Henry R. Black, MD; Domenic A. Sica, MD

Disclosures

July 23, 2012

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Henry R. Black, MD: Hi. I'm Dr. Henry Black. I'm Clinical Professor of Internal Medicine at the New York University School of Medicine and a member of the Center for the Prevention of Cardiovascular Disease at that institution. I'm here today with my friend and colleague, Dr. Domenic Sica. Dom?

Domenic A. Sica, MD: Thank you, Henry. I'm Dr. Domenic Sica, Professor of Medicine and Pharmacology and Eminent Scholar at Virginia Commonwealth University Health System in Richmond, Virginia. I am also President-Elect of the American Society of Hypertension.

Dr. Black: One of the things you have written and talked about a lot is how we deal with serum potassium disorders. What is your approach to that?

Dr. Sica: How many days do we have?

Dr. Black: Hyperkalemia. Let's start with that.

Dr. Sica: If you go to the nuts and bolts, there is a lot of ascertainment bias in obtaining the sample and in measurement. The reminder is that you can get a hemolyzed sample, where the serum on top of the clot may artificially have an increase in potassium owing to lysis of cells.

Dr. Black: Shouldn't the laboratory tell you that?

Dr. Sica: They may tell you that it is hemolyzed, but you can't always tell what the quantity of potassium is when it is hemolyzed, so you always have to repeat the sample. There are issues of thrombocytosis in a platelet count above about 500,000 cells/μL. If it participates in the clotting process (in a red-top tube), then what lies on top of it (the serum) will have a higher potassium concentration. So you are always looking at the platelet count before you make a determination of what the serum potassium is.

Dr. Black: In someone who has a high potassium level, would you measure serum and plasma potassium?

Dr. Sica: If the platelet count is up, then yes, you would. You can see a 0.3- to 1-mEq/L difference between serum (higher) and plasma (lower). Remember that plasma would be a purple top or a green top.

Dr. Black: I think a lot of physicians who don't appreciate the high potassium ignore it instead of getting an ECG to see whether it is really a problem. Is that what you tend to do?

Dr. Sica: If you have anything above a value of about 6 mEq/L, then it is worth understanding whether it is a true value, whether there is any cardiac aspect to it, and why the value is 6 mEq/L. Oftentimes, there is an explanation for it. An ECG showing you that the patient is not cardiotoxic and a treatment plan that allows you to systematically have the value come down becomes very important.

Dr. Black: As we are using more and more aldosterone blockers, such as spironolactone or eplerenone, don't you think we are going to have more trouble with hyperkalemia now?

Dr. Sica: We do. The RALES data showed that patients in systolic forms of heart failure with an average dose of about 25 mg of spironolactone clearly had more frequent hyperkalemia.[1]

When you start spironolactone, you should make an assessment of the risk factors for an inordinate increase in potassium. You are going to look at the glomerular filtration rate (GFR) and try to estimate the prevailing intake, the fluid status of the patient, other medicines that may influence potassium, and the sampling conditions in which you can obtain it. You need to think preemptively rather than react to the circumstance.

There is a finite rise that occurs. Not everyone goes up 2 mEq/L. An average increase might be 0.5-1.2 mEq/L, so if you start out at 4 mEq/L, you are in a safe range. If you start at 4.5 mEq/L, you are beginning to run into the chance that you may get closer to 6 mEq/L, which would be a problem area. If you are at 4.8 mEq/L, then that is going to dictate earlier surveillance.

How quickly do you measure a value after starting the drug? Generally, if you have a reduction in GFR to start with, somewhere between 3 and 7 days would be reasonable. It is a range, so if you started on a Monday, you are fully capable of checking on Friday because you don't do blood draws on the weekend. If you are starting on Thursday, then you are going to go into the early part of the following week.

Dr. Black: Wouldn't you prefer eplerenone, which is a shorter-acting drug?

Dr. Sica: It has never been studied. Interestingly, you would presume that because spironolactone has 2 very long-acting metabolites and has considerable affinity for the receptor, those 2 criteria are going to make it more likely to have a prolonged effect. Eplerenone's on/off time for its receptor is shorter and it has no active metabolites, so you would expect less exposure to a potassium-conserving environment, but it simply has not been studied yet.

However, I think it would be an effective strategy to consider, and it would be as follows. Someone is given 25 mg of spironolactone. The patient becomes unnecessarily hyperkalemic. The potassium level goes to 5.7 mEq/L, and you get a little bit edgy about that. You decide to make a switch to eplerenone. I can't tell you what the dose equivalence is, but you start out at something like 25 mg twice daily. The patient doesn't get the same blood pressure reduction with that low of a dose and has less hyperkalemia, but then you have to titrate up the eplerenone.

You have to determine a titration scheme for eplerenone starting at low doses, and that is difficult. I think it is an option, but it is not the easiest of options. People get really scared once you get hyperkalemic with any mineralocorticoid receptor antagonist. They are worried about the drug and whether it is going to cause a problem.

Dr. Black: Let's switch gears a little bit to hypokalemia. It is my impression that we are not going to have as much hypokalemia because we don't use high-dose thiazides as much as we used to. Is that accurate?

Dr. Sica: It's accurate that the frequency is diminished. There are so many variables to potassium that determine what we do. If it is a transient process -- let's say it's a 3.3 value, and you take steps to eliminate that with maybe a longer diuretic dose and decreasing sodium intake -- all is well and you may not need to do much.

Dr. Black: Why does lowering sodium intake matter?

Dr. Sica: Hypokalemia treatment is a tricky issue. First, you have to determine the threshold below which you want to treat. If it is a clearly reversible cause, short-lived in nature, and you could remedy it, then you may not need the supplement. Or it might be something more permanent in nature. For example, there are what I call immutable forms of hypokalemia, which are potassium-wasting disorders that occur sometimes with gentamicin therapy with certain cisplatin chemotherapy agents, in which case you are obligated to keep treating almost for perpetuity.

If you are going to be on diuretic therapy persistently, you take certain steps, you limit the salt intake, and you limit the dose of the agent in question. If you have to give a potassium supplement, you give potassium chloride rather than potassium acetate or potassium citrate.

Dr. Black: But why does reducing the sodium intake make any difference?

Dr. Sica: Sodium intake is the purveyor of all evil. Sodium exposure to the distal tubule creates the need to absorb, creating an intraluminal electronegativity in the distal tubule. Because potassium is a cation, it is secreted down an electrochemical gradient. If you limit sodium, there is less sodium to resorb, less electronegativity in the distal tubule, and less potassium loss or kaliuresis. That is one issue.

Some people say to just give some potassium chloride, but potassium chloride oftentimes has a bitter taste, and although there are various forms you can take, it's just not very palatable in many cases. When you give potassium chloride, you may take a potassium level of 3.2 mEq/L and bring it up to 4 mEq/L, but it is almost like you have to keep the patient on potassium chloride in perpetuity.

In reality, if you look at what happens in the body, taking potassium chloride corrects the plasma deficiency but doesn't change cellular deficiency. Therefore, the cell complement is still reduced, with whatever the consequences of that are. If you use a potassium-sparing diuretic, you actually correct the serum value and you correct the cellular deficiency, which is often present in these patients. Therefore, it is a more prudent step.

If you have latent magnesium deficiency, you may wonder why there is no improvement when you take potassium chloride, whereas if you have latent magnesium deficiency and you take a potassium-sparing diuretic, you can be assured that the magnesium value in the serum will go up and magnesium homeostasis will be restored in the cellular compartment. That may be the basis for the greater retention of potassium in the cellular compartment when you take a potassium-sparing diuretic. They are triamterene, amiloride, spironolactone, and eplerenone. Those are our 4 potassium-sparing diuretics stateside.

Dr. Black: We always think of primary aldosteronism or aldosterone excess when we see a low potassium value. When do you worry about that?

Dr. Sica: If the patient is hypertensive and it is unprovoked, I do. By the way, only 25%-30% of all people with aldosteronism have hypokalemia. The large majority are normokalemic. If the patient is on a low-dose diuretic, sodium intake is not that high, and the potassium level is very low -- 3 mEq/L or below -- that is a consideration for checking for aldosteronism.

Dr. Black: What do you do if you suspect hyperaldosteronism?

Dr. Sica: Usually, the screening test is a random plasma aldosterone/renin activity ratio. The endocrine guidelines suggest that you have to really have the patient under controlled conditions for a couple of weeks off of all therapies that influence it. The long and short of it is that it is very difficult in clinical practice to take patients off therapies that influence their aldosterone/renin levels, put them on drugs that don't, and exert some influence on blood pressure.

Random renin and aldosterone levels obtained in the early morning before morning dosing is, in most cases, interpretable. If the value is very high and the aldosterone and renin are suppressed, then you could take a secondary step in the workup. If the values are mid-range, then you may have to subject the patient to a more rigorous way to check renin and aldosterone. They are not expensive tests anymore, so if you get them, you are perfectly fine interpreting them half the time. However, there is a gold standard to obtaining them that most people would suggest you undertake.

Dr. Black: Thank you very much.

Dr. Sica: You're welcome.

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