Hyperkalemia

Etiology : Pseudohyperkalemia (In Vitro Release of Potassium From Cells)

  • Familial Pseudohyperkalemia
    • Genetics
      • Autosomal Dominant Inheritance (Maps to the 16q23–ter Locus)
    • Mechanism
      • Abnormally Increased Potassium Permeability of the Red Blood Cell Membrane, Resulting in a Temperature-Dependent Loss of Potassium from Red Blood Cells When Stored at Room Temperature
    • Clinical
      • Characterized by Hyperkalemia in Whole Blood Stored At or Below Room Temperature, Without Additional Hematologic Abnormalities
  • Phlebotomy-Related Cell Lysis
    • Mechanisms
      • Delay in Processing of Blood Sample: may result in red blood cell lysis
      • Excessive Vacuum with Very Small Gauge Needle During Phlebotomy: may result in red blood cell lysis
      • Prolonged Tourniquet Time or Fist-Clenching During Phlebotomy: may result in efflux of potassium from myocytes (fist-clenching during phlebotomy may increase potassium by as much as 1–2 mmol/L)
      • Transportation of Blood Samples in Pneumatic Tube System: may result in mechanical red blood cell lysis
  • Severe Leukocytosis (>70k)
    • Mechanism
      • Due to Potassium Release from White Blood Cells in Sample
    • Clinical
      • Plasma, Rather than Serum, Potassium Should Be Measured (Plasma Potassium Will Be Normal in These Cases)
  • Severe Polycythemia (Hct >55%)
    • Mechanism
      • Due to Potassium Release from Red Blood Cells in Sample
    • Clinical
      • Plasma, Rather than Serum, Potassium Should Be Measured (Plasma Potassium Will Be Normal in These Cases)
  • Severe Thrombocytosis (>500k)
    • Mechanism
      • Due to Potassium Release from Platelets in Sample
        • For Every 100 x 10(9)/L of Platelets, Potassium Increases Approximately 0.07 to 0.15 mmol/L [MEDLINE]
    • Clinical
      • Plasma, Rather than Serum, Potassium Should Be Measured (Plasma Potassium Will Be Normal in These Cases)
  • Subset of Patients with “Leaky” Cell Membranes
    • Mechanism
      • These Patients Appear to Be Prone to Hemolysis During Phlebotomy

Etiology : Excessive Potassium Intake

  • Excessive Oral/Intravenous Potassium Chloride Replacement
    • Mechanism
      • May Be Iatrogenic (in the Inpatient Setting) or Patient-Related (in the Outpatient Setting)
  • Excessive Oral Salt Substitute Intake
    • Clinical
      • Usually Causes Hyperkalemia Only in the Setting of Impaired Renal Function
  • Lethal Injection
    • Mechanism
      • Capital Punishment Technique Uses Lethal Injection of Potassium Chloride
  • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition)
    • Mechanism
      • Due to Excessive Potassium Content (Relative to the Patient’s Renal Function)

Etiology : Intracellular -> Extracellular Potassium Shift


Etiology : Impaired Renal Potassium Excretion

Decreased Distal Potassium Delivery

Renal Disease

Hypoaldosteronism (see Hypoaldosteronism)

Decreased Aldosterone Synthesis

  • Inherited Disorders
    • Congenital Isolated Hypoaldosteronism
      • 21 Hydroxylase Deficiency
      • Other Defects
    • Pseudohypoaldosteronism Type 2 (Gordon’s Syndrome)
      • Physiology
        • Defects in WKNK1 or WNK4 Kinases
      • Clinical
        • Familial Hypertension (see Hypertension)
        • Hyperkalemia (see Hyperkalemia)
        • Low or Low-Normal Plasma Renin Activity and Aldosterone Level
        • Metabolic Acidosis
        • Normal Renal Function
  • Hyporeninemic Hypoaldosteronism
    • General Comments
      • Hyporeninemic Hypoaldosteronism is Characterized by a Combination of Decreased Renin Release and an Intra-Adrenal Defect, Resulting in Decreased Systemic and Intra-Adrenal Angiotensin II Synthesis, Culminating in Decreased Aldosterone Secretion
        • The Intra-Adrenal Defect May Be Related to the Local Renin-Angiotensin System (This is Supported by the Fact that Angiotensin II Produced Locally Within the Adrenal Gland May Stimulate the Release of Aldosterone)
        • Many of These Patients May Also Have Decreased Aldosterone Responsiveness, Since They Require a Higher Mineralocorticoid Dose for Physiologic Replacement
    • Advanced Age
    • Drug-Induced Hyporeninemic Hypoaldosteronism
      • Beta Blockers (see β-Adrenergic Receptor Antagonists)
      • Calcineurin Inhibitors (see Calcineurin Inhibitors)
        • Pharmacology: due to decreased secretion of aldosterone and decreased responsiveness to aldosterone (likely due to decreased mineralocorticoid receptor expression)
        • Cyclosporine A (see Cyclosporine A)
        • Tacrolimus (see Tacrolimus)
      • Nonsteroidal Anti-Inflammatory Drug (NSAID) (see Nonsteroidal Anti-Inflammatory Drug)
        • Pharmacology: dose-dependent COX-inhibition -> decreased renal prostaglandin synthesis -> since PGI2 stimulates the juxtaglomerular cells in the kidney to release renin, this results in decreased renal renin secretion
        • Additionally, impaired angiotensin II-induced release of aldosterone may occur
        • NSAID-induced decrease in glomerular filtration rate may also contribute to the development of hyperkalemia
    • Intrinsic Renal Disease
      • Acute Glomerulonephritis with Volume Expansion (see Acute Glomerulonephritis)
        • Treatment: responds to mineralocorticoid replacement
        • Prognosis: recovery of renal function (typically within 1-2 wks) leads to resolution of hyperkalemia
      • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease): with chronic interstitial nephritis
      • Diabetic Nephropathy (see Diabetes Mellitus): accounts for 50% of cases of hyporeninemic hypoaldosteronism
  • Drugs
    • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors)
      • Pharmacology
        • Angiotensin Converting Enzyme Inhibitors Decrease the Conversion of Angiotensin I to Angiotensin II Systemically (and Possibly Within the Adrenal Zona Glomerulosa)
        • Since the Normal Stimulatory Effect of Hyperkalemia on Aldosterone Release May Be Mediated in Part by the Adrenal Generation of Angiotensin II, ACE Inhibitors Can Decrease Both Angiotensin II-Mediated and Potassium-Mediated Aldosterone Release
        • In Contrast to ARB’s and Renin Inhibitors, ACE Inhibitors Increase Renin Levels
      • Captopril (Capoten) (see Captopril)
      • Enalapril (Vasotec, Enalaprilat) (see Enalapril)
      • Fosinopril (Monopril) (see Fosinopril)
      • Lisinopril (Zestril) (see Lisinopril)
      • Moexipril (Univasc) (see Moexipril)
      • Perindopril (Coversyl, Coversum, Preterax, Aceon) (see Perindopril)
      • Quinapril (Accupril) (see Quinapril)
      • Ramipril (Altace) (see Ramipril)
      • Trandolapril (Mavik) (see Trandolapril)
    • Angiotensin II Receptor Blockers (see Angiotensin II Receptor Blockers)
      • Pharmacology
        • Angiotensin II Receptor Blockers Inhibit Angiotensin II Activity at its Receptor
      • Candesartan (Atacand) (see Candesartan)
      • Fimasartan (Kanarb) (see Fimasartan)
      • Irbesartan (Avapro, Aprovel, Karvea) (see Irbesartan)
      • Losartan (Cozaar) (see Losartan)
      • Olmesartan (Benicar, Olmecip) (see Olmesartan)
      • Telmisartan (Micardis) (see Telmisartan)
      • Valsartan (Diovan) (see Valsartan)
    • Heparins
      • Pharmacology
        • Heparins Have a Direct Toxic Effect on the Adrenal Zona Glomerulosa Cells (This May Be Mediated by a Decrease in the Number and Affinity of Adrenal Angiotensin II Receptors)
        • May Occur Even with the Low Doses of Heparin Used for Deep Venous Thrombosis Prophylaxis
      • Enoxaparin (Lovenox) (see Enoxaparin)
      • Heparin (see Heparin)
    • Renin Inhibitors
      • Pharmacology
        • Renin Inhibitors Directly Inhibit Renin Activity
      • Aliskiren (Tekturna, Rasilez) (see Aliskiren): renin inhibitor (may cause hyperkalemia when used in combination with ACE inhibitors or ARB’s)
  • Other
    • Severe Illness
      • Physiology
        • Decreased Adrenal Aldosterone Synthesis (Perhaps Complicated by Volume Expansion)
        • Additionally, Stress-Induced ACTH Hypersecretion May Decrease Aldosterone Synthesis by Diverting Substrate to the Synthesis of Cortisol
    • Primary Adrenal Insufficiency (see Adrenal Insufficiency)
      • Physiology
        • Decreased Cortisol and Aldosterone
        • In Contrast, Pituitary Disease Does Not Result in Hypoaldosteronism, Since Corticotropin (ACTH) Does Not Play a Major Role in the Regulation of Aldosterone Release

Aldosterone Resistance

  • Inherited Disorders
    • Pseudohypoaldosteronism Type 1
      • Subtypes
        • Autosomal Recessive Pseudohypoaldosteronism Type 1
        • Autosomal Dominant/Sporadic Pseudohypoaldosteronism Type 1
      • Physiology: resistance to action of aldosterone
  • Drugs
    • Aldosterone Antagonists
      • Pharmacology
        • Aldosterone Antagonists Antagonize the Activity of Aldosterone on the Collecting Tubule Cells by Competition for the Aldosterone Receptor
      • Drospirenone (Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, Angeliq) (see Drospirenone): synthetic hormone used in birth control pills
      • Eplerenone (Inspra) (see Eplerenone)
      • Spironolactone (Aldactone) (see Spironolactone)
    • Epithelial Sodium Channel (ENaC) Antagonists (see Epithelial Sodium Channel Antagonists)
      • Pharmacology
        • Epithelial Sodium Channel (ENaC) Antagonists Act to Close Sodium Channels on the Luminal Membrane of Collecting Tubule Cells (Collecting Tubule is the Site of Action of Aldosterone)
      • Amiloride (see Amiloride)
      • Cimetidine (Tagamet) (see Cimetidine)
      • Nafamostat: synthetic serine protease inhibitor, used as an anticoagulant
      • Pentamidine (see Pentamidine)
      • Triamterene (see Triamterene)
      • Trimethoprim (see Sulfamethoxazole-Trimethoprim)
  • Other

Diagnosis

Transtubular Potassium Gradient

  • Transtubular K Gradient= (Urine K/Plasm K)/(Urine Osm/Plasma Osm)
    • TTKG>8: normal aldosterone effect
    • TTKG<2: hypoaldo/aldosterone resistance of tubule
    • TTKG Assumes urine Na >20 and Urine Osm >300

Urine Potassium/Sodium Ratio

  • Urine K/Na Ratio = Urine K/Urine Na
    • Ratio <1: impaired aldosterone effect
    • Ratio >1: normal aldosterone effect

Clinical Manifestations

Cardiovascular Manifestations

Atrioventricular Heart Blocks

Sinus Bradycardia (see Sinus Bradycardia)

  • Epidemiology
    • May Occur in Some Cases

Cardiac Arrest (see Cardiac Arrest)

  • Epidemiology
    • May Occur in Cases of Acute/Severe Hyperkalemia

Electrocardiographic (EKG) Changes

  • Tall, Peaked T-Waves with Shortened QTc Interval (see xxxx): initial change which is usually noted
  • Widened PR Interval and Widened QRS Duration: seen later
  • Disappearance of P-Wave: may occur
  • QRS Widened to a Sine Wave Pattern: typically a late EKG finding
  • Ventricular Standstill (with Complete Absence of Electrical Activity)/Asystole: latest change

Gastrointestinal Manifestations

  • Hypoactive Bowel Sounds/Ileus (see Ileus)

Neurologic Manifestations

  • Depression (see Depression)
  • Fatigue (see Fatigue)
  • Hyporeflexia (see Hyporeflexia)
  • Muscle Weakness/Flaccid Paralysis (J Neurol Neurosurg Psychiatry, 1998) [MEDLINE]
    • Clinical
      • May Be Severe Enough to Mimic the Symptoms of Guillain-Barré Syndrome
      • Cranial Nerve Function and Sphincter Tone Function are Generally Intact
      • Respiratory Muscle Weakness is Rare

Pulmonary Manifestations

  • Acute/Chronic Hypoxemic/Hypercapnic Respiratory Failure (see Respiratory Failure)
    • Epidemiology
      • Respiratory Muscle Weakness is Rare (Br J Anaesth, 1993)[MEDLINE]
    • Physiology
      • Due to Respiratory Muscle Weakness

Treatment

Insulin (see Insulin)

  • Administration
    • UIntravenous: 5-10 U regular insulin + 1 ampule D50
  • Mechanism
    • Drives Potassium into Cells
  • Onset
    • Decreases Potassium by 1-2 within 30-60 min
  • Duration: hours
  • Adverse Effects
    • Hypoglycemia (see Hypoglycemia)
      • Weight-Based Intravenous Insulin Dosing (0.1 U/kg up to maximum of 10 U) for Hyperkalemia Decreases the Risk of Hypoglycemia (J Hosp Med, 2016) [MEDLINE]

Calcium

  • Agents
  • Indication
    • Fastest Treatment for Cardiac Toxicity (Although it Has No Effect on the Serum Potassium Level)
  • Administration
    • Intravenous: 1 ampule calcium gluconate
  • Mechanism
    • Calcium Counteracts Potassium Effect on Neuromuscular Membranes
  • Onset: immediate
  • Duration: transient

Sodium Bicarbonate (see Sodium Bicarbonate)

  • Indication
    • Useful Even in Absence of Acidosis
  • Administration
    • Intravenous: 1 ampule sodium bicarb
  • Mechanism
    • Drives Potassium into Cells
  • Onset: 1 hr
  • Duration: hours
  • Adverse Effects
    • Possible Increase in Intracellular Calcium, Increasing the Risk of Arrhythmias

Hypertonic (3%) Saline (see Hypertonic Saline)

  • Indication
    • Useful for Cardiac Toxicity in Cases with Coexistent Hyponatremia (Due to Dilution of Plasma Potassium and Antagonism of Neuromuscular Toxicity)
  • Adverse Effects

Kayexelate (Sodium Polystyrene) (see Kayexelate)

  • Pharmacology
    • Sodium Polystyrene Sulfonate Cation Exchange Resin
      • Sodium Ions are Partially Released from the Resin and are Replaced by Potassium Ions
      • This Occurs Mostly in the Colon, Which Excretes Potassium Ions to a Greater Degree than Does the Small Intestine
  • Administration
    • Oral
    • Retention Enema
  • Mechanism
    • Binds Intestinal Potassium, Resulting in Enhanced GI Potassium Excretion
  • Onset: 50 g enema decreases K by 0.5-2.0 mEq within 1 hr
  • Adverse Effects
    • Hypokalemia (see Hypokalemia)
    • Metabolic Alkalosis (see Metabolic Alkalosis): reported when kayexelate has been given in combination with non-absorbable cation-donating antacids and laxatives (such as magnesium hydroxide and aluminum carbonate)

Patiromer (Veltassa) (see Patiromer)

  • Indications
    • FDA-approved for hyperkalemia in the setting of renin-angiotensin-Aldosterone System (RAAS) Inhibitors
  • Pharmacology
    • Non-Absorbable Potassium Binder
  • Onset: takes hours-days
  • Administration
    • Oral

Albuterol (see Albuterol)

  • Administration
    • Inhaler
    • Nebulizer
  • Mechanism
    • Drives Potassium into Cells
  • Adverse Effects

References

General

  • A case of pseudohyperkalaemia and thrombocytosis. Ann Acad Med Singapore. 1998 May;27(3):442-3 [MEDLINE]
  • Acute hyperkalemia associated with intravenous epsilon-aminocaproic acid therapy. Am J Kidney Dis. 1999 Apr;33(4):782-5 [MEDLINE]
  • An unusual case of pseudohyperkalaemia. Nephrol. Dial. Transplant. (2003) 18 (8): 1657-1659 [MEDLINE]

Etiology

  • Studies in disorders of muscle. VII. Clinical manifestations and inheritance of a type of periodic paralysis without hypopotassemia. J Clin Invest. 1951;30(5):492 [MEDLINE]
  • Periodic paralysis and voltage-gated ion channels. Kidney Int. 1996;49(1):9 [MEDLINE]
  • Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004;63(9):1647 [MEDLINE]
  • Review of the Diagnosis and Treatment of Periodic Paralysis. Muscle Nerve. 2018;57(4):522 [MEDLINE]

Clinical

  • Clinical syndrome of potassium intoxication. Am J Med. 1946;1:337 [MEDLINE]
  • Hyperkalemia Paralysis Due to Adrenal Insufficiency. Arch Intern Med. 1965;115:418 [MEDLINE]
  • Muscular paralysis and ventilatory failure caused by hyperkalaemia. Br J Anaesth. 1993;70(2):226[MEDLINE]
  • Secondary hyperkalaemic paralysis. J Neurol Neurosurg Psychiatry. 1998;64(2):249 [MEDLINE]
  • How Dangerous Is Hyperkalemia? J Am Soc Nephrol. 2017;28(11):3155 [MEDLINE]

Treatment

  • Effect of bicarbonate administration on plasma potassium in dialysis patients: interactions with insulin and albuterol. Am J Kidney Dis. 1996 Oct;28(4):508-14 [MEDLINE]
  • Fludrocortisone for the treatment of heparin-induced hyperkalemia. Ann Pharmacother. 2000 May;34(5):606-10 [MEDLINE]
  • Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors. N Engl J Med. 2015 Jan 15;372(3):211-21. doi: 10.1056/NEJMoa1410853. Epub 2014 Nov 21. [MEDLINE]
  • Weight-based insulin dosing for acute hyperkalemia results in less hypoglycemia. J Hosp Med. 2016 May;11(5):355-7. doi: 10.1002/jhm.2545. Epub 2016 Jan 13 [MEDLINE]