CONTENTS

• Rapid Reference 🚀
• Physiology:  Potassium pharmacokinetics
• Diagnosis
• Clinical significance
• Causes
• Workup
• Risk stratification
• Treatment
  • Target potassium level?
  • Enteral route generally preferred
  • Intravenous potassium
  • Magnesium repletion
  • Other measures
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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consider risk factors for arrhythmia (more)

• EKG changes (especially QT prolongation).
• Digoxin.
• Myocardial ischemia.
• Concomitant severe hypomagnesemia.
• Severe hypokalemia (<2.5 mM).
• Ongoing fall in potassium likely (e.g., DKA or refeeding syndrome).

evaluation (more)

• Repeat electrolytes if doubt exists about their validity (e.g., inconsistent with clinical context & EKG).
• Check magnesium level if not known.

consider magnesium repletion (more)

• IV magnesium may be the fastest way to reduce the risk of arrhythmia (because magnesium can be given rapidly).
• Repletion of magnesium is often necessary to successfully replete the potassium.

consider target potassium level (more)

• Nearly all patients:  >3.5 mM.
• Severe renal failure:  >3 mM.
• DKA with adequate renal function:  >5-5.3 mM.

enteral potassium is usually preferred (more)

• Contraindications to enteral route:
  • Severe hypokalemia (<2.5 mM).
  • NPO or unable to take PO.
  • Profound shock with questionable absorption.
• Selection of agent:
  • Potassium chloride generally utilized.
  • Potassium citrate may be useful for patients with metabolic acidosis.

intravenous potassium (more)

• Use only if enteral route is contraindicated (see contraindications above).
• Selection of agent:
  • Potassium chloride is generally utilized.
  • Potassium acetate may be useful for patients with metabolic acidosis.
• Typical rates:
  • Rate of 10 mEq/hr for routine repletion.
  • Rate of 20 mEq/hr for severe hypokalemia or DKA (either via a central line, or split into two simultaneous infusions of 10 mEq/hr in two peripheral lines).

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physiology: potassium pharmacokinetics

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the potassium deficit is often large

• Patients with hypokalemia often have a large total-body potassium deficit.  This varies depending on acid/base status, but to get a general idea: (31227226)
  • K of 3 mEq/L may correlate with a potassium deficit of 100-200 mEq.
  • K of 2 mEq/L may correlate with a potassium deficit of 400-600 mEq.
• The relationship between potassium level and total-body potassium deficit is exponential (figure below).  As the potassium level falls progressively lower, this represents an exponentially large increase in the total body potassium deficit.

estimating the potassium deficit in clinical context

• This depends on two factors:
  • The serum potassium level.
  • The presence of any factors which may cause shifting of potassium in or out of the cells.
• For example, diabetic ketoacidosis causes potassium to shift out of the cells.  Therefore, the potassium deficit may be even larger than would be estimated based on the above formula.

most of the deficit occurs intracellularly

• The vast majority of potassium in the body is located intracellularly.  Thus, most of the total body potassium deficit represents deficient intracellular potassium.
• The intracellular nature of the potassium deficit means that IV potassium must be administered slowly:
  • Time is required for potassium to enter the cells.
  • Rapid administration may cause serum levels to be elevated (even though there is a total-body potassium deficit!).  Serum hyperkalemia is dangerous.  Furthermore, serum hyperkalemia may cause poor retention of potassium (as it will tend to encourage potassium excretion in the urine).
• Bedside clinical implications:
  • (1) IV potassium should never be given as a bolus.
  • (2) Even in severely hypokalemic patients, aggressive IV potassium administration can be dangerous (more on this below).

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diagnosis

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causes of spuriously low lab values (pseudo-hypokalemia)

• (1) Delayed sample analysis (cells absorb potassium while the blood tube is sitting around).
• (2) Markedly elevated cell counts (leukocytes take up potassium while the blood is awaiting analysis).
• 💡Unlike pseudohyperkalemia, pseudohypokalemia is uncommon.(33974032)

EKG changes

• T-wave abnormalities
  • May flatten or invert.
  • Inverted T-wave followed by prominent U-wave may create a biphasic “down-up” morphology.
• U-wave prominence
  • May fuse with the T-wave to produce a prolonged QT interval (technically a Q-T-U interval).
• ST segments may appear depressed.
• QT prolongation, which may predict risk of arrhythmia.
•  Arrhythmias
  • Torsades de pointes may be the most classic.
  • Other possibilities include atrial fibrillation, ventricular tachycardia, and ventricular fibrillation.

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clinical significance

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causes

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reduced potassium intake (rarely the sole cause)

• Anorexia nervosa.
• Alcoholism.

potassium shifts into the cells

• Insulin (e.g. during DKA resuscitation).
• Beta-agonists (albuterol, terbutaline, epinephrine – including endogenous epinephrine surges from stress).
• Hypothermia.
• Alkalemia (small effect).
• Hypokalemic periodic paralysis. (31227226)
  • #1) Familial form with onset <20 years old.  
  • #2) Acquired form associated with hyperthyroidism, typically in Asian and Mexican men.  

extra-renal potassium loss

• Diarrhea.
• Vomiting or large-volume gastric suction.
• Profound sweating.

renal potassium loss

• Secondary to another electrolyte abnormality:
  • Hypomagnesemia.
  • Metabolic alkalosis.
• Polyuria with increased distal delivery of sodium and water to the tubule:
  • Potassium wasting diuretics (e.g. thiazides, loop diuretics, acetazolamide, mannitol).
  • Sodium-wasting nephropathy (e.g. post-ATN or post-obstructive).
• High-dose penicillins.
• Mineralocorticoid excess:
  • Cushing's syndrome.
  • Primary hyperaldosteronism.
  • Exogenous steroid.
  • Licorice ingestion.
• Renal tubular acidosis types I or II (see table below)

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workup

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(#1) check additional electrolytes

• The magnesium level is the most important contributing factor, for several reasons:
  • (a) Hypomagnesemia is common (most patients with hypokalemia have hypomagnesemia as well).(29540487)
  • (b) Treatment of hypomagnesemia may be required to effectively treat hypokalemia.
  • (c) Expedient treatment of hypomagnesemia may reduce the risk of Torsade de pointes.
• May consider checking a full electrolyte panel (including Calcium, Magnesium, and Phosphate):
  • Electrolyte abnormalities often occur in pairs and triplets (“electrolytic disarray”).

(#2) review the medication list, focusing on:

• Diuretics.
• Insulin.
• Beta-agonists.
• Steroid.
• Antibiotics:
  • Penicillins, including piperacillin.
  • Amphotericin.
  • Aminoglycosides.
  • Tenofovir, antiretrovirals.
  • Foscarnet.
• Chemotherapeutics:
  • Platinum agents.
  • Ifosfamide.
• Miscellaneous:
  • Mafenide acetate.
  • NSAIDs.
  • Lithium.
  • Topiramate.
  • Valproic acid.

(#3) review recent history & data

• Historical clues:
  • Diarrhea
  • Polyuria
  • Profound sweating
  • Vomiting or gastric suction
• Lab clues:
  • Nonanion-gap metabolic acidosis (look for RTA-1 or RTA-2)
  • Metabolic alkalosis (may cause hypokalemia, but can also result from hypokalemia!)

(#4) additional diagnostic tests usually aren't needed

• Careful consideration of the above etiologies combined with the clinical context will usually provide an explanation for the hypokalemia.
• In the context of an ICU patient with no obvious GI potassium losses, persistent/recurrent hypokalemia implies renal potassium wasting.
• If the etiology of hypokalemia remains elusive, the following approach may be helpful:

Advanced diagnostic testing:  Begin by checking urine potassium, creatinine, sodium, and chloride.

• Fractional excretion of potassium (FEK) helps sort out renal vs. non-renal potassium loss:
  • This be calculated based on spot urine potassium and creatinine levels (using a calculator found here).
  • A fractional excretion of potassium >9.3% suggests renal potassium wasting (with sensitivity of 81% and specificity of 86%).(33096028)  In reality, values close to the cutoff of 9.3% are ambiguous, with values further away being more definitive.
  • If the urine creatinine level isn't known, then the urine potassium concentration can be used as a rough surrogate (with a cutoff of  >>15-19 mM indicating renal potassium wasting).
  • The transtubular potassium gradient (TTKG) is no longer recommended.(33755054)
• Aldosterone/Renin Ratio:
  • An elevated aldosterone/renin ratio suggests hyperaldosteronism (>750 pmol/L per ng/ml/h, or 27 ng/dL per ng/mL/h).(33755054)  
  • Aldosterone and renin levels should ideally be measured after correction of potassium, because otherwise hypokalemia may suppress the aldosterone level.(33755054)  

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risk stratification

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risk factors for complications from hypokalemia

• Severe hypokalemia (potassium <2.5 mM).
• Clinical context where potassium is likely to fall further (e.g. DKA or re-feeding syndrome)
• EKG changes due to hypokalemia (e.g. QT prolongation).
• Increased risk of arrhythmia:
  • Patients on digoxin
  • Myocardial ischemia or scarring
  • Concomitant deficiency of magnesium

hypokalemia is generally well tolerated

• Overall, hyperkalemia is much more dangerous than hypokalemia.
• In the absence of the above factors, hypokalemia is well tolerated (and can be treated gradually).
• For patients with hypokalemia plus hypomagnesemia, a reasonable strategy is often to treat the hypomagnesemia fairly aggressively (because this is safe), but to be a bit more conservative with treatment of hypokalemia.
  • 🔑 For patients with hypokalemia and hypomagnesemia, rapid correction of hypomagnesemia is safe and may quickly decrease the risk of arrhythmia.

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target potassium level?

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most patients:  target >3.5 mM ?

• Targeting a potassium level >3.5 mM seems reasonable for most patients.
• Cardiac patients
  • Traditionally, the target has been >4 mM in efforts to reduce the risk of arrhythmia.
  • Larger, modern studies have shown that the safest potassium range in patients with myocardial infarction may be 3.5-4.5 mM (22235086, 26714972, 24560065).  Either higher or lower potassium values correlate with worse outcomes (figure below).  This is admittedly correlative data, but it's the best data that we have.
  • An evidence-based potassium target for cardiac patients would therefore seem to be >3.5 mM.

renal failure: target >3 mM

• It's usually best to be conservative in the absence of any specific factors which increase the risk of arrhythmia (see “risk stratification” above).  In renal failure, the primary concern is generally development of hyperkalemia (rather than hypokalemia).  For patients with acute or worsening renal failure, potassium is likely to rise over time.
• A target potassium of >3 mM may be reasonable in most patients with severe renal failure (in the absence of digoxin or myocardial ischemia).  This is particularly true in oliguric renal failure, wherein there is little risk that the patient will suddenly develop worsening hypokalemia.

diabetic ketoacidosis:  target >~5-5.3 mM

• Patients being resuscitated from DKA will generally tend to drop their potassium levels over time.
• In the absence of renal dysfunction, it's often useful to target a high-normal potassium level.

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enteral route generally preferred

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reasons that enteral potassium is preferred

• (1) Cheaper and generally easier.
• (2) Doesn't irritate veins.
• (3) Safer (oral potassium is overall more idiot-proof than IV potassium).

formulations of oral potassium

• Potassium chloride (KCl)
  • Most commonly used formulation.
  • Especially useful in patients with metabolic alkalosis (since potassium chloride will increase the serum chloride level).
  • Slow-release microencapsulated (wax-matrix) KCl formulations are suboptimal if an immediate effect is desired.  However, they may be better tolerated with less emesis (31227226).
• Potassium citrate
  • Potassium citrate is equally effective as KCl for the repletion of potassium.(6699979, 1988724)
  • Potassium citrate be useful in patients with nonanion-gap metabolic acidosis (NAGMA).  The citrate will be converted into bicarbonate, thereby improving the acidosis.
  • Commonly available in the form of potassium citrate-citric acid* (e.g., POLYCITRA-K), which contains 2 mEq of potassium per ml.

dose & schedule

• This involves clinical judgement based on consideration of two factors:  total body potassium deficit and renal function.
• If the renal function is adequate and stable (e.g., GFR is >30 ml/min and the patient is not oliguric), then it's unlikely that oral potassium will cause hyperkalemia.  In this scenario, oral doses of potassium may be scheduled and the potassium level can be checked intermittently.
  • For example:  In a patient with normal renal function and K = 3 mM (estimated deficiency of ~100-200 mEq), a dose of 40 mEq KCl could be given q8hr with daily measurement of electrolytes.
• For patients with oliguria or renal insufficiency, closer monitoring is required to avoid overshoot hyperkalemia.

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intravenous potassium

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indications for IV potassium

• (1) Lack of gut access or function.
• (2) Severe hypokalemia in need of emergent treatment (see “risk stratification” above).
• (3) Profound shock plus severe hypokalemia (unclear whether potassium would be adequately absorbed from the gut).

selection of IV potassium formulation

• Potassium chloride is generally utilized.
• Potassium acetate may be useful for patients with metabolic acidosis (acetate is metabolized into bicarbonate).

typical rates of IV potassium administration

• 10 mEq/hour
  • Commonly used rate for routine potassium repletion.
• 20 mEq/hr
  • Commonly used for severe hypokalemia or DKA.
  • Ideally, this shouldn't be run through a single peripheral IV line (to prevent vein sclerosis).  This can be run either through a central line, or split into two 10 mEq/hr infusions through two different peripheral lines.
• The frequency of monitoring electrolytes depends on clinical acuity and renal function (similar to the monitoring of oral repletion above).

high-dose IV potassium administration

• Using high-dose IV potassium is rarely necessary.  However, this might be preferable to the combination of simultaneously given intravenous and enteral potassium (which can lead to erratic pharmacology in critically ill patients, if the enteral potassium is absorbed in a delayed fashion).
• Possible regimens are listed below (none of which are supported by high-level evidence).   A useful concept is that potassium levels should be repeated after every ~60 mEq of potassium administered (22901631).  If potassium is given more rapidly, then it must be monitored more frequently.
• (1) Cardiac arrest due to hypokalemia (e.g. VT, VF, or asystole)
  • Start with 20 mEq potassium IV over 2-3 minutes  (16600469).
• (2) Recurrent malignant arrhythmias with a pulse
  • Start with 20 mEq potassium IV over 10-20 minutes (infusion rate of 60-120 mEq/hr) (16600469).
  • Down-titrate the rate rapidly as the EKG improves and the patient stabilizes.
• (3) Severe hypokalemia plus {DKA or overdose of beta-blocker/calcium channel blocker}
  • Hypokalemia itself isn't immediately life-threatening here, but hypokalemia impedes the ability to provide insulin (which is needed for the treatment of DKA or for high-dose insulin therapy for poisoning).
  • Infusion of potassium at a rate of 40-60 mEq/hr is reasonable if the patient is extremely unstable (with the judgement that the inability to provide insulin is a life-threatening problem).
  • Check potassium level very frequently (e.g., every hour) with a point-of-care monitor to allow for real-time titration of potassium at the bedside.  Don't give more than ~60 mEq potassium without repeating the level.

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magnesium repletion

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• Magnesium depletion is very common in patients with hypokalemia.
• Failure to treat the magnesium deficiency will make it difficult or impossible to fix the hypokalemia (hypomagnesemia causes renal potassium-wasting, so the patient will keep on spilling potassium until their magnesium level is repleted).
• Magnesium repletion is also useful because it will reduce the risk of Torsade de pointes in these patients.
  • Magnesium can be repleted rapidly (faster than potassium).  This may be the fastest approach to decrease the patient's risk of arrhythmia.
• Hypomagnesemia is discussed further in this chapter.

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other measures

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gastric losses

• For patients with ongoing gastric fluid loss, initiation of a proton pump inhibitor may minimize electrolyte derangements being caused by this.  (The main driver of hypokalemia due to gastric fluid loss is the metabolic alkalosis, so avoiding loss of gastric acid will prevent this.)

potassium-sparing diuretics

• May be useful in the following situations:
  • (1) Patients with severe volume overload who require ongoing diuresis.
  • (2) Patients with persistent renal potassium wasting, with inadequate response to potassium supplementation alone.(32138884)
• Options:
  • Spironolactone may be useful (e.g., 50-100 mg BID), but spironolactone only becomes effective after ~1-2 days.
  • Amiloride has the advantage of working more rapidly, making it the most attractive option in the ICU.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to check and replete magnesium levels.
• Excessive use of intravenous potassium repletion, when enteral potassium would be a safer and easier strategy.
• Aggressive repletion of mild hypokalemia in patients with renal failure (hyperkalemia is generally much more dangerous than hypokalemia, so better to err on the low side).

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Going further

• Hypokalemia (CORE EM, Anand Swaminathan)
• Hypokalemia (Chris Nickson, LITFL)
• Hypokalemia (WikEM)