Time Stamps

  • 01:37 Pearl 1: Magnesium
  • 09:39 Pearl 2: Framework for hypomagnesemia
  • 16:53 Pearl 3: Magnesium repletion
  • 22:39 Pearl 4: Phosphorous
  • 28:36 Pearl 5: Phosphorous repletion

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Show Notes

Pearl 1: When is Magnesium indicated and what are the major considerations to keep in mind?

  • Magnesium’s allure stems from its potential benefits, capturing interest in medical circles!
    • Established uses:
      • Torsades
      • Eclampsia 
    • Potential uses (being investigated, mostly associations and limited evidence): 
      • Asthma Exacerbation 
      • Migraines 
      • Sleep Quality 
      • Cataracts 
      • Depression
    • However, consider in Gitelman syndrome
      • Patients with chronically low magnesium WITHOUT higher rates of migraines or asthma
  • Magnesium is excreted in urine and feces
    • Requires cautious administration in patients with kidney dysfunction
  • Obstetrics Patients vs. Medicine Patients
    • Obstetrics Patients
      • Normal Kidney Function
        • Supratherapeutic magnesium levels in obstetrics protect against seizures
    • Medicine Patients
        • Impaired kidney function can lead to high magnesium levels (above >4 meq/L), which can cause:
          • Neuromuscular issues
          • Weakness
          • Confusion
  • Data favors magnesium repletion among electrolytes
    • Potential benefits in acute MI!
      • Studies supporting benefit
        • A 1995 study supports IV magnesium for better outcomes in acute MI cases
      • Studies showing inconsistent benefit
        • ISIS-4 study
          • Control group mortality rate was 7.2% (significantly lower than previous trials)
            • Raising the possibility that more ISIS-4 patients were in a low-risk group unlikely to benefit from magnesium
        •  MAGIC study
    • Magnesium’s strongest data lies in heart failure and post-MI care!
      • BUT potential associations exist between magnesium repletion and morbidity/mortality benefits in many other areas
  • Magnesium’s impact varies, suggesting a cautious approach—neither highly effective nor harmful. 
    • However, some evidence indicates a potential for being optimistic…
      • Mortality with hypomagnesemia
        • Hypomagnesemia is associated with higher mortality in critically ill patients
      • Atrial Fibrillation
        • A 2007 meta-analysis supports magnesium’s role in rapid atrial fibrillation control
      • Hypokalemia
        • Mg supplementation can be helpful when mg and K are both low since Mg deficiency leads to K wasting in the distal nephron

Pearl 2: Common Etiologies of hypomagnesemia

  • GI Losses/Impaired Absorption (1/3rd of Mg absorption through GI tract)
    • Proton-pump inhibitors
      • Altering gastric pH and affects magnesium absorption
      • Take a look at the figures here where you see “PPI stopped  magnesium goes up, PPI reinstituted, it plummets again.
    • Acute or chronic diarrhea
    • Malabsorption
    • Small bowel bypass surgery
    • Pancreatitis
  • Urinary loss aka “Renal magnesium wasting”
    • Medications
      • Diuretics
        • Thiazide 
        • Loop 
      • Antibiotics 
        • Aminoglycosides
        • Amphotericin B 
        • Foscarnet
      • Chemotherapeutic agents
        • Cisplatin 
        • EGFR inhibitors
      • Immunosuppressive agents 
        • Calcineurin inhibitors 
          • Tacrolimus 
          • Cyclosporine 
        • mTor inhibitors
      • NOTE: Addressing the root cause, such as discontinuing PPIs ,can be crucial for effective magnesium management!
    • Osmotic diuresis in the setting of elevated blood sugars
    • Alcohol use disorder
    • Hypercalcemia
    • Genetic Tubular Disorders
    • Other Acquired Tubular Dysfunction
      • Post-obstructive diuresis  
      • Osmotic diuresis s/p kidney transplant
  • If the cause is not obvious, urinary magnesium levels can indicate whether urine (kidney) or stool (GI tract) is the source of magnesium wasting
    • Renal Magnesium Wasting:
      • 24 hour urinary magnesium >10-30 mg OR
      • Fractional excretion of magnesium (FEMg) >3-4% 
        1. If FEMg <1% probably non-renal causes!

Pearl 3: Correcting hypomagnesemia and magnesium repletion

  • How to correct hypomagnesemia?
    • Limit losses:
      • Address correctable causes (PPI, kidney function, etc)
    • Increase intake:
      • Consider supplementing with magnesium-rich foods
        • Nuts, legumes, pumpkin seeds, leafy vegetables, chocolate, lima beans, and avocados
  • Magnesium repletion
    • IV administration
      • Can lead to transient increases in serum magnesium levels
        • Should be administered over extended periods to prevent rapid renal excretion!
        • Loop of Henle largely reabsorbs magnesium, influencing transient serum increase
    • Oral administration (PO magnesium oxide)
      • Can cause diarrhea
        • May be preferred in patients with constipation
          • Dual-purpose regimen: magnesium repletion + address constipation
    • Unlike in potassium supplementation, there is not a good rule of thumb to predict how repletion with a certain amount of PO magnesium (in milligrams) translates to an increase in serum magnesium level (in milligrams per deciliter).

Pearl 4: Phosphorus

  • What causes hypophosphatemia?
    • Low intake
      • Not as common
        • Phosphate is plentiful in foods
        • Kidneys can limit phosphate loss to 0%
    • GI losses
      • Any malabsorption or diarrhea
      • Common OTC antacids with aluminum or magnesium
        • Binds to phosphate → insoluble salts → pooped out
    • Kidney loss
      • Mostly governed by hormones
        1. Vitamin D deficiency
        2. Primary or secondary hyperparathyroidism
      • Proximal tubule defect and proximal tubulopathy
    • Cellular shifts
      • DKA 
      • Refeeding syndrome in malnourished patients
      • Respiratory alkalosis
      • Hungry bone syndrome
  • What could happen to a patient with severe hypophosphatemia?
    • Rhabdomyolysis and diaphragmatic weakness!
      • < 1 millimole per liter → concerning 
      • < 2 millimole per liter → aggressive repletion needed!
  • How to replenish phosphorus?
    • What to use?
      • Neutra-phos packets
        • Contain 8 millimoles of phosphate + 7 millimoles of sodium and potassium
          • Consider the patient’s potassium levels when administering phosphate-containing supplements to avoid excessive intake 
          • Make sure you understand how much sodium and potassium you’re giving your patient!
      • Phosphorus-rich foods examples:
        • Milk
          • Contains about as much phosphorus as two packets of neutra-phos!
        • Eggs
        • Nut butters
          • Protein drinks
        • IV Phosphate
          • Be mindful of the amount of fluid given in our fluid sensitive patients
    • How much to use?
      • Algorithms suggest 40-80 millimoles of phosphate repletion for asymptomatic patients with low phosphate levels
        • The volume of distribution of phosphate varies among patients, making repletion challenging.

Transcript

Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidenced-based pearls. I’m Dr. Shreya P. Trivedi

Dr. Ben Osher: I’m Dr. Ben Osher, an internal medicine resident at BIDMC. On today’s 5 Pearls episode, we’ll be  covering all things mag, phos, and electrolytes in general!  Let’s start with the pearls we’ll be covering in this episode. 

Dr. Shreya Trivedi: Test yourself by pausing after each of the 5 questions. Remember the more you test yourself, the deeper your learning gains.

Dr. Ben Osher: Pearl 1 – Magnesium

Dr. Shreya Trivedi: Can magnesium supplementation really help improve things like asthma and restless leg syndrome?

Dr. Ben Osher: Pearl 2 – Framework for hypomagnesemia

Dr. Shreya Trivedi: When you see a low mag, what are you thinking about? And can PPIs effect magnesium absorption?

Dr. Ben Osher: Pearl 3 – Magnesium repletion

Dr. Shreya Trivedi: Does the length of time that magnesium is infused over matter?

Dr. Ben Osher: Pearl 4 – Phosphorus

Dr. Shreya Trivedi: What is your framework when you see a low phosphate in the EMR?

Dr. Ben Osher: Pearl 5 – Phosphate repletion

Dr. Shreya Trivedi: How much sodium and potassium are typically found in oral phosphorus supplement?

Pearl 1: Magnesium

Dr. Ben Osher: When I first started digging into the evidence behind magnesium repletion, I actually got really excited initially!

Dr. Shreya Trivedi: Oh yea how come, Ben?

Dr. Ben Osher: Well, in addition to the benefits of magnesium that we all know and love related to things like preventing Torsades, treating  eclampsia. Good things, I think we can all agree. There’s been a lot of buzz recently about magnesium as a potential panacea for all sorts of random medical conditions like asthma exacerbation, poor sleep, cataracts, depressions, migraine, hot flashes, atopic dermatitis, all sorts of things. So I was really excited to sit down with our favorite nephrologist, Dr. Melanie Hoenig to learn about how magnesium as a potential cure for pretty much anything that ails ya!

Dr. Melanie Hoenig: Oh my gosh, Ben, so much to unpack here. First of all, please don’t be upset as much as I love potassium, I do not love magnesium. It’s just not my favorite cation. I’m not really sure about magnesium as this sort of panacea for all things.

Dr. Shreya Trivedi: She particularly brought up all the patients that she sees who have Gitelman syndrome. And as a refresher, in Giteman you have mutations in the sodium and magnesium transport, so its like you’re are chronically on thiazides and have low magnesium.

Dr. Melanie Hoenig: One way to, to look at that in my mind is to say what happens when patients have low magnesium chronically?  Do they have asthma or migraines or whatnot? That would be better when we treated those. And I do follow some patients who have Gitelman’s syndrome. And those patients generally don’t have migraines and asthma and whatnot. So I’m reassured by that, or I’m convinced by that.

Dr. Ben Osher: Okay, that’s a valid point. So Dr. Hoenig is right- while there is some association between mag level and some of these illnesses and symptoms, I haven’t seen super persuasive evidence that repleting their mag will fix these diabetes or their cataracts. Or what have you. The other reason I was really excited about magnesium initially is that I think about magnesium repletion as a pretty benign thing to give someone. Basically it’s this thing that can hypothetically treat all these kinds of unrelated seeming problems and on top of that, it’s something that doesn’t really cause problems after you give it to people. After all, OB/GYNs give their patients supra-physiologic doses of magnesium, and those patients generally tolerate those doses pretty well.

Dr. Shreya Trivedi: Yeah, yeah. That is true! Yes, but Dr. Hoenig did bring up the typical patient on the OB/GYN service who’s getting pre-eclampsia dose magnesium looks pretty different than the typical patient on the medicine service.

Dr. Melanie Hoenig: Luckily most of the time in obstetrics, the patient’s kidney function is normal. And then, with time they’ll excrete that magnesium and they’ll do well. Patients who don’t have kidney normal kidney function though can get into trouble with neuromuscular symptoms.

Dr. Shreya Trivedi: Uh oh, especially in someone with severe renal dysfunction who cannot excrete their magnesium, when that mag gets over 4 meq/l, you can start seeing decreased reflexes and even more too much mag leading to weakness, confusion. 

Dr. Ben Osher: Yeah, too much of pretty much anything can cause problems, especially when we consider magnesium excretion and homeostasis is very dependent on the kidneys and the gut.

Dr. Shreya Trivedi: But Ben, I know you were really excited about magnesium and being “bullish” about repleting it so there is must be some upside to repleting that magnesium. 

Dr. Ben Osher: Yep, so we also sat down with Dr. Tony Breu, hospitalist and educator extraordinaire about what the evidence does and does not say about magnesium repletion.

Dr. Tony Breu: I think the data is best for magnesium. And by data I mean the data for repleting is best for magnesium amongst the three electrolytes that we’re talking about.

Dr. Ben Osher: And by the 3 electrolytes, he means potassium, mag, and phos.

Dr. Tony Breu: There were randomized control trials of giving magnesium to patients with acute MI that you would benefit. This wasn’t born out in the most recent rigorous trials, but there’s at least something that said if we give magnesium to a patient with acute MI outcomes are better. They weren’t all hypomagnesemic, but it’s just the idea of giving magnesium. 

Dr. Ben Osher: Dr. Breu is referring to an RCT from the 90’s that showed that IV mag in patients with acute MI who couldn’t get thrombolytics had decreased mortality compared to placebo. 

Dr. Shreya Trivedi: Yeah, Ben, but how do studies from 90s apply to today’s age where there are so many more medical therapies?

Dr. Ben Osher: Yeah, he said it wasn’t born out in more recent studies, which have kind of wild names like MAGIC, ISIS-4. These didn’t show a statistically significant mortality benefit from mag infusion in post-heart attack patients. But to give some context, some people have pointed out that the ISIS-4 trial’s population wasn’t as sick and so those people may not have been in as much of a position to benefit from IV mag supplementation.

Dr. Shreya Trivedi: So it sounds like its a mixed bag of evidence in post-MI patients. Any other conditions that mag has been a little bit better studied and more helpful in?

Dr. Tony Breu: Atrial fibrillation. I love giving it for patients with atrial fibrillation though again the data is plus or minus on that.

Dr. Ben Osher: So, one of my favorite papers to cite on rounds is this meta-analysis from 2007 that looked at RCTs using mag for the acute control of rapid afib. They found increased success of either rate or rhythm control as well as faster time to response to therapy, so mag is potentially something to reach for in rapid asymptomatic afib. 

Dr. Shreya Trivedi: Oh! I love me a harmless intervention.

Dr. Ben Osher: And lastly, another good reason for upping someone’s mag is that it can actually help out other electrolytes in terms of repletion. For instance, it can help our other friend potassium.

Dr. Melanie Hoenig: Magnesium also sabotages my favorite cation on potassium, since it’s long been known that, uh, hypomagnesemia can lead to hypokalemia and the mechanism has been worked out, it’s pretty cool. It turns out that if the intracellular magnesium is low, then magnesium, which normally blocks the potassium egress from cells in the distal nephron, if those magnesium ions are not there, then potassium could just, uh, sort of leave those cells more quickly.

Dr. Tony Breu: There is data that if you have a patient who is hypokalemic, if you give them magnesium, the hypokalemia will get better. So if I have someone who’s got a potassium, a 3.2 and a magnesium 1.4, my advice is just give them magnesium. The magnesium will get better and you know what the potassium will probably get better too. And that is two birds with one stone.

Dr. Ben Osher: With that said, if someone’s total body potassium is down, you’re probably not going to be able to completely solve that just by repleting magnesium, but sure, repleting mag will make the job of repleting potassium much easier, as you’re not going to have to actively fight against ongoing potassium wasting as much.

Dr. Shreya Trivedi: Ah! That is a win! And then another bonus one of our reviewers pointed out that is that repleting magnesium can also help with hypocalcemia! It turns out that chronic low mag is associated with impaired PTH secretion which in turn leads to low calcium.

Dr. Ben Osher: See, mag does do a bunch of stuff!

Dr. Shreya Trivedi: Yeah, it does, it does! But maybe Ben this might be a good point to summarize what is actually really great about it and what are just some associations? 

Dr. Ben Osher: Okay, so the best data for aggressive mag repletion is in the acute post MI period, in rapid afib and in helping in repleting patients who are hypokalemic. I was really excited about this list of disparate conditions that magnesium repletion could potentially be helpful in, including asthma, restless leg syndrome, and sleep apnea. It’s a little disappointing mayble that magnesium hasn’t been shown to be this silver bullet that can single handedly fix cataracts and insomnia. And its also worth keeping in mind that just because OB patients can tolerate whopping doses of magnesium, that doesn’t mean we shouldn’t be a little more careful when giving liberal doses of magnesium to 80 year olds with CKD  on medicine floors.

Pearl 2: The ‘why’ behind hypomagnesemia

Dr. Shreya Trivedi: So now, similar to our hypokalemia episode, both Dr. Hoenig and Dr. Breu stressed the importance of not just mindlessly throwing an elemental supplement at a number, and instead stepping back and thinking about why that magnesium is low.

Dr. Melanie Hoenig: So the approach to hypomagnesemia is actually really not that different from potassium or phosphate for that matter, because you want to ask yourself, well, where did it go? Why is it low? And there can be renal losses of magnesium or GI losses of magnesium. 

Dr. Shreya Trivedi: So my new framework when I look at electrolytes and some spaced repetition from the hyopk episode is to think through these 4 buckets: is the patient not eating enough, is the patient urinating it out, is the patient pooping it out, or is it being shifted into cells?

Dr. Ben Osher: For our hypoMg framework we can pretty much get rid of shifts into cells since there’s not much of that, outside of very specific medical conditions like hungry bone syndrome. And the most bang for our buck is gonna be from the middle two, so any magnesium wasting that may be happening is probably due to renal or GI losses.

Dr. Melanie Hoenig: Normally when we eat, about a third of the magnesium is reabsorbed by the GI tract, and then the rest is lost in the stool. And then that same magnesium that’s absorbed then, because we’re typically in balance, will be excreted by the kidneys. 

Dr. Shreya Trivedi: So a 1/3rd Mg is absorbed in the GI tract, and then things like diarrhea and malabsorption conditions, history of small bowel bypass surgery will decrease how much Mg gets absorbed in that GI tract. 

Dr. Ben Osher: Actually, one of the most common causes for loss through the stool is on most people’s medication lists. Those are proton pump inhibitors.

Dr. Melanie Hoenig: And it turns out it’s not the kidney’s fault, it’s the enterocytes because using proton pump inhibitors changes the pH and affects the way we absorb dietary magnesium. So not my fault. Um, so if you could stop approach on pump inhibitor, that will help otherwise giving oral magnesium probably is not gonna get you where you wanna go. So that is worth noting.

Dr. Shreya Trivedi: Yep, so PPIs affect the pH of the lumen of the bowels and affect magnesium absorption, so its certainly worth trying to stop the PPI, transition them to say, a H2 blocker and then start magnesium repletion.

Dr. Ben Osher: H2 blockers haven’t been shown to have an effect on the magnesium levels.

Dr. Shreya Trivedi: Yes, that is a win! So how soon after stopping the PPI should we see that magnesium go up?

Dr. Tony Breu:  I think you can see it pretty soon, within day. There’s a fascinating New England Journal Medicine case report that shows these curves just up and down like PPI stopped magnesium goes up, PPI re-instituted, it plummets again.

Dr. Shreya Trivedi: So crazy we will link those eye-opening changes of the mag level with the PPI in our graphic and show notes. 

Dr. Tony Breu: It’s not uncommon that I’m telling teams to check a urinary magnesium on a patient, on a PPI. Cause if the urine magnesium is low, that suggests that the kidneys are not the source of the magnesium wasting, but rather than the stool. 

Dr. Shreya Trivedi: And just to round that out, PPIs will cause mag wasting through stool, not in the urine. So if you look at the urine magnesium and plug it into the fractional excretion of magnesium calculator, you’d expect a low fractional excretion of mag, or FeMg,

Dr. Ben Osher: I wonder if the nephrologist call it FeMg like we do with FeNa.

Dr. Shreya Trivedi: I don’t know if it has the same ring to it! FeMg, maybe we can make it a thing! But let’s say a fractional excretion of mag, a FeMg, comes back high, say >3-4. It’s going to point us to renal losses of magnesium and the way to remember that is understand how good to kidneys are in limiting renal loss of Mg if the kidneys sense it.

Dr. Melanie Hoenig: The kidneys can alter how much magnesium is excreted, and generally in the setting of hypomagnesemia, then the fractional excretion of magnesium can go down to less than 2% of what is filtered. 

Dr. Shreya Trivedi: And another reviewer noted that a fractional excretion of magnesium, or FeMg as that cool kids say it, a FeMg <1% really points us away from renal magnesium wasting and points to GI loss or something else.

Dr. Ben Osher: So if the kidneys are sensing low Mg, they will decrease their FeMg all the way to <2% but if its a renal insult then all bets are off and Mg may be wasted in the urine and you’ll detect it with a FeMg >3-4%.

Dr. Shreya Trivedi: Yep! That was a great summary. So speaking of renal losses, what are some of the more common offenders?

Dr. Melanie Hoenig: Thiazide diuretics also cause hypomagnesia and poorly controlled diabetes mellitus, uh, was one of, used to be one of the more common causes before proton pump inhibitors, uh, because of the osmotic diuresis and the loss there.

Dr. Shreya Trivedi: So both loop diuretics and thiazide diuretics inhibit net magnesium reabsorption but often this lead to mild hypomagnesemia.

Dr. Ben Osher: The other offender is alcohol use, which actually also leads to renal wasting of magnesium. 

Dr. Shreya Trivedi: And thankfully that tubular dysfunction from alcohol is actually reversible after 4 weeks or so of abstinence so another thing to plug in our alcohol cessation conversations. 

Dr. Ben Osher: So that pretty much puts a bow on our most common high-yield drivers of hypomagnesiumia. There are whole host of other causes like potentially nephrotoxic medications. Things like tacrolimus and cyclosporine. Or other electrolyte disturbances like hypercalemia, that can also play a role. 

Dr. Shreya Trivedi: Yep and lots other that are more rare and cumbersome to list off. So now that we thought of the most common reasons for loss of magnesium in stool and urine. Let’s get to that last bucket and think about that PO intake of magnesium and where that can be an issue? 

Dr. Melanie Hoenig: Magnesium is felt to be very plentiful in green, leafy vegetables and greens, nuts, legumes, chocolate! There is a good one.

Dr. Shreya Trivedi: Yep I can imagine unless someone is very health conscious, getting veggies, legumes and nuts that may contribute to some mild magnesium deficiency. Though it get’s me wondering how much chocolate one would need to get sufficient mag stores.

Dr. Ben Osher: Yeah! Once I heard chocolate on the list, I thought I was good! But obviously too much of anything is not great.

Dr. Shreya Trivedi: Yeah I’m just imagining that lots chocolate may be offset by the hyperglycemia and potential osmotic diuresis that osmotic diuresis would lead to more mag loss. It could be a vicious cycle! Like everything! That’s the theme of the episode. too much of anything is no bueno.

Dr. Ben Osher: So my big takeaway if I see a low mag is to think of urinary versus stool loss of Mg. When i am thinking of stool loses, I am going to look into the patient’s history to see if they are on a PPI? Do they have any history of malabsorption, small bowel surgery, diarrhea. Anything like that. 

Dr. Shreya Trivedi: Yep and then for urinary causes, we think about low magnesium may be from diuretics they are on, related to alcohol or osmotic diuresis. And if we are not sure, we can get a fractional excretion of Mg or FeMg, as the cool kids say, and see if it’s greater than 3-4% that really points you, when it’s that high to renal losses of magnesium.

Pearl 3: Mg repletion

Dr. Shreya Trivedi: Now that we’ve gone over the data we have and don’t have on magnesium. We reminded ourselves of the common offenders, let’s think about the nuances of magnesium repletion!  

Dr. Ben Osher: And just to remind ourselves, how low is too low where you start to worry about symptoms and what even are those symptoms?

Dr. Melanie Hoenig: Most patients who have hypomagnesemia are asymptomatic. If they’re going to have symptoms, I suppose they could complain of fatigue or weakness. The severe symptoms that we worry about are arrhythmias, tetany, and seizure. And so obviously we would like to avoid those. And generally those are not going to occur unless the magnesium is well under one. 

Dr. Shreya Trivedi: And everyone is fatigued and weak in the hospital so I have a pretty low threshold to replete.

Dr. Ben Osher: Yeah, that’s right, Shreya! But to channel the hypoK episode for a second – It’s worth noting we see very mild hypomagnesemia somewhat frequently, and if someone’s hanging out at a magnesium level 0.1-0.2 mg/dl lower normal then as long as they don’t have terrible cardiac comorbidities or arrhythmia you don’t need to rush to replete.

Dr. Shreya Trivedi: Thats a good point. So I don’t need to feel guilty if it’s not a perfect 2.0. So I guess in my experience when it comes to mag repletion I always think IV is a little better, it’s faster, is that true?

Dr. Melanie Hoenig: If you suspect magnesium deficit as a cause of an arrhythmia you’re going to give something quickly, but otherwise you’re going to need to give it slowly. And the reason is that if you try and give it quickly, the magnesium in the serum is transiently higher and the kidney will detect that and then favor losses. And so you’ll actually just urinate out the magnesium you’re infusing, you won’t get anywhere. So you need to give it slowly. 

Dr. Shreya Trivedi: Yeah! So we do see someone’s magnesium increase much faster with IV repletion, but maybe not in a way that actually keeps it at a higher level.

Dr. Tony Breu: Because what you wanna do is you wanna slowly raise that serum value, or not necessarily slowly raise it, but you wanna raise it and give it time to get into the cells and not jump it up to a high value, excrete it all and then your back to sort of square one. The biggest problem with this of course is no one patient really wants to be hooked up to an IV magnesium pole for 8 or 12 hours. Or else it’s an empiric victory where the patient’s just going to excrete a lot of what you give them. And I don’t think that most orders, most nurses hang it for more than a couple hours.

Dr. Ben Osher: Huh, I didn’t realize that the secret to IV mag is give it slowly if you want to make sure patients retain it. 

Dr. Shreya Trivedi: Yeah! Now I can appreciate why the nurses will tell me they cant give x or y other medication until a few hours because the mag is running. 

Dr. Ben Osher: I’m glad we’re going over our blindspots, and this maybe helps explain why we might not see the mag bump we’re expecting when were trying to replete someone. 

Dr. Shreya Trivedi: Now that we went over some nuances with IV mag repletion, let’s switch to oral magnesium! With oral mag, I think the biggest thing people think about is ‘oh, the diarrhea it’ll cause!’ I’m just wondering how much of an issue is that really? 

Dr. Tony Breu: I think amongst nephrologists on Twitter that if they had a choice between magnesium and IV magnesium with the formulations that we currently have, they would choose PO because it, you’re not going waste as much of it. For my garden variety patient, I prefer magnesium oxide, oral. Because most of my patients are constipated and so I’m not actually not causing harm. But what percentage of my patients are already on polyethylene glycol and senna? And it’s like over 80% replacing that senna with some magnesium oxide. How about we just do that?

Dr. Shreya Trivedi: Whoa I hadn’t thought of that – it is probably a daily occurrence that I am giving IV mag and also increasing someone’s bowel regimen. And now that I’m hear this, maybe mag ox can be killing two birds with one stone. 

Dr. Ben Osher: Though the caveat that our peer reviewer did point out that it can be a zero sum game if the patient does develop diarrhea on PO Mg. If those mag supplements cause diarrhea then that diarrhea will then worsen mag stool losses. And things get worse.

Dr. Melanie Hoenig: And then of course when you give it orally, that’s a problem because as you know, we use magnesium as a cathartic, so you’re going to stool that out. And so it’s really hard to manage magnesium deficits. 

Dr. Shreya Trivedi: So, what I learned is that most magnesium formations – mg sulfate, mg hydroxide, mg citrate – these formulations are osmotic cathartic in 6% isotonic solution. So that high osmolarity of the solution which draws large amounts of fluid into space and maybe the ones that make patients poop more!  

Dr. Ben Osher: Now there are other formulations like Slow Mag, which is a mix of mag, chloride and calcium, that stick around longer and theoretically are better for absorption, but it depends on what your hospital formulary may have.

Dr. Shreya Trivedi: Yep, another day in formulary-based medicine! Not evidence-based medicine as much as we’d like. Maybe thats too dark to say on air? But Ben, maybe we should recap, what are you taking away from mag repletion?

Dr. Ben Osher: Anyway! So my takeaway is that if my patient is constipated and has a low mag, it may be good to reach for oral magnesium.

Dr. Shreya Trivedi: Yes! And I am going to think about that twice  same when giving IV magnesium, miralax, and senna all at once, and I maybe just reach for that PO mag instead. The other thing for me is when I am giving IV magnesium, say in a patient who can’t really tolerate any orals, I am to give instructions to maybe try to run it over 2 hours or longer if possible, if it doesn’t interfere with any other meds.

Pearl 4: Phosphorus

Dr. Shreya Trivedi: Alright, this brings us to our last electrolyte we’ll be talking about – phosphorus. Of course, both Dr. Breu and Dr. Hoenig brought us back to think about the most important question which is – why is that phosphate low?

Dr. Ben Osher: So if we go back to our framework that we learned in the hypokalemia episode: we have inadequate intake, lost in the urine, loss in the stool, or being shifting into cells. We can usually eliminate the first one: oral phosphate intake tends not to be much of a problem for most people.

Dr. Melanie Hoenig: So hypophosphatemia is very uncommon in healthy people. And when we, especially severe hypophosphatemia, very uncommon in healthy people. When I see hypophosphatemia, I like to divide it into GI losses and renal losses. It’s true that I suppose you could develop hypophosphatemia from nutritional deficiency, but typically would also have losses because phosphate is in so many foods and so easy to supplement in contrast to magnesium, which is a little bit challenging to supplement, like pumpkin seeds. But anyway, phosphate’s pretty easy to supplement. 

Dr. Shreya Trivedi: And another reason why inadequate phosphate intake is rarely the reason is because the kidneys adapt rapidly and urinary excretion of phosphate can actually approach zero if needed.

Dr. Melanie Hoenig: The the kidney is rocking awesome at limiting phosphate loss. If the kidney is normal, like, you know, like we can go to zero, we can go very, very low.  

Dr. Ben Osher: So if inadequate intake is rarely the cause, what about the rest of the GI tract? 

Dr. Shreya Trivedi: So here again, we’re thinking about most things that impact intestinal absorption, diarrhea or malabsorption conditions but if we come back to the patient’s med list, common things being common, a lot of patients are on meds for heartburn, so common over the counter antacids that have aluminum or magnesium can be the culprit. Those antacids will bind phosphate and create insoluble aluminum or magnesium phosphate salts that get pooped out!

Dr. Ben Osher: Ah even benign over the counter things can be playing a role! What about the urinary causes?

Dr. Melanie Hoenig: On the kidney side, phosphate losses are typically governed by hormones. One of the more common sort of benign causes of hypophosphatemia in the outpatient arena is, uh, vitamin D deficiency and secondary hyperparathyroidism. So because we need vitamin D, to absorb, dietary calcium, and if you don’t have that, then the calcium’s low that turns on parathyroid hormone. And in addition to leaching calcium and phosphate from bone, it’s telling the kidneys to get rid of phosphate, and then we have deficiency problem.

Dr. Shreya Trivedi: Yikes! I can imagine most of listening work  in clinics and hospitals get pretty low vitamin D in the day to day, and internalize it differently when we think, oh gosh, our vitamin D levels are low, we have this inability to absorb Ca which then turns up PTH, then that causes calcium and phosphate to be leaked out from our bones and then our kidneys see that phosphate and get rid of it because of the PTH being high – wam, wam.

Dr. Ben Osher: Yep and I think we just inspired half the people listening to go take a walk, get some sunlight, prevent Vitamin D deficiency-related secondary hyperparathyroidism. So it sounds like primary or secondary hyperparathyroidism, including vitamin D deficiency, can lead to increased phosphate excretion in the urine.

Dr. Shreya Trivedi: Alright on to our our last bucket, shifts into cells. So a lot of that internal redistribution is going to be seen in cases of refeeding syndrome with alcohol use or eating disorders when carbohydrate intake, again, this is going to be a bit too complicated to explain on air but in a very simplified sense, when there is  carbohydrate intake after a long time, there is increased insulin secretion, glycolysis and that leads to phosphorylated carbohydrate compounds that makes the phosphate look pretty low.

Dr. Tony Breu: I think the more severe hypophosphatemia that I have seen accepting again may be that patients with alcohol use disorder are these patients with shifts. The patients with DKA for example, who have massive shifts of phosphorus into their cells or refeeeding syndrome. I think those are the scenarios where I think I’ve seen the worst values.

Dr. Shreya Trivedi: And then last big one for internal shifts of phosphate is acute respiratory alkalosis. In resp alkalosis, there is low Co2 from  hyperventilation, and again, the pathophys is a bit complicated but in a simple sense, when there is  low Co2 from  hyperventilation, carbon dioxide shifts out of cells. This increase in intracellular pH stimulate glycolysis and, again, leads to those pesty phosphorylated carbohydrate compounds, which makes the phosphate low.

Dr. Ben Osher: Those gosh darn phosphorylated carbohydrates! What’s the Scooby-doo think? Those metallsome phosphorylated carbohydrates! So, to pull this back and to summarize, it sounds like hypophosphatemia is pretty uncommon in healthy people, and so when you see it, it’s really worth thinking about why. You should consider GI and renal losses. For stool and GI losses, think about aluminum or magnesium based antacids, or anything that causes malabsorption or diarrhea. For urinary losses, think about vitamin D, hyperparathyroidism, in general.

Dr. Shreya Trivedi: And lastly we talked about shifts into cells in situations like refeeding syndrome, DKA, and acute respiratory alkalosis.  

Pearl 5: Phosphorus Repletion

Dr. Shreya Trivedi: Alright, last but not least, phosphate repletion! But again, let’s think back to what is too low and what are worried that we want to replete phosphate. You know, other than treating ourselves and making numbers in the EMR look better and less red.

Dr. Tony Breu: Okay, so what do we worry about when the phosphorus is low? I think we worry about things like muscle weakness, we worry about things like rhabdomyolysis.

Dr. Melanie Hoenig: Most people are asymptomatic when they have hypophosphatemia, but we do worry in hospitalized patients when the phosphate gets severely reduced that it will affect respiratory function, particularly because of the diaphragm and might affect the ability to wean from the ventilator or liberate from the ventilator.  And so, will attend to that and want to improve phosphate. Phosphate is the P and ATP. So it’s going to be important for muscular function.    

Dr. Ben Osher: So I really pressed our discussants, is there a number that makes you worried? Is there a number that you say, ‘Hey I really need to make sure that this person’s phosphate is higher the next time that we check it?’

Dr. Tony Breu: I would say less than one. I mean I think all of us will be very anxious if we see it less than one.

Dr. Shreya Trivedi: Yeah numbers less than 1 make me worry, too. So now onto repletion. You know if phosphate is so plentiful in our diets and say our patient has their appetite back, what are things we should be pointing them to?

Dr. Melanie Hoenig: I think the diet’s such a great way to get phosphate as well. A glass of milk has 15, uh, millimoles of potassium per serving. So that’s a great way to get phosphate. Also eggs, nut butters.  

Dr. Shreya Trivedi: This also raises the question for me, how much phos is actually in a packet of neutra-phos? If milk has about 1 mmol per fluid ounce, so a 15 oz glass milk as 15 mmols of phosphate, how much does our go-to supplement have? And what else is in there?

Dr. Melanie Hoenig: Neutro phos packet which is a common one, has eight millimoles of phosphate and about seven each of sodium and potassium. So it’s actually not that much phosphate. If you, if the patient has significant hypophosphatemia, one packet only has eight millimoles, you might need a few, a little bit more or you know, so several packets divided over the day.

Dr. Shreya Trivedi: Wait, 8 mmols in 1 one neutraphos? That’s about the same in a standard cup of milk?! Gosh, maybe we should prescribe milk instead of packets of neutraphos?

Dr. Ben Osher: So that’s one takeaway for me! Another real clinical pearl that I am pulling out of this is that that when you give phosphate repletion you are not just giving phosphate because the standard repletion agents, like neutra-phos, also have potassium and sodium. Different hospitals have different things on formulary for this, and so it’s really important you know which other electrolytes are coming along for the ride.

Dr. Tony Breu: And the reason  I bring this up is most of them contain potassium. My hospital uses this version of Neutro phos that’s called Neutro phos neutral, where the amount of potassium is only one milliequivalent. But I think the listeners should know what they’re giving their patient. They’re giving them phosphorous, yes, but they’re also giving them sodium and they’re giving them potassium. They wanna know how much of those things as well because it can be something more than just an innocent bystander.

Dr. Ben Osher: So with that caution about maybe not so innocent bystanders in our phosphate formulation, let’s lean more into the phos, and try to figure out how much we should give to make someone’s serum phosphorus increase?

Dr. Shreya Trivedi: Yeah do we have a  good idea of how many millimoles of phosphate is needed for a phos of 2.5 to 3.3 or so?

Dr. Ben Osher: So I was kind of given as algorithm as an intern for this,  and here it is. So basically if their phos is a “little low” then you give one packet of Neutra phos and if it’s just “low” then you give two packets of Neutra phos. And then re-check the value the next day. Except is the value is “dangerously low”. 

Dr. Shreya Trivedi: Oh gosh! And that makes me wonder, is one to two packets enough? Is there is other things we should be doing?

Dr. Melanie Hoenig: There’s no real, there are algorithms that suggest how much we should give. So as an example, you know, if a patient is asymptomatic and has a phosphate of 1.5 to 2, then typical algorithms suggest giving 40 to 80 millimoles of phosphate. That’s why I’m saying one packet might be a little low. Um, but again, if you’re going to sit down with them and see what they’re eating for the day, if they are eating, you’re gonna be able to get some nice phosphate into their diet. Um, well also many of the patients, um, in the hospital are maybe taking nutritional supplements like in, uh, you know, like a protein drink and those often have a lot of phosphate.

Dr. Ben Osher: So just to say it explicitly, we don’t have a good rule of thumb for how much someones serum phos is gonna go up like we do for potassium.

Dr. Melanie Hoenig: With many other electrolytes, we don’t have a good understanding of how much that meant change. And maybe that’s because patients are so different and have so many different reasons for these, uh, deficiencies, but it is handy to at least work with an algorithm. This gives you some comfort, I think in our messy lives and, and, uh, without good evidence. 

Dr. Ben Osher: And one of the reasons the amount required to restore the phos by a certain amount is variable across patients is that the volume of distribution of phosphate across patients is highly variable. (Review article). 

Dr. Shreya Trivedi: That reminds me of the hemoglobin bump episode we did after a transfusions and the main point there was of why don’t we always see that rule of thumb 1g/dl (or S.I Unit) bump after 1 unit of transfusion? And it’s also, one of big things is that the plasma volume can be so different in say an 80 year old who is thin or short versus someone who is much bigger or taller.

Dr. Ben Osher: The graphic of this actually made it into a lecture that I give.

Dr. Shreya Trivedi: Aw, yay! So Ben, that’s oral phosphate repletion. What about IV phosphate? Someone’s not eating. We’re really worried about them. What should we know about IV phosphate repletion?

Dr. Ben Osher: So I think it’s worth noting that IV phosphate repletion, while it can be a really, really useful thing to reach for, have in your arsenal, especially given there are multiple different formulations, you can do sodium phos. You could do potassium phos, if you’re trying to kill two birds with one stone. It comes in a lot of fluid relative to a lot of these other electrolytes that we’re repleting, it’s something like two 50 ccss per 15 millimoles, and oftentimes you’re giving someone 30 or even 45 millimoles. And so you could be giving someone like half a liter of extra fluid or even more that you weren’t really accounting for. And then on top of that, it takes forever to run something like six hours. And it’s not really why citable with a bunch of other things because it’s not compatible. And so you’re potentially tying up a line for a lot longer than you appreciated. This is a problem that I’ve run into on services where you’re really aggressively diuresing people. You end up in the situation where you are just kind of mindlessly ordering phosphorus repletion because their phos keeps hanging out at 1.3 or 1.5 or something and then you’re trying to dice them and you don’t understand why you can’t get them negative. And then suddenly you walk into the room like I did as an intern and saw the nurse hanging this large bag of fluids and I was kind of like, what is happening right now? We’re trying to diurese this guy. And they were like, you literally just ordered this phosphorus repletion. I don’t know what you want from me. And I felt very stupid in that moment.

Dr. Shreya Trivedi: No, no. We’re all learning. Thank you for helping us all learn too. Thanks, Ben. 

Dr. Ben Osher: One of my big takeaways from this conversation was that our oral repletion agents we use to replete phosphorus often have a lot of potassium and sodium as well, but that the amounts are variable, so it’s important to check in with your friendly neighborhood pharmacist to see how much sodium or potassium is in your local variant of neutra-phos. I was also surprised that a glass of milk has about as much phos as two packets of neutraphos, I guess depending on the size of the glass. It’s still frustrating there’s not an easy way to predict how much someone’s phos should go up when we replete, but it’s nice that there are algorithms out there to help guide us and we will link to some of those.

Dr. Shreya Trivedi: Yes! That’s a wrap for our episode. If you want more from these interviews, check out our YouTube channel. We have a bunch of  behind the scenes or snippets from the original interviews that you can go check out.

Dr. Ben Osher: If you want to add any of your own tips or share challenges, tweet us or x- us and leave a comment on our website page, on instagram or facebook page. 

Dr. Shreya Trivedi: Thank you to our peer reviewer Dr. Jeff William, Dr. Larissa Kruger Gomes Gomes, Dr. Jonathan A. Jefferson, and Dr. Fabrizio Canepa Escaro. Thank you to Daksh Bhatia for the audio editing. Dr. Sam Woodworth for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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