Podcast 131 - Outer Limits - Cations


Lab value interpretation sadly wasn't included in my initial paramedic education. I was absolutely ecstatic to attend a critical care program and learn about lab values - I had always found it very impressive when people could interpret lab values. I wanted to be a lab value wizard too! Unfortunately, in critical care class, our lectures and resources were nothing like what I had hoped for. I hope this series of blogs serve as a resource for those who are eager to learn more about the art of interpreting labs. I wouldn't recommend tackling this whole thing in one sitting ;) We'll be starting with the positive charges (cations) in this blog, then handling the other parts of the basic metabolic panel in weeks to come (negative charges, renal, and glucose).


Before we get started, I want to get us in the right headspace for learning about lab values. This stuff is kind of dense, and there are a lot of different conditions that will cause lab values to reach their outer limits, or beyond. While I'll present a lot of information for each lab value abnormality, the theory of what's going on is far more important. Once you understand the theory of why a problem occurs, you can find a formula, calculator, or treatment guideline to get you the rest of the way.


Now let's what happens when cations reach their outer limits!

Speaking of difficult things... I immediately regretted starting this series off with sodium - it's a little complicated. Sodium is kind of like the cat of the cations... it's very particular, only wants your attention on its own terms, and might turn around and bite you.


Outer Limits: Sodium (NA+)

Sodium is our most abundant positive charge outside of our cells (and main extracellular cation). Because there is so much of it outside of the cells, it's pretty sensitive to being diluted or concentrated by water. Imagine that the amount of sodium doesn't change, and we just change the amount of water around it. Losing water would mean that the sodium would concentrate (read higher/hypernatremia) and gaining water would mean the sodium would become dilute (read lower/hyponatremia). Or the amount of water could stay the same and the sodium could change (or a combination of those two). Hence why I regretted this decision. I read this book called "Acid-Base, Fluids, and Electrolytes - Made Ridiculously Simple (2nd Edition)" by Richard A. Preston, M.D. It had the chart you see below on page 14. This chart is really good for reference, but I'm not really sure that any of us are going to be memorizing it any time soon. Take a look and you'll see what I mean.

You skipped over it, didn't you? That's okay. Alright, enough of me complaining about how complicated sodium and water balance is. Let's take a quick look at a few of the conditions above, and see what we can learn from this chart, and I'll throw in a few interesting ones that are not on the chart. As confusing as sodium and water can be, the conditions associated with it are actually very interesting. Of note, we're only likely treating this in the emergent setting if the patient is symptomatic for hyponatremia, which manifests as signs and symptoms of increased intercranial pressure due to cerebral edema and swelling. This occurs because as sodium drops, our serum osmolality drops, which causes water to leave our blood vessels. As water leaves our blood vessels, the main area we worry about is our skull - since this fixed container cannot adapt to the extra volume inside of it very well. You might remember this as the Monroe-Kellie doctrine. The cranial compartment well rid itself of CSF and venous volume to a point, but as it reaches maximum compensation, ICP increases.

Going back to the sodium chart above, notice how CHF, cirrhosis of the liver, nephrotic syndrome, and renal failure are all in the same box? And actually in two different places? They all cause sodium retention. Sometimes, the patient will also have a large increase in free water, which causes relative hyponatremia. What does this mean? It means that these patients have plenty of sodium, but a lot of water usually goes along with it. This is why they can appear edematous at various places around the body.


Vomiting, diarrhea, and diuretics can cause hyponatremia, with varying amounts of lost water. With diarrhea, water loss can become so severe that the sodium can actually go the other way and become high because the sodium is so concentrated (1).


SIADH (syndrome of inappropriate anti-diuretic hormone) causes the body to retain water, so it dilutes the sodium and causes hyponatremia (1).


Diabetes Insipidus is the opposite, in which the kidneys excrete a large amount of insipid urine (insipid means dilute, colorless, odorless). This causes free water loss, which will raise the serum sodium by concentrating it (1).


Insensible loss is when we lose water through breathing and through our skin in the form of perspiration. The average adult loses about 750mL/day from their skin and their lungs alone. This could become extreme in cases such as burns where the patient is losing massive amounts of water through their burns (2).


Sodium bicarb can cause iatrogenic (clinician-caused) hypernatremia. A lot of people think about bicarbonate in sodium bicarb, but not sodium. Even though the box says 8.4%, this doesn't mean that it's equivalent to 8.4% NaCl, it's actually approximately equivalent to what would be 6% NaCl (3).


Beer Drinker's Potomania, as well as Tea and Toast syndrome, are forms of chronic hyponatremia that we have to be really careful with when it comes to deciding if we'll correct the sodium or not. When sodium is low due to decreased intake, the renal system can rapidly correct since they are not diseased. This can cause massive free water urination along with other complications. Tyler wrote a great blog on this called The Sodium Trap (4).


Exercise-associated hyponatremia can happen when athletes only replace water. If you've ever seen sodium as an ingredient in sports drinks, this is why - you can get life-threatening hyponatremia from replacing only water. These patients present with signs and symptoms of increased intercranial pressure (because they're developing acute cerebral edema) (5). Water intoxication falls into this same category as exercise-associated hyponatremia (like when someone does a water-drinking challenge). On the topic of challenges, people who have drunk entire bottles of soy sauce usually don't do too well either - this has the opposite problem of life-threatening hypernatremia.


Pseudo-Hyponatremia is another interesting condition where other solutes cause the sodium to look low. One of the most common conditions that we see that causes this dilution to happen is DKA. Glucose, BUN, and sodium make up the serum osmolality on a basic metabolic panel, so if one of them is very high, it will draw water into the serum and dilute the others. It's interesting to note that you will get similar symptoms if you lower any of these too quickly. Lower glucose too quickly with insulin and you'll cause cerebral edema (6). Lower BUN too quickly with dialysis and you'll get dialysis disequilibrium syndrome that causes cerebral edema (7). And as we noted earlier, lowering sodium too quickly by diluting the sodium with water will cause cerebral edema. There is actually a corrected sodium calculator to see what the sodium likely is without the dilution from hyperglycemia present.


Remember how I mentioned that sodium is a very finicky cation to alter? And that sodium is kind of like the cat of the cations... it's very particular, only wants your attention on its own terms, and might turn around and bite you? I said that because correcting low sodium too quickly can have major consequences - namely, osmotic demyelination syndrome (ODS). If a patient has had hyponatremia for several days (over 48 hours), and the value is generally less than 120 mEq/L, the brain makes adaptations to this sodium level. If we come along and correct this sodium more quickly than about 6 mEq/L in 24 hours, we risk causing osmotic demyelination syndrome. Rapidly correcting sodium in a patient with acute hyponatremia (onset within ~24 hours) who is experiencing signs and symptoms of increased ICP is thought to be safe because the brain has not made the adaptations that the chronic hyponatremic patient has (8). To wrap that up... Sodium goes too low too fast, cerebral swelling. Sodium gets corrected up too quickly, cerebral nerve damage (and other issues).


Serum Os = 275 to 295 mOsm/kg


Demyelination (degradation of the myelin sheath on the axon)

Treatment for hypernatremia usually includes replacing free water, which means D5W infusions. Treating hyponatremia, however, is a little more complicated. A clinician should always use a sodium calculator and use a reference such as the one below to guide treatment. As you can see, there are many pathways to take and many things to consider when sodium is low. This treatment pathway is from UpToDate, but I'm sure there are many more out there. Just a reminder that if you did use 8.4% sodium bicarb (~6% NaCl equivalent) in place of 3% NaCl, you would use half the volume of sodium bicarb because it has ~twice the strength of the 3% NaCl.


Flow chart from UpToDate (9):

What else can we learn from our sodium? (As if that stuff up above wasn't enough.) We can use it to evaluate our strong ion difference, as well as our anion gap. The three things that influence your acid-base status is:

  • Strong Ion Difference

  • Weak Acids

  • CO2

The strong ion difference is simply the difference between your sodium and your chloride (Na - Cl = SID). A SID under 38 is considered acidic. As your sodium and chloride get closer together, the patient becomes more acidic. 0.9% Normal Saline has equal parts sodium and chloride (154 mEq of each), which is why it's so acidic - it has a SID of zero. Once you have your SID, just subtract your bicarb from that number, and you have the anion gap. Na - (Cl + Bicarb) = Anion Gap. More on anions and acid-base when we hit on our negative charges next time!


SID:

Anion Gap:

When you evaluate sodium, perhaps this would be a good mental model:

  • Is it high or low?

  • Do I believe it's diluted or concentrated?

  • How long has it likely been that way (more than 48 hours or not)?

  • Is this patient having any symptoms that I attribute to this sodium derangement?

  • Where can I find resources to help me with this?

It would also be beneficial to compare the sodium to the chloride with and without the bicarb to evaluate the SID and Anion Gap (more on that in the next blog).


Let's move on to our next cation - what happens when we get to the outer limits of potassium?


Outer Limits: Potassium (K+)

Potassium is the major positive charge inside of our cells. This is why its reference range is so low outside of the cell. You can think about sodium and potassium in opposite locations. Sodium is found in large amounts outside the cell, and potassium is found in large amounts inside the cell. Since we only measure what's in the serum (outside the cell) when we draw labs, we see this very small reference range for potassium. Not only is the reference range pretty narrow, but the body is also very sensitive to changes in potassium (especially the heart).


Notice how the cations on a Chem-7 are in the stack all the way to the left.

The renal system is very closely tied to our potassium levels. The kidneys are responsible for ~90% of your potassium management, with the remaining ~10% being managed through the GI system. It's usually pretty safe to assume that when a patient has hyperkalemia the kidneys are somehow not working correctly - they have some form of renal failure/injury (10). When the potassium is low, it's likely that the kidneys are over-correcting in some way (probably from a diuretic). A safe mental model is that whenever someone has renal disease, their serum potassium deserves investigation. These renal issues are the most common reasons for derangement in potassium, but there are of course many exceptions. Besides renal failure, here are some other common examples of conditions that may cause potassium derangements. This is not an exhaustive list.


GI-related issues, such as vomiting, diarrhea, or malnutrition can cause a decrease in the amount of potassium we absorb, so they can cause hypokalemia. This would include chronic alcoholism where we are likely to see multiple lab values present low because of the low nutritional value in chronic alcoholic diets (11).


Diuretic use is another cause of hypokalemia. Ideally, this shouldn't happen because patients are supposed to take a potassium supplement along with diuretics such as furosemide (a non-potassium sparing diuretic). However, you can easily understand that if they don't take their potassium supplementation as they should, their potassium will become low. Or, if they take the potassium without the diuretic, the potassium would raise. It is not uncommon for patients to make errors with their diuretic and potassium supplements.


Diabetes is another issue that can cause both high or low potassium - typically DKA in the patient populations that we see. DKA starts off with high serum potassium (early DKA) and ends with low serum potassium (late DKA) (although the whole body potassium is decreasing the entire time). Potassium initially raises due to acidosis - H+ shifting into cells, and pushing K+ out. However, as ketone production ramps up and the patient begins to excrete large volumes of ketone-rich urine, the negatively charged ketones pull positively charged potassium with them. Thus, DKA patients start with hyperkalemia, then pseudo-normalize (on their way from high to low), and finally dump down to hypokalemia. That point above about the H+ and K+ shift occurs in all forms of acidosis, which is why pH and K+ have an inverse relationship. As pH drops, K+ rises. As pH raises, K+ drops (12).


Beta stimulation or blockade also alters potassium levels. Beta stimulation encourages potassium shift into cells, and beta-blockade discourages potassium shift into cells. ACE Inhibitors and Angiotensin II receptor blockers can cause hyperkalemia as well.

Tissue death or cell lysis releases potassium from inside the cells into the serum. This can happen in a crush injury where cells burst, and from blood transfusions since some of the cells lyse in the bag. Anything that causes hemolysis can increase potassium, which is why care must be taken when obtaining blood for lab values in the first place - too much pressure (positive or negative) on the blood causes cell lysis and a false elevation in potassium (a rather common cause of false-positive hyperkalemia) (13).


Aldosterone causes us to excrete potassium, so any alteration in it will either cause high or low potassium. A disease like Addison's disease is associated with hypoaldosteronism (low aldosterone), which will cause potassium retention (hyperkalemia) (14). On the other hand, a disease like Primary aldosteronism will cause excessive potassium excretion (hypokalemia) due to high levels of aldosterone.


Potassium and the heart

One of the key issues to understand about potassium is how it affects the heart. I didn't realize how long medicine had known about the issues with potassium and the heart until I saw a tweet thread by @tony_breu about Sydney Ringer (the guy who invented Ringer's Lactate). @tony_breu referenced a paper (link here) from 1883. Here was the snippet of the paper he highlighted:

Well, there you have it. If there is too much potassium in the serum, the heart stops. Doctor Ringer's observation from this 1883 paper (15) has stood the test of time. It's also interesting to note that "lime salts" were calcium. We know better than ever now that too little calcium and too much potassium cause cardiac dysfunction. Why does this occur? And what should we do about it?


Here's a great graphic by Jared Patterson from his blog Kombatting Hyperkalemia (awesome blog if you want to dive deeper into understanding hyperkalemia and the ECG).

As we can see from the graphic above, potassium generally causes the ECG to appear differently. But what's the actual problem going on at the myocyte level? Hyperkalemia causes the resting membrane potential (RMP) to rise, which makes the myocyte more irritable and unpredictable because it becomes closer to the threshold potential (TP). There is simply less distance to travel in order to cause depolarization. This is why we must provide calcium, because calcium will raise the TP and restore a gradient, reducing ventricular irritability.

At first, you might look at this picture and think the patient would present in a tachycardia because there is such little effort needed to depolarize. After all, if you haven't given calcium, that higher resting membrane potential from the hyperkalemia is super close to the threshold potential. However, in hyperkalemia we often see bradycardia. Why does this occur? It has to do with the concentration gradient of potassium during REpolarization. In hyperkalemia, there is less of a gradient between potassium concentrations on the inside and the outside, so it doesn't move as fast. This causes the myocyte to take longer to REpolarize, resulting in a slower heart rate (16). What about Hypokalemia?


As you would expect, hypokalemia is the exact opposite. The lack of potassium makes a more negative resting membrane potential. However, there is more of a gradient between potassium concentrations inside and outside the cell. This causes REpolarization to happen very rapidly, which causes tachycardia (16).

We see ECG changes in hypokalemia as well, but they're usually not as obvious as the hyperkalemia changes. These changes are usually the opposite of what we see in hyperkalemia. Instead of peaked T waves, we see flat or inverted ones (sometimes with U waves). Instead of losing a P wave, we get a bigger one. Instead of ST elevation, we get ST depression. Instead of bradycardia, we get tachycardia. Both hyperkalemia and hypokalemia can lead to fatal arryhthmias (16).

Hyperkalemia is typically treated with (17):

  • Calcium Chloride

  • Albuterol (high-dose nebs)

  • Isotonic Bicarbonate (not straight from the amp)

  • Insulin and glucose

  • Furosemide

Calcium chloride stabilizes the membrane, but will not change serum potassium levels. Albuterol is a beta-agonist that will shift potassium into cells. Isotonic bicarbonate (3 amps in 1L D5W, or 1.5 amps in 500mL D5W, or 0.75 amps in 250mL D5W) will buffer hydrogen and allow potassium to enter cells. Insulin pulls glucose into cells, which drags water, which in turn drags potassium into cells through something called solvent drag. You need the glucose along with the insulin to ensure the patient doesn't become hypoglycemic. Furosemide is the only medication on this list that will actually cause the potassium to leave the body - everything else is a temporizing measure(17). As a side note, Ringer's Lactate is safe in both high and low potassium states (18).


Hypokalemia is treated with (19):

  • Potassium chloride

  • Magnesium (usually)

  • Potassium-sparing diuretics (sometimes)

Potassium must be replaced, so potassium chloride is your way to go. Make sure this is on an IV pump, and check your guidelines for how quickly you can administer it. Generally, potassium chloride (40 mEq/L) is not administered at rates higher than one liter per hour. If the patient has some kind of potassium wasting condition, sometimes potassium replacement is not enough, so they'll need potassium-sparing diuretics to maintain the potassium in their system while excreting fluid. Also, magnesium is often low in these patients and is sometimes empirically administered (19). Follow your local guidelines, but it's generally very safe to administer magnesium, and may further protect the patient from arrhythmias. Hypokalemia is almost always safe to correct when done in a controlled way, but there is a warning to monitor patients with thyrotoxic periodic paralysis closely since they can experience rebound hyperkalemia after treatment (check if the patient has a thyroid history) (20).


Let's move on to the last cations that we'll consider - what happens when we get to the outer limits of calcium and magnesium?


Outer Limits: Calcium (and Magnesium)

Anytime that there is work being done in the body, I always think of calcium. When a muscle contracts, a nerve impulse is sent, blood is clotting or a bone under stress keeps its form - calcium. The regulation of calcium in the body is handled by parathyroid hormone and calcitonin. If calcium gets too high, the thyroid gland sends out calcitonin, which causes the kidneys and the intestines to excrete calcium, and to place more calcium into bones (lowering serum calcium levels). Parathyroid hormone is the counter-regulatory hormone that comes from your parathyroid glands. The parathyroid hormone tells the kidneys and intestines to reabsorb calcium and to bring calcium out of the bones (raising the serum calcium levels).


While that may sound a little confusing, a picture makes everything better.

What about iCal (ionized calcium)? iCal is metabolically available calcium, which means it's the calcium that's actually free to move into a cell or perform processes if needed. It's the calcium that's ready to work. As you can see from the reference ranges above, a normal value for iCal is usually about half of the normal serum calcium. There are conditions in which regular calcium measurement does not correlate well with the iCal, so it is good to evaluate both if you have the ability.


Some of your calcium gets bound to anions like sulfate, phosphate, lactate, and citrate (~15%). Other calcium gets bound to proteins, mostly albumin (~45%). 15% + 45% = 55%. That leaves about 45% free to do other things. Did you notice how that works out pretty well with our normal ranges for calcium and iCal? The remaining 45% (about half of the calcium) is the ionized calcium that isn't bound to anything and can perform other tasks (21). This is why changes in albumin concentrations can create different amounts of calcium in the serum. When calcium is measured, it includes what's bound to albumin. If albumin is low, you may have low serum calcium, but the iCal may be unchanged (showing no real signs of hypocalcemia). Let's hit some of the common conditions that might cause either a high or low calcium and how those derangements can manifest. This is not an exhaustive list.


Respiratory Alkalosis is a very common cause of hypocalcemia. When CO2 becomes depleted and the pH rises, calcium becomes more bound to albumin. This causes a reduction in iCal and manifests with clinical signs and symptoms of hypocalcemia. Trousseau’s sign for latent tetany, along with Chvostek Sign can be observed in these patients (and other patients with hypocalcemia). Although these are interesting physical signs to observe, they point to a more serious issue - these patients are at risk of cardiac arrhythmia due to hypocalcemia (22,23).


Thyroid/parathyroid issues can cause abnormal secretion of either calcitonin or parathyroid hormone, with subsequent hyper or hypocalcemia. These issues can arise from a problem at the gland such as cancer, surgery, or an autoimmune condition, as well as problems in the intestines or kidneys in responding to these hormones.


Increases in any of the anions mentioned above can soak up more iCal and cause hypocalcemia. Lactate and citrate are of special interest to us since we commonly see these elevated. Lactate for obvious reasons, but citrate for less obvious reasons. Citrate toxicity occurs due to blood transfusions. Citrate is added to stored blood for the purpose of soaking up calcium so that the blood cannot clot. Hence, when we administer blood to a patient that has a lot of citrate in it, it will also soak up the calcium (and magnesium) in the patient's blood and prevent clotting. Obviously, this is a big problem if you're giving blood products to a patient who is bleeding. This is why we also administer calcium chloride to patients who are receiving blood transfusions (often with the first or second unit of blood) (24).


Hypomagnesemia (low magnesium) will usually correlate with hypocalcemia. Hypermagnesemia can also cause the same problem but is rarely seen. A lack of magnesium will interfere with parathyroid hormone secretion and action. In these cases, both magnesium and calcium will have to be replaced to correct the calcium levels. Other conditions that cause an issue with both magnesium and calcium are ones in which they are not absorbed through the diet, such as alcoholism, malnutrition, or any condition where the GI system doesn't absorb well (25).


Fluoride poisoning is one condition I wanted to put in a category of its own because it's pretty interesting. Fluoride is an anion, that when it enters the system wants to combine with strong positive charges, such as Ca++ and Mg++ (calcium and magnesium). Once these two are bound to the fluoride, they become inactive. This gives way to cardiac arrhythmias due to hypocalcemia and hypomagnesemia. Fluoride poisoning can occur for ingestion or transdermal exposure to certain strong pest control agents, or acids. If you were to be aware of a couple of chemicals, ammonium bifluoride and hydrofluoric acid would be the ones to know. Of note, there is a case report of high concentration hydrofluoric acid being fatal at only ~3% TBSA burned due to the high amount of fluoride absorbed through the burn (26). In chemical burns, it might be good to watch the ECG - you never know when some rogue anion will pick up the cations that are supposed to be stabilizing the heart.


How can these conditions manifest? We read a little bit up above about how hypocalcemia can be seen physically with Trousseau and Chvostik signs, and those signs actually help us understand why low levels of calcium (and magnesium) are an issue. Hypocalcemia lowers the threshold potential (TP).

This makes it easy for depolarization to occur, which is why we see things like neurological and muscular irritability (including cardiac conduction and contraction). To make matters even worse, calcium is needed for cardiac inotropy (the strength of the contraction). So, not only is the heart irritable, but it's also weak. Calcium is on many clinician's checklists for when a patient is not responding well to pressor/inotropic agents. You may see changes on the ECG at the ST segment as well (27).


Hypocalcemia will prolong the ST segment, creating a long QTc(27).


Hypercalcemia will shorten the ST segment, creating a short QTc. This could manifest with Osborn waves, J-point notching, and hyper-acute T waves(27).

Since we've learned all this stuff about calcium and magnesium, when might we administer one of these agents? Some indications for calcium (chloride or gluconate) administration that were not directly related to our high/low conditions mentioned up above might be (28):

  • Antidote for hypermagnesemia (such as giving too much mag as a tocolytic)

  • Cardiotoxicity for hyperkalemia (we covered that in the potassium section)

  • Calcium channel and beta-blocker overdose

Magnesium sulfate is common in these situations (29):

  • Hypomagnesemia

  • Eclampsia/preeclampsia

  • Use as a tocolytic

  • Bronchospasm

  • Torsades de pointes or Polymorphic VTACH


Conclusion