If you are reading this monograph, it’s perhaps because you have had to manage a patient with a dangerously high potassium level – possibly on several occasions. When confronted with such a patient who has an ECG that shows significantly widened QRS complexes, we reach for the calcium chloride or calcium gluconate. After giving one or two amps, the QRS interval begins to narrow and the ECG takes on a more normal appearance.
But why are we giving the calcium and how is it able to do this? If you try looking this up, you are not likely to find anything other than the fact that calcium helps manage hyperkalemia and is involved – somehow – with “moving” the threshold potential. To understand why calcium is indicated in this condition, we need to review a little about action potentials and also how K+ exerts its effect on the myocardium.
The normal working myocyte has a resting transmembrane potential of around -90 mV. This is maintained primarily by K+ ions. K+ is the only major ion that can freely pass back and forth through the cell membrane (sarcolemma) without having to be transported or ushered in depending on certain phenomena (depolarization, for instance). Na+ and Ca++ do not have this ability. Because there are some large negatively-charged ions trapped in the cell, their electrostatic force draws in very large amounts of K+ in an attempt to achieve neutrality. However, once the transmembrane potential reaches -90 mV, the osmotic force generated by the remaining extracellular K+ (or, more precisely, the lack thereof) achieves enough strength to resist any further attraction by the large negatively-charged sulfates and phosphates. This results in a large concentration of K+ ions INSIDE the cell and a much smaller concentration OUTSIDE the cell (a 50:1 ratio).
This scale on the upper left depicts values for the resting transmembrane potential. As we move toward zero, the resting potential decreases since there is less difference in the K+ concentrations between the inside and the outside of the cell (I’ll repeat this numerous times in this monograph). Since we are normally in negative territory (-90 mV), a decrease in resting membrane potential means we are moving UP the scale – not DOWN the scale! This is where everyone gets very confused. Just remember that the term “membrane potential” is really an abbreviation of the actual term, membrane potential difference! Therefore, the resting membrane potential decreases (depolarizes) whenever it moves closer to ZERO (“0 mV” on the scale).
As for depolarization, when the depolarizing impulse from an adjacent cell arrives, it causes enough Na+ channels to open simultaneously to create an action potential – which, in turn, causes the rest of the Na+ channels to open, allowing the sudden, rapid and quite massive influx of Na+ ions into the cell. So far, so good. Everything appears to be working normally. But let’s see what happens when the extracellular K+ level begins to rise.
First, a brief word about the Na+ channels themselves: you must understand that Na+ channels open because of depolarization of the cell. A small or slight depolarization may open a few Na+ channels but that won’t do anything. There must be enough Na+ channels opened simultaneously to create enough depolarization to cause the opening of all the remaining Na+ channels. Therefore, the arriving impulse must be strong enough (manifested by the height of Phase 0) to achieve the “threshold” potential and it must do so rapidly enough (manifested by the slope of Phase 0) to assure the simultaneous activation of the “threshold” number of Na+ channels. One other thing you must understand: the Na+ channels are only open for a msec or so and then they slam shut! At this point they are essentially locked and the only thing that can unlock them is repolarization. Repolarization does not “re-open” the Na+ channels; it only “unlocks” them making them available to re-open with the next depolarization. Now if the elevated extracellular K+ level continues to cause a baseline decrease in the membrane potential (i.e., move the membrane potential UP the scale closer to 0 mV), repolarization is going to be less and less effective because the baseline resting transmembrane potential will be less and less negative. Fewer Na+ channels will be “unlocked” (available to open) because the membrane potential must repolarize down to around -90 mV to “unlock” all the Na+ channels. More and more of those Na+ channels are going to remain shut and locked and fewer and fewer will be available to initiate an action potential!
What effect does an increase in extracellular K+ have on the cell? As the extracellular K+ begins to rise, there is less voltage difference between the inside and outside of the cell (reduction of resting transmembrane potential). This constitutes depolarization, though not the type of depolarization that triggers an action potential like an arriving impulse. As this slower depolarization continues, the resting transmembrane potential gradually decreases. This causes some Na+ channels to open and shut but there are never enough Na+ channels open simultaneously to sustain an action potential and thus open the rest of the Na+ channels. So, the transmembrane resting potential gradually decreases and fewer and fewer Na+ channels remain open. As the impulses continue to arrive, there are fewer and fewer Na+ channels available for this massive influx of Na+ to pass through. It begins to take each action potential longer and longer and soon significantly fewer Na+ ions are entering the cell during the action potential. This causes the QRS (which represents Phase 0 of the action potential on the ECG) to widen and the maximum voltage to decrease. As the extracellular K+ level rises even more, there comes a point when there are simply too few Na+ channels available to initiate an action potential. This is how hyperkalemia kills!
In the beginning – when the resting transmembrane potential has decreased just a small amount, the myocytes become “irritable.” It now takes less stimulation to cause an action potential and some ectopy may occur. This is because the resting transmembrane potential – by decreasing slightly – has moved closer to the threshold potential (around -70 mV) yet there are still sufficient Na+ channels remaining to be activated. This can predispose to increased ectopy since it takes less depolarization now to trigger an action potential.
But this “irritability” is short-lived. As the K+ level rises further, it inactivates too many Na+ channels to allow for an effective action potential. It is at this point that we see the QRS interval on the ECG begin to widen and start to take on a sine wave appearance. Also, by this time the atria have become paralyzed and there are no more P waves. The ventricles are still functioning because the conducting system is more resistant to the effects of hyperkalemia and the ventricles are now activated by sinoventricular conduction.
Please note that I am NOT relating any of these changes to a specific serum K+ level. I feel that the patient is in danger whenever any ECG manifestations of hyperkalemia begin to appear. Remember that prolongation of the P wave and the PR interval are both manifestations of hyperkalemia! Obviously, neither is very specific, but if you have reason to suspect hyperkalemia and these findings are present, be extremely vigilant!
So now you want to give Ca++ intravenously to improve the situation. Excellent decision… but WHY are you giving it? What do you intend for it to do?
We know that at this point the rising K+ level has inactivated a large number of Na+ channels. We used to think that increasing the extracellular concentration of Ca++ caused the threshold level of the Na+ channels to move away from the depolarized resting membrane potential, thus allowing action potentials to take place. This was called a “membrane-stabilizing effect.”
In the September 2010 issue of Annals of Emergency Medicine, Piktel et al. published an abstract of an experiment that demonstrated improvement in the electrocardiogram during hyperkalemia after the administration of IV calcium. First, they blocked the Na+ channels pharmacologically so that activation of Na+ channels could not play any role in improvement of the action potential (and QRS) following Ca++ administration. After giving the calcium, the QRS narrowed and the ECG normalized except for the action potential duration manifested on the ECG as the QT interval which remained shortened by the hyperkalemia. Therefore, the calcium was able to exert its effect without any involvement of the Na+ channels. Then they blocked the L-type calcium channels and once again administered calcium to a hyperkalemic heart. The calcium had no effect on the action potential. The QRS remained wide and the ECG did not normalize.
Therefore, at this time it appears that the benefit of administering IV calcium to patients with hyperkalemia is due to enhanced conduction through the L-type calcium channels and not due to “membrane stabilization.” The L-type calcium channels are much more resistant to hyperkalemia and are quite capable of initiating an action potential in the conducting tissue (His-Purkinje system) and the working myocytes.
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