@Kidney_Boy returns to school us on metabolic alkalosis and hypokalemia! What do diuretics, hyperaldosteronism, black licorice, and milk-alkali have in common? Our Chief of Nephrology, Dr. Joel Topf, talks through the pathophysiology of metabolic alkalosis, the utility of urine chloride and pH measurements, why normal saline is sometimes better than balanced solutions, when to reach for acetazolamide, and more! Urine for a good time ; )
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Metabolic alkalosis is the most common disorder seen on a blood gas in hospitalized patients (Hodgkin, 1980). Dr. Topf says, “Metabolic alkalosis is the Rodney Dangerfield of electrolyte disturbances”. A big reason is because severe clinical consequences like seizures are uncommon (Emmett, UpToDate 2021). Symptoms can often be attributed to associated electrolyte disturbances, namely hypokalemia (Emmett, UpToDate 2021).
Dr. Topf notes that under normal circumstances the proximal tubule reabsorbs thousands of mEq of bicarbonate each day (Emmett, 2020). Therefore, to correct metabolic alkalosis it just needs to work less and let that bicarb “pour out of the kidney”.
Metabolic alkalosis is generated by the addition of alkali (e.g. bicarbonate), volume depletion, or the loss of hydrogen ions (Topf, Fluid Electrolyte and Acid Base Companion, 1999). It’s maintained by inability of the kidneys to excrete bicarbonate. As Dr. Topf puts it, “something paralyzes the kidney and forces it to reabsorb bicarb against its will”. Potential mechanisms include excess alkali intake with a low GFR (acute or chronic failure), volume depletion/chloride deficiency, hypokalemia (intracellular acidosis fools the kidney into retaining bicarbonate), and increased mineralocorticoid activity (due to volume depletion, primary hyperaldosteronism, Cushing’s syndrome) —Topf, Fluid Electrolyte and Acid Base Companion, 1999.
Use saline to correct volume and restore chloride levels (Metha, UpToDate 2021, Emmett, 2020). Don’t choose a “balanced” IV fluid (e.g. lactated ringers) for the patient with metabolic alkalosis from vomiting. Dr. Topf cautions, “This patient is starving for chloride and sodium so normal saline is the fluid of choice in this situation.” Technically, the diagnosis requires a blood gas, but this presentation is so classic that it would be reasonable to avoid the extra stick (expert opinion).
Kashlak Pearl – When someone develops a metabolic alkalosis from vomiting they begin to excrete the excess bicarbonate in their urine. This acts like a magnet for potassium and causes increased renal excretion.
Kashlak Pearl – A baking soda teaspoon has 60 mEq of bicarb while a 650 mg bicarb pill has only 8 mEq. Thus, patients with renal insufficiency or volume depletion who consume baking soda can get into trouble.
Kashlak Pearl – Baking soda is a major component of crack cocaine and thus patients receive high doses of bicarb. This can cause profound metabolic alkalosis for patients with advanced renal disease who cannot excrete bicarb on their own. Case reports exist (Diskin, 2006).
Patients receiving aggressive diuresis (decreased effective arterial blood volume) commonly develop metabolic alkalosis. Clinicians seem to become uncomfortable when bicarb exceeds 40. The mechanism here is multifactorial: intravascular volume depletion (which turns on aldosterone production), chloride depletion, and often hypokalemia (from diuretics, aldosterone) —Emmett, UpToDate 2021. Each of these can be targeted for treatment.
Kashlak Pearl – Anecdotally, most clinicians continue diuretics despite an elevated bicarb and implement some of the measures discussed below (expert opinion).
Dr. Topf recommends giving potassium chloride at slowly escalating doses until the potassium hits 5 or above to prevent/treat hypokalemia, hypochloremia, and provide a buffer during diuresis (expert opinion). Further, this gradual increase in potassium chloride supplementation allows us to correct the chloride without giving normal saline, and without potassium reaching dangerous levels (expert opinion).
Kashlak Pearl – Don’t give potassium acetate because acetate will be converted to bicarbonate in the liver (see Pfizer package insert), which can potentiate metabolic alkalosis. Similarly, potassium citrate is also an alkali.
Kashlak Pearl – Dr. Topf notes that patients with metabolic alkalosis from diuretics have acidic urine pH (e.g. pH of 6 or less) even with a serum bicarb of 45! Track the urine pH during potassium chloride supplementation and you’ll know they’re getting better (i.e. corrected chloride deficiency) when the urine pH suddenly jumps above 7 –(Metha, UpToDate 2021).
Acetazolamide induces a proximal renal tubular acidosis (Type II RTA) to slow bicarb reabsorption in the proximal tubule. Theoretically, metabolic alkalosis can depress respiratory drive to generate a compensatory respiratory acidosis. Thus, hypoventilation is a concern. In the DIABLO trial (Faisy, 2016), patients with COPD and mechanical ventilation were given acetazolamide to correct metabolic alkalosis in hopes of improving respiratory drive. They found a nonsignificant decrease in time spent on mechanical ventilation in the acetazolamide group (read NephJC discussion here).
Kashlak Pearl – Dr. Topf recommends giving acetazolamide 500 mg twice daily to help lower the bicarb (a usual response is a drop of about six points e.g. from 45 to 39). Monitor the urine pH, which should become elevated once acetazolamide starts working.
Spironolactone, often at a “diuretic dose” of 100 mg per day in patients hospitalized with heart failure can be a good preventive or preemptive measure given in addition to loop diuretics (expert opinion). Dr. Topf notes that the outpatient dose of 25 mg spironolactone can provide a neurohormonal effect, but is probably not enough to achieve the diuretic effect desired during acute heart failure exacerbation.
Should potassium supplements, acetazolamide, and spironolactone be continued at hospital discharge? Dr. Topf notes that acetazolamide is intolerable as a long term therapy because it makes any carbonated beverages taste terrible (Muñoz, 2018). Potassium supplements might be continued at discharge, but lower doses will probably be sufficient once aggressive diuresis has ceased (expert opinion). The same goes for spironolactone as normal chronic doses are in the 25-50 mg range (UpToDate 2021) and these high doses can cause sexual side effects (gynecomastia, loss of libido, etc).
It’s a bit unclear which comes first the acute kidney injury (AKI) or the hypercalcemic, metabolic alkalosis. Hypercalcemia decreases the GFR (Medarov, 2009). And with decreased GFR the kidneys are unable to clear the calcium and bicarb, and we are “off to the races”. Dr. Topf notes that classic milk alkali from milk consumption featured elevated phosphorus, but modern milk alkali syndrome typically has low phosphorus because calcium carbonate is a good phosphate binder.
Historical note: Ingestion of milk and sodium bicarbonate to treat peptic ulcer disease (PUD) was the classic cause of milk alkali syndrome. This went away with the advent of new therapies for PUD. Modern milk alkali is largely due to calcium carbonate supplements in patients looking to treat or prevent mineral bone diseases (Yu, UpToDate 2021).
Treat milk alkali by stopping supplements and giving normal saline (replaces chloride and corrects volume depletion) at a rate as fast as you can (Yu, UpToDate 2021).
Kashlak Pearl – Most AKIs have metabolic acidosis and hypocalcemia. Thus, think of milk alkali in patients who have a metabolic alkalosis with hypercalcemia. With significant hypercalcemia, make sure to rule out dangerous causes like cancers.
Hyperaldosteronism illness script: Hypertension, hypokalemia, metabolic alkalosis, and worsening of hypokalemia with diuretics. Look for a suppressed renin and elevated aldosterone, though a normal plasma aldosterone is not sensitive enough to rule out hyperaldosteronism (Hung, JCEM 2021).
Syndrome of apparent mineralocorticoid excess (SAME) is loss of function of 11-beta-hydroxysteroid dehydrogenase (He, 2020). How does it work? Cortisol has the capacity to activate mineralocorticoid receptors. It circulates at 100 times the concentration of aldosterone (Young, UpToDate 2021). The 11-beta-hydroxysteroid dehydrogenase enzyme is necessary to deactivate cortisol and prevent it from overpowering aldosterone as a signal at the mineralocorticoid receptors. Thus, patients with 11-beta-hydroxysteroid dehydrogenase deficiency have hypertension and hypokalemia and present just like hyperaldosteronism except aldosterone levels are suppressed. This enzyme is deactivated by glycyrrhetinic acid in black licorice (Touyz, 2008). Here’s the case report of a fatal dose of black licorice from NEJM.
How can we figure out the cause of metabolic alkalosis? Look at the urinary chloride.
Patients with low urine chloride, under 20 mEq/L (e.g. vomiting, milk alkali, volume depletion, diuretics) will respond to chloride replacement (e.g. potassium chloride supplements). Urine sodium as a measure of volume depletion is less reliable in patients with metabolic alkalosis because it is attracted to urinary bicarb and thus falsely elevated (Emmett, UpToDate 2021).
Metabolic alkalosis driven by mineralocorticoid receptor activation (hyperaldosteronism, SAME, Cushing’s syndrome) will have high urinary chloride, above 20.
See prior Curbsiders episodes on Acid-Base and RTA with @Kidney_Boy
#104: Renal tubular acidosis with Kidney Boy, Joel Topf MD
#88: Acid base, boy bands, and grandfather clocks with Joel Topf MD
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Listeners will develop a framework for the evaluation and management of metabolic alkalosis
After listening to this episode listeners will…
Dr. Topf has commercial interest with Bayer, Cara Therapeutics, Astra Zeneca, and Tricida. He’s been an advisory board member for all except Astra Zeneca. The Curbsiders report no relevant financial disclosures.
Watto MF, Topf J, Garbitelli B, Williams PN, Okamoto E. “#308 Metabolic Alkalosis and Hypokalemia”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date November 29, 2021.
The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org and search for this episode to claim credit.
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Just a heads up, drivers can now obtain and keep a CDL while on insulin if they’ve gone through the appropriate steps to document good control and stability on insulin. Forms for this are available through FMCSA. Obviously not the most important take away from the episode, but I didn’t want listeners to potentially advise patients incorrectly about pursuing a CDL. Love the pod, especially kidney boy episodes. Very helpful to my practice. Thanks!
Great info! Thanks for sharing!
Very great, informative, and practice changing lecture! I have always struggled with the patients that I previously thought were 'over-diuresed' once they developed metabolic alkalosis, low chloride / potassium but this lecture gives me another way to look at it and approach it. Thanks Dr. Topf!
Wonderful to hear :) Thanks for listening!