias, an experience, which had been reported from many teams.
A small magnesium dose, which is not sufficient to normalize an electrolyte imbalance, can be very helpful according to its pharmacological calcium-antagonistic effect. In this case here a unique intravenous dose of only 8 mmol magnesium causes a transitory deflation of the smooth coronary muscles with a considerable increase of the ischemic tolerance during coronary dilatation. The serum magnesium level increases for a short time over the upper normal range, which is a desirable effect.
Furthermore the ischemia-dependent ST elevation is decreased considerably and can be recognized primarily after more than twice the time and with much lower incidence of angina pectoris. The great advantage is to have more time for the procedure of coronary dilatation, thanks to magnesium.9
Table 9. Ischemic tolerance at coronary dilatation (PTCA)
|Mg++ mmol/l||ST-elevation mV||after sec||Ang. pect.|
|+ 8 mmol Mg++ i.v.||1||.36||0||.49||44||
The importance of magnesium for the electrolyte homeostasis can be summarized now:
1. Wang, R., Flink, E.B., Dyckner, T. et al. (1985): Magnesium depletion as a cause of refractory potassium repletion Arch. Intern. Med. 145, 1686.
2. Hasselbach, W., Makinose, M. (1961): Die Calciumpumpe des Muskels und ihre Abähngigkeit von der ATP-Spaltung Biochem. Z. 333, 518.
3. Achenbach, C., Daying, H., Schweikart, P. et al. (1991): Unterschiedliche Effekte von Mg, Ca, Mn und Nifedipin auf den Na/Ca-Austausch während des Aktionspotentials der Herzmuskelzelle. Int. Symposium Edinburgh New approaches in the Pathophysiology and Treatment of Cardiovascular Disease.
4. Dyckner T., Wester, P.O. (1979): Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusions in patients on diuretic treatment Am. Heart J. 97, 12.
5. Schroll, A. (1981): Optimierte Magnesium-Substitution bei extrakorporaler Zirkulation Mg. Bull. 3, 163.
6. Schroll, A. (1986): Magnesium in open heart surgery: its role in ischemia and arrhythmia Internat. Symposium on Anaesthesia for Cardiac Patients, München.
7. Wischnik, A., Schroll A., Kollmer, W.E. et al. (1982): Magnesium-aspartat als Kardioprotektivum und Adjuvans bei Tokolyse mit Betamimetika Z. Geburtsh. und Perinat. 186, 326.
8. Borman, B. von, Scheld, H.H., Kling, D. et al. (1983): Concentrations of cations in the tissue of papillary muscle under different modes of supplementation 5th Annual Meeting of the Society of Cardiovascular Anesthesiologists, San Diego.
9. Kahles, H., Riegger, A.J.G., Kromer, E.P. et al. (1991): Wirkungen von hochdosiertem Magnesium-aspartat wahrend Koronarangioplastie Deutscher Anästhesiekongreß Mannheim.
ADVANCES IN MAGNESIUM RESEARCH: 1 MAGNESIUM IN
Edited by Ronald Smetana
Published as Supplement 1 (1997) to Magnesium Research
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This page was first uploaded to The Magnesium Web Site on January 30, 2002