Hyperkalemia

Hyperkalemia is defined as a serum potassium (K+) concentration > 5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia is usually asymptomatic if minor in severity; however, acute elevations or severe hyperkalemia can lead to potentially fatal cardiac arrhythmias. Management is guided by severity and includes measures to stabilize the myocardial membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential, transiently shifting K+ intracellularly, removing K+ from the body, and treating the underlying predisposing conditions.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

General considerations

K+ is the main intracellular cation in all cells and is distributed unevenly between the intracellular fluid (98%) and extracellular fluid (2%). 

  • Disparity is necessary for maintaining the resting membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential of cells → K+ balance is tightly regulated
  • Hyperkalemia causes depolarization (i.e., decrease) of the resting membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential, leading to the inactivation of Na+ channels → decreased excitability of cardiac cells →  predisposition for arrhythmias 
  • The kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys are responsible for 90%–95% of the overall K+ regulation.
  • The GI tract secretes 5%–10% of absorbed K+ daily.

Sites of action in the kidney

  • Glomerulus: K+ is freely filtered.
  • Proximal tubule: 65%–70% of filtered K+ is reabsorbed. 
  • Thick ascending limb of the loop of Henle: 10%–25% of filtered K+ is reabsorbed. 
  • Principal cell (cortical collecting duct): K+ is secreted. 
  • 𝛼-intercalated cell (collecting duct): K+ is reabsorbed (final fine-tuning mechanism).

Normal response to ingested K+

A normal Western diet contains approximately 70–150 mmol of K+ per day. This diet is unlikely to lead to the development of hyperkalemia from increased intake only, owing to the following mechanisms:

  1. Gut absorbs dietary K+ into the bloodstream.
  2. Transcellular shift prevents excessive increase in extracellular fluid (ECF) K+ concentration.
    1. Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin- and β2-mediated
    2. K+ shifts primarily into muscle and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver cells.
  3. Increased ECF K+ concentration triggers mechanisms for renal K+ excretion.  
  4. Transcellular shifting into muscle/ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver cells gradually reverses.
  5. Remainder of ingested K+ load is renally excreted.

Etiology

The etiologies of hyperkalemia can be grouped into 5 categories: transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shifts, tissue breakdown, inadequate renal excretion, drug-induced, and pseudohyperkalemia.

Transcellular shifts

  • Certain factors cause K+ to move transiently into or out of cells.
  • The effect of this shift can be significant enough to decrease or increase the measured serum K+.
  • The total body K+ does not change.
  • Factors that cause shifting out of the cell (→ raise of plasma K+):
    • Acidosis: H+/K+ exchange maintains electroneutrality → moves H+ into cell to help balance extracellular pH in exchange for K+ moving out of the cell
    • Hyperosmolality (hyperglycemia, IV contrast, mannitol):
      • High ECF osmolality → shift of water into ECF → decreases ECF K+ concentration → more favorable gradient for diffusion of K+ out of cells
      • Solvent drag on K+ as water leaves the cell may also contribute.
      • Common mechanism in hyperglycemia (i.e., diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises))
    • Exercise: K+ is intentionally released by muscle cells to act as a local vasodilator.
  • Factors that cause shifting into the cell (→ lowers the plasma K+):
    • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin: stimulates Na+/K+ ATPase → 3 Na+ move out of cell, 2 K+ move into cell
    • β2-Adrenergic agonist (i.e., albuterol; stimulates Na+/K+ ATPase)
    • Alkalosis: H+/K+ exchanger moves H+ out of cell to help balance extracellular pH in exchange for K+ moving into cell

Tissue breakdown

  • Similar to transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shift, but the shift is not reversible
  • Damage to cell results in release of the highly concentrated intracellular K+:
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome (high-volume malignant cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death after chemotherapy)
    • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis (muscle cells; trauma, crush injuries, prolonged immobilization)
    • RBC transfusion (if multiple units or old blood RBCs lyse over time in storage)
    • GI bleeding (RBC metabolized by GI tract → intracellular K+ released)
    • Large hematoma (RBC reabsorbed and metabolized → intracellular K+ released)
    • Burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cells)

Inadequate renal excretion

Renal failure:

  • Oliguria → ↓ distal flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure rate → ↓ K+ secretion 
  • Oliguria plus excess K+ load or aldosterone blocker (ACEi/ARB) will result in hyperkalemia.
  • Oliguria by itself may not cause hyperkalemia.

Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration:

  • Hypovolemia → ↓ distal Na+ delivery → ↓ K+ secretion 
  • Also occurs in states of total body fluid overload, but with effective arterial blood volume depletion ( congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis)
  • Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration can also cause AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury → hyperkalemia from oliguria

Functional hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism:

  • Mineralocorticoid deficiency:
    • Primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
    • Hyporeninemic hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism
  • Tubulointerstitial disease: sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease, urinary tract obstruction Urinary tract obstruction Urinary tract obstruction (UTO) refers to the blockage of the urinary tract, which can occur anywhere in the urinary tract. Urinary tract obstruction can be acute or chronic, partial or complete, and unilateral or bilateral. Urinary tract obstruction can cause acute or chronic kidney disease. Urinary Tract Obstruction
  • Drugs (see table below) 

Drug-induced hyperkalemia

Drugs are a very common cause of hyperkalemia and cause it by a variety of the previously mentioned mechanisms. A key part of the diagnosis of hyperkalemia is to review all the recent drugs and medications that a patient has received.

Table: Drug-induced hyperkalemia
Medication class (examples) Mechanism
ACEi (e.g., lisinopril, captopril) Inhibits angiotensin II formation → decreases aldosterone secretion → decreases renal K+ secretion
ARB (e.g., losartan, valsartan) Blocks angiotensin receptor → ↓ aldosterone secretion → ↓ renal K+ secretion
Direct renin inhibitors (e.g., aliskiren) Blocks renin from converting angiotensinogen to angiotensin l → decreases aldosterone secretion → ↓ renal K+ excretion
K+-sparing diuretics (e.g., amiloride, triamterene, spironolactone) Block epithelial sodium channel (ENaC) (amiloride, triamterene) or the aldosterone receptor (spironolactone, eplerenone) → ↓ renal K+ excretion
Cardiac glycosides Cardiac glycosides Cardiac glycosides are a class of drugs reversibly inhibiting the sodium-potassium ATPase pump in myocardial cells and increasing vagal tone, which results in increased cardiac contractility and slowed conduction through the atrioventricular node. Cardiac Glycosides (digoxin) Inhibits Na+/K+ ATPase pump → less K+ moved into cells
NSAIDs (e.g., ibuprofen) Decreases renin and aldosterone → ↓ renal K+ secretion
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus) Multifactorial/incompletely understood: ↓ aldosterone release, ↓ aldosterone sensitivity, inhibition of Na+/K+ ATPase pump, blocking of ENaC channel
Succinylcholine Causes extracellular leakage of K+ through acetylcholine receptor-gated channels
Antimicrobials (e.g., trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim, pentamidine) Block ENaC channel

Pseudohyperkalemia

  • False positive hyperkalemia, due to process of drawing and/or processing of a blood sample
  • Related to blood draw: 
    • Damaged RBCs lyse and release their intracellular K+.
    • Prolonged tourniquet
    • Excessive fist clenching
    • Venipuncture trauma
  • Related to blood sample processing: 
    • Severe thrombocytosis or leukocytosis 
    • More likely if blood sample analysis is delayed
    • Intracellular K+ is released from platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets after clotting in the test tube.
    • WBCs lyse and release intracellular K+

Clinical Presentation

The most severe symptoms of hyperkalemia are impaired electrical conduction in the heart. Cardiac symptoms are more likely to occur with increasing severity and acuity of hyperkalemia; however, even relatively severe hyperkalemia can be asymptomatic. Muscular symptoms may be observed, and these include weakness and paralysis. 

Cardiac symptoms

Cardiac symptoms are the most important symptoms of hyperkalemia, as they can be rapidly fatal.

  • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes follow a characteristic progression with increasing K+:
    • Peaked T waves and short QT interval → PR interval prolongation and QRS widening → loss of P waves → QRS widens to sine wave → asystole
    • This classic progression is often not observed clinically.
    • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) findings are helpful if present but are not sensitive for hyperkalemia overall.
  • Arrhythmias:
    • Advanced atrioventricular block Atrioventricular block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block
    • Sinus bradycardia
    • Sinus arrest
    • Slow idioventricular rhythm
    • Ventricular tachycardia Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia, ventricular fibrillation Ventricular fibrillation Ventricular fibrillation (VF or V-fib) is a type of ventricular tachyarrhythmia (> 300/min) often preceded by ventricular tachycardia. In this arrhythmia, the ventricle beats rapidly and sporadically. The ventricular contraction is uncoordinated, leading to a decrease in cardiac output and immediate hemodynamic collapse. Ventricular Fibrillation, and/or asystole if severe
  • Monitoring:
    • Important at all levels of hyperkalemia
    • Can be done with repeat ECGs and/or continuous cardiac monitoring 

Some patients will not have ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes or arrhythmias, even with severe hyperkalemia.

Hyperkalemia ekg

ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes in hyperkalemia:
In reality, ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes in hyperkalemia are more variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and less predictable.

Image by Lecturio.

Muscular symptoms

  • Muscle weakness
  • Ascending flaccid paralysis (can resemble Guillain–Barré syndrome)
  • Unlikely to have respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure due to respiratory muscle weakness

Management and Diagnosis

The management of hyperkalemia often takes precedence over the diagnosis because of the possibility of life-threatening arrhythmias and is guided by determining the level of urgency needed for treatment. Usually, the etiology of hyperkalemia is not difficult to determine and is not impeded by treating it first.

Management

  1. Hyperkalemic emergency?  
    • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes, arrhythmia, or severe muscle weakness/paralysis
    • Serum K+ usually > 6.5 mEq/L 
    • Options for emergency treatment:
      • IV calcium to stabilize myocardium
      • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin/glucose +/– sodium bicarbonate +/– β2 agonist, to shift K+ into cells
      • Cation exchange resin +/– loop diuretic to remove K+
      • Hemodialysis
    • Monitor serum K+ frequently
    • Continuous cardiac monitoring and/or repeat ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) while treating
    • Consult nephrology early
  2. Lab result accurate?
    • Hemolyzed specimen?
      • Very common type of pseudohyperkalemia
      • Most labs will routinely indicate if specimen is hemolyzed.  
      • Redraw lab prior to making treatment decisions.
    • Less common causes of pseudohyperkalemia?
      • Severe thrombocytosis (i.e., > 1000 × 109/L)
      • Severe leukocytosis (i.e., > 50,000 × 109/L)
      • Measure plasma K+ (rather than routine serum K+) to obtain accurate level.
  3. Moderate hyperkalemia with high risk?
    • Generally asymptomatic and without ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes
    • Serum K+ 5.5–6.5 mEq/L with high-risk factor:
      • Sudden increase (e.g., 3.7 mEq/L to 6 mEq/L overnight) 
      • Ongoing K+ release (e.g., tumor lysis, rhabdomyolysis)
      • Ongoing K+ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption (e.g., GI bleeding) 
      • Kidney dysfunction
      • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • Treat similarly to hyperkalemic emergency, but no need for IV calcium.
  4. Moderate hyperkalemia without high risk?
    • Generally asymptomatic and without ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes
    • Serum K+ 5.5–6.5 mEq/L without any of the above risk factors
    • Treat urgently:
      • Cation exchange resin +/– loop diuretic +/– hemodialysis to remove K+
      • Differences with emergent treatment:
        • Do not need IV calcium 
        • Do not necessarily need shifting measures
    • Monitor serum K+ frequently
    • Continuous cardiac monitoring and/or repeat ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) while treating
  5. Mild hyperkalemia?
    • Generally asymptomatic and without ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes
    • Serum K+ < 5.5 mEq/L 
    • Does not require urgent treatment
    • Management is primarily risk-factor modification:
      • Dietary K+ restriction if renal dysfunction
      • Stop/adjust offending medications (e.g., ACEi/ARB, NSAIDs, etc.).
      • Start/adjust loop or thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics.
      • Start/adjust oral sodium bicarbonate.
      • Start/adjust cation exchange resin.
  6. Identify and treat any contributing underlying diseases.
Table: Acute therapeutic options for hyperkalemia
Goal Intervention Properties/indication
Stabilize the myocardium IV calcium
  • Antagonizes effect on membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential
  • Indicated in hyperkalemic emergency
  • Onset within minutes, lasts 30–60 minutes
  • May require repeat doses if emergent symptoms remain
  • Worsens digoxin toxicity (use cautiously)
Shift K+ into cells Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • ↓ ECF K+ via transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shift
  • Most effective transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shifting option
  • Onset 10–20 min, lasts 4–6 hours
  • Repeat every 2–4 hours, if needed.
  • Usually given with dextrose (D50W), to avoid hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Monitor fingerstick blood glucose closely.
Sodium bicarbonate (NaHCO3)
  • ↓ ECF K+ via transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shift
  • Onset 15–30 minutes
  • Lasts as long as serum bicarbonate remains improved
  • More effective if metabolic acidosis is initially present
β2 agonist
  • ↓ ECF K+ via transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shift
  • Onset 30 minutes, lasts for 2 hours
  • Can cause tachycardia (caution in heart disease)
Remove K+ from the body Via urine
  • Furosemide +/– normal saline (NS)
  • NS avoids hypovolemia from diuretic → maintains distal tubular flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure rate needed for K+ secretion
Via GI tract Cation exchange resins: bind K+ in exchange for Na+ or Ca2+
Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis
  • Primary option if patient is on long-term dialysis
  • Indicated for any patient with life-threatening hyperkalemia unresponsive to other measures
  • Hemodialysis is preferred (removes K+ faster than peritoneal dialysis)

Diagnosis

  1. AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury or CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease present?
  2. Recent process that could cause transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shift? 
    • New or worsening metabolic acidosis (including DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises)
    • Recent intense exercise
    • Recent surgery
  3. Other predisposing disease process present?
    • Hypovolemia or other states of decreased effective arterial blood volume ( congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis)
    • High cell turnover (tumor lysis syndrome, rhabdomyolysis, burns)
    • RBC absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption (RBC transfusion, GI bleeding, large hematoma reabsorption) 
  4. Review medication list carefully.
  5. Check plasma renin activity and aldosterone if etiology is still not identified.

Differential Diagnosis

  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis: large-scale muscle cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death, which can result from many possible etiologies (trauma, drugs, toxins, infections): Serum K+ can increase suddenly if rhabdomyolysis is unrecognized or inadequately treated or if AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury develops (common complication). Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis is diagnosed by a serum CK level > 5 times the upper limit of normal and treated with IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids.
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome: large-scale malignant cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death, often sudden and brought on by the initiation of chemotherapy: Large amounts of intracellular K+, phosphate, and uric acid are released when malignant cells die. Treated with rasburicase (for hyperuricemia), calcium supplementation, and dialysis, if necessary.
  • Digoxin toxicity: Digoxin is the only commonly used cardiac glycoside. Toxicity is common, as the therapeutic window is narrow and excretion is renal. Clinical presentation includes arrhythmias, hyperkalemia, and characteristic vision changes, including increased yellow colors in vision (xanthopsia). Treated with digoxin-specific antibody (Fab) fragments, which bind to and thereby inactivate the circulating drug. 
  • Malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia: a life-threatening syndrome characterized by hyperthermia, muscle rigidity, and hyperkalemia (via rhabdomyolysis): Malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia is triggered by perioperative volatile anesthetic use in genetically predisposed patients. Treatment includes dantrolene (skeletal muscle reluctant) and supportive care.
  • Primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease ( Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease): a rare, autoimmune type of destruction of the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease is diagnosed by measuring aldosterone (low), renin (high), serum cortisol (low), and ACTH (low) and ACTH stimulation test. Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease leads to hyperkalemia primarily through hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism. The disease manifests acutely as adrenal crisis, which is an emergency because of circulatory shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock. Acute treatment is high-dose glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and supportive care. Long-term treatment is by substituting glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids (hydrocortisone) and mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids (fludrocortisone).  
  • Diabetic ketoacidosis ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises): severe acidosis caused by insulin deficiency, usually in the setting of type 1 diabetes: Presents with total body K+ deficit (urinary losses from osmotic diuresis/polyuria); however, serum K+ will be normal or high. Treatment is by insulin replacement followed by K+ supplementation once the plasma level falls. If there is even mild hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia on presentation, this represents severe total body K+ deficit, and the plasma K+ will decrease even further once an insulin drip is started. In this situation, K+ must be replaced until the plasma level is at least 3.3 mEq/L prior to starting insulin. 
  • Hyperkalemic periodic paralysis: a rare genetic disease with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance: Hyperkalemic periodic paralysis is characterized by acute attacks of muscle weakness and/or paralysis due to hyperkalemia from severe transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System shifting of K+. Attacks are precipitated by cold temperatures, rest after exercise, and/or K+ ingestion. If recovery is not spontaneous, treatment is with inhaled β2 agonists and K+-removing therapies (e.g., furosemide, cation exchange resins, dialysis).
  • Type IV renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis ( RTA RTA Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis): a syndrome of decreased urinary secretion of K+ and H+ at the principal cell, resulting in a non–anion gap metabolic acidosis and hyperkalemia: Common causes include diabetes, NSAIDs, calcineurin inhibitors, heparin, and Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease. Diagnosed by history and measuring serum cortisol, renin, and aldosterone. Treatment is by mineralocorticoid replacement (e.g., fludrocortisone). Hyperkalemia is usually not severe unless concurrent predisposing factors are present.

References

  1. Gutmann, L., Conwit, R. (2021). Hyperkalemic periodic paralysis. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/hyperkalemic-periodic-paralysis
  2. Hyperkalemic cardiac arrest during anesthesia. (2017, April 21). Lecturio Online Medical Library. /magazine/hyperkalemic-cardiac-arrest-during-anesthesia/
  3. Hypokalemia—Complications and side effects (2017, August 28). Lecturio Online Medical Library. /magazine/hypokalemia-complications/
  4. Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., Loscalzo, J. (2015). Harrison’s principles of internal medicine (19th ed..). New York: McGraw Hill Education.
  5. Levine, M.D., O’Connar A. (2020). Digitalis (cardiac glycoside) poisoning. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/digitalis-cardiac-glycoside-poisoning
  6. Mount, D.B. (2020). Causes and evaluation of hyperkalemia in adults. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/causes-and-evaluation-of-hyperkalemia-in-adults
  7. Mount, D.B. (2020). Clinical manifestations of hyperkalemia in adults. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-hyperkalemia-in-adults
  8. Mount, D.B. (2020). Treatment and prevention of hyperkalemia in adults. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-hyperkalemia-in-adults
  9. Nieman, L. K. (2020). Causes of primary adrenal insufficiency (Addison’s disease). UpToDate.  Retrieved March 9, 2021, from  https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addisons-disease
  10. Nieman, LK. (2020). Treatment of adrenal insufficiency in adults. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/treatment-of-adrenal-insufficiency-in-adults
  11. Young, W. F., Jr. (2019). Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA). UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-hypoaldosteronism-type-4-rta

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