The American Journal of Medicine
Volume 122, Issue 3 , Pages 215-221, March 2009

The Management of Hyperkalemia in Patients with Cardiovascular Disease

  • Apurv Khanna, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Apurv Khanna, MD, Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3940
    • ,
  • William B. White, MD

Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Conn

Article Outline

Abstract 

The development of hyperkalemia is common in patients with cardiac and kidney disease who are administered drugs that antagonize the renin-angiotensin-aldosterone system (RAAS). As the results of large-scale clinical trials in hypertension, chronic kidney disease, and congestive heart failure demonstrate benefits of RAAS blockade alone or, in some cases, in combination therapies, the incidence of hyperkalemia has increased in clinical practice. Although there is potential for adverse events in the presence of hyperkalemia, there also are potential benefits of RAAS blockers that support their use in high-risk patient populations. Management of hyperkalemia may be improved by identifying the levels of potassium that may potentially induce harm and using appropriate strategies to avert the levels that may be dangerous or life threatening.

Keywords: Antihypertensive drug therapy, Cardiovascular disease, Chronic kidney disease, Hyperkalemia

 

The benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are established in patients with hypertension, congestive heart failure, coronary artery disease, and diabetic nephropathy.1, 2, 3 Hyperkalemia caused by therapy with agents that interfere with the renin-angiotensin-aldosterone system (RAAS), including ACE inhibitors, ARBs, aldosterone antagonists, and direct renin inhibitors, occurs infrequently in patients who lack preexisting factors for its development. In contrast, patients with heart disease, congestive heart failure, severe hypertension, and diabetes often have renal insufficiency, putting them at increased risk for hyperkalemia.1 Renal insufficiency also is recognized as a robust independent predictor of death in patients with cardiovascular disease.4 Thus, the typical patients who might derive the most benefit from use of a RAAS-blocking agent are those at enhanced risk for development of hyperkalemia.

Clinical Significance

 


•Hyperkalemia is increasingly common because of the use of drugs affecting the renin-angiotensin-aldosterone system.

•The use of these drugs is, however, of proved benefit in patients with congestive heart failure and chronic kidney disease.

•Hyperkalemia can be safely managed in patients by dietary restriction, regular review of medication lists, and use of diuretics, cation-exchange resins, and sodium bicarbonate.

Because of the increasingly common use of antihypertensive and cardiovascular treatment strategies that often include multiple levels of blockade of the RAAS, we present a current review on the evaluation and management of hyperkalemia in patients with underlying cardiovascular disease.

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Case Presentation 

A 73-year-old woman with hypertension, type 2 diabetes mellitus, and chronic heart failure was determined to have a serum potassium of 6.1 mEq/L at an outpatient visit. Her medications included hydrochlorothiazide 25 mg daily, metoprolol XL 100 mg daily, perindopril 8 mg daily, and spironolactone 25 mg daily. Three months earlier on the very same regimen, her serum potassium had been 4.8 mEq/L. On examination, her seated blood pressure was 128/76 mm Hg. Repeated serum potassium was 6.2 mEq/L, serum creatinine was 1.0 mg/dL, estimated glomerular filtration rate (GFR) was 43 mL/min, and urinalysis showed normal results. The electrocardiogram demonstrated sinus rhythm at 64 beats/min, with normal conduction intervals and normal morphology of the P and T waves.

Questions of clinical importance for this patient include the following: What are the likely causes of hyperkalemia in this patient? How should the hyperkalemia observed in this patient be managed acutely? How should the hyperkalemia observed in this patient be managed over the long term?

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Regulation of Potassium Homeostasis 

Potassium stores in the adult are approximately 3500 mEq, making it the most abundant cation in the human body.5 Potassium is mainly distributed in the intracellular space. This intracellular-extracellular K+ gradient is maintained by the Na+-K+ adenosine triphosphatase (ATPase) pump, which transports 3 Na+ ions out of the cell in exchange for 2 K+ ions into the cell.6 Potassium stores are determined by dietary intake and renal excretion of potassium. Most potassium filtered in the glomeruli is reabsorbed at the proximal tubule. The distal nephron accounts for only a small percentage of the K+ reabsorbed, but the secretion of K+distally is under the control of the RAAS and becomes the major determinant of plasma K+ concentration.7

Hyperkalemia can occur as the result of 1 or more of 3 processes: increased potassium intake; impaired movement of potassium from the extracellular to the intracellular space; or impaired renal excretion of potassium.

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Increased Potassium Intake 

Increased potassium intake is an uncommon cause of hyperkalemia unless it is accompanied by an underlying impairment of renal function. Oral intake of large amounts of potassium in a single dose (eg, >160 mEq of K+) can increase plasma K+ concentrations to more than 7.0 to 8.0 mmol/L, even in patients with a normal GFR.8 Excessive potassium intake also can occur as the result of blood transfusions, potassium-containing “salt substitutes,”9 and low-sodium foods that may contain potassium (Table 1).10

Table 1. Common Foods Rich in Potassium
Fruits
Apricot
Avocado
Banana
Cantaloupe
Grapefruit
Orange
Prunes
Raisins
Vegetables
Acorns
Bakedbeans
Carrots
Lentils
Legumes
Potatoes
Pumpkins
Spinach
Tomatoes
OtherFoods
Bran
Chocolate
Milk
Nutsandseeds
Peanutbutter
Saltsubstitutes
Yogurt
Snuff

Adapted from the National Kidney Foundation website, http://www.kidney.org/ATOZ/atozItem.cfm. Accessed October 14, 2008.

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Impaired Movement of Potassium into Cells 

β-Adrenergic Blockade 

β-Adrenergic–blocking drugs can induce hyperkalemia by reducing the cellular uptake of K+. This process is typically manifested by only minor elevations in the serum K+, because the kidney is usually able to compensate by increasing urinary excretion of potassium.11 This effect can be problematic in patients with chronic kidney disease or when there is concomitant use of other RAAS blockers. β1-Selective adrenergic blockers are less likely to reduce cellular uptake of K+ than nonselective β-blockers when used in low doses.12

Digoxin Toxicity 

The Na+-K+ ATPase receptor has been found to be highly specific for digoxin, which inhibits the activity of the pump in a dose-dependent manner.13 The increase in plasma K+ associated with digoxin on this mechanism of cellular transport is usually not at levels of clinical importance. However, after ingestion of large amounts of digoxin, severe hyperkalemia has been reported.14

Cardiopulmonary Bypass 

Hyperkalemia has been described during cardiopulmonary bypass using warm blood cardioplegia15 and is caused by washout of ischemic areas of the myocardium that were previously underperfused and develop restoration of blood flow.

Metabolic Acidosis 

In metabolic acidosis, there is K+ movement into the extracellular compartment. This movement occurs to preserve electroneutrality in exchange for excess H+ ions, which then moves back across cell membranes into the cytosol. The increase in the plasma K+ concentration ranges from 0.2 to 1.7 mEq/L for every 0.1 unit reduction in the arterial pH.16

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Types of Impaired Excretion of Potassium 

Chronic Kidney Disease 

The kidney has a great capacity for excreting potassium; consequently, in a non-oliguric patient, hyperkalemia is manifested only with a GFR less than 15 mL/min. However, in patients who have oliguria with concurrent use of RAAS blockade, elevated plasma K+ levels may be induced in earlier stages of chronic kidney disease.17 The retention of K+ in chronic kidney disease occurs because of an inadequate number of nephrons.18

Congestive Heart Failure 

Decreases in cardiac output lead to diminished renal perfusion and urinary excretion of potassium. In addition to renal dysfunction in patients with heart failure, the risk of hyperkalemia is increased because most of these patients also are maintained on RAAS blockers. In a case-control study involving 938 patients with heart failure, Ramadan and colleagues19 showed that diabetes mellitus (odds ratio [OR]=2.42), reduced creatinine clearance (OR=8.36), use of spironolactone (OR=4.18), and use of ACE inhibitors (OR=2.55) were all independent risk factors for the development of hyperkalemia.

Inhibition of aldosterone as a cause of hyperkalemia has assumed increasing relevance after the Randomized Aldactone Evaluation Study (RALES) demonstrated that spironolactone improved outcomes in patients with chronic heart failure.20 The incidence of hyperkalemia in patients randomized to spironolactone in RALES was 2%, but patients with serum creatinine more than 2.5 mg/dL and serum K+ concentration more than 5 mmol/L were excluded.

A prospective cohort study of more than 1000 patients with heart failure done after publication of the RALES trial showed that spironolactone had a survival benefit (relative risk 0.09; confidence interval 0.02-0.39) even in a population in whom 78% of the patients did not meet RALES eligibility criteria. However, 25% of patients had spironolactone withdrawn because of side effects. Only 1 patient developed serum K+ greater than 6 mmol/L.21

Renin-angiotensin Blockers 

Administration of ACE inhibitors or ARBs does not typically result in hyperkalemia in most patients.15 The mean increase in plasma K+ concentration after ACE inhibition is less than 0.3 to 0.4 mEq/L if renal function is normal.22 Clinically important hyperkalemia could occur if patients are coadministered K+ supplements or aldosterone antagonists, or have chronic kidney disease.22, 23

Aldosterone Antagonists 

Aldosterone antagonists induce hyperkalemia by impairing the ability of the distal nephron to excrete potassium. Drugs such as spironolactone and eplerenone block the interaction of aldosterone with its mineralocorticoid receptor.24 In a retrospective cohort study of 100 patients with heart failure, Cruz and colleagues25 compared the rates of hyperkalemia (serum K+≥5.5 meq/L) for patients receiving an ACE inhibitor versus those receiving both the ACE inhibitor and an aldosterone antagonist over a period of several years. In all, 16 patients receiving the combination treatment developed a serum K+ more than 5.5 mEq/L versus 1 patient receiving the ACE inhibitor alone. The proportion who developed a serum K+ greater than 6.0 meq/L in patients taking spironolactone was 14% versus 0% for patients taking ACE inhibitors alone.

Other Potassium-Sparing Diuretics 

The potassium-sparing diuretics amiloride and triamterene impair distal K+ secretion by closing the Na+ channel in the luminal membrane of the collecting tubular cell.26 Data from case-control studies in older patients show that those admitted to the hospital because of hyperkalemia were 20 times more likely to be taking a potassium-sparing diuretic in combination with an ACE inhibitor than those taking an ACE inhibitor alone.27

Heparin 

Heparin can lead to decreased renal excretion of potassium in patients with underlying chronic kidney disease. Hyperkalemia occurs in approximately 7% of patients who receive long-term heparin. Heparin is a potent inhibitor of aldosterone secretion via attenuation of the affinity and number of angiotensin II receptors.28 It is recommended that monitoring for hyperkalemia be performed at 3- to 4-day intervals in patients receiving prolonged heparin, including deep venous thrombosis prophylaxis.

Nonsteroidal Anti-inflammatory Drugs 

Nonsteroidal anti-inflammatory drugs (NSAIDs) might cause hyperkalemia and renal insufficiency, particularly in patients with underlying chronic kidney disease and heart failure.29 By inhibiting both prostaglandin E and prostacyclin synthesis, NSAIDs decrease renin secretion and renal blood flow, and impair natriuresis.30 In patients with normal kidney function, the mean increase in plasma K+ is typically on the order of 0.2 mEq/L. However, in patients with chronic kidney disease, elevations in plasma potassium can exceed 1 mEq/L.31

Combination of RAAS Blockers in Patients with Vascular Disease 

The risk of hyperkalemia increases when ACE inhibitors and ARBs or ARBs and renin inhibitors are used together or in disorders that interfere with the function of the cortical-collecting tubule.17 In patients with hypertension and persistent proteinuria on ACE inhibitor or ARB monotherapy, combining these agents may prove effective in further reduction in proteinuria.17, 32 In the AVOID trial,32 combining the renin inhibitor aliskiren with the ARB valsartan led to an additional 20% reduction in proteinuria, with a similar rate of hyperkalemia.

Combining ACE inhibitors and ARBs in patients with heart failure provides moderate benefits,33 but in patients with vascular disease, the combination of an ACE inhibitor and an ARB has not been proven to improve outcomes compared with ACE inhibitor monotherapy.34 In the ONTARGET trial,34 ACE inhibitor-tolerant patients randomized to telmisartan 80 mg daily had outcomes similar to patients randomized to ramipril 10 mg daily and with fewer adverse effects. When the combination of the 2 agents was evaluated, the cardiovascular event rate was similar to that of ramipril alone but with an increase in adverse events, including hyperkalemia.

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Clinical Manifestations of Hyperkalemia 

Signs and Symptoms 

Common clinical consequences of changes in cell membrane potentials as the result of hyperkalemia are muscle weakness and cardiac arrhythmias.35 Symptoms of hyperkalemia are usually observed at high levels of serum potassium (>8 mmol/L). Rarely, muscular weakness may be severe and involve ascending flaccid paralysis that can manifest as quadriplegia. The cranial nerves and respiratory muscles are usually not involved.36

Electrocardiography Findings 

Electrocardiographic (ECG) findings are useful in detecting hyperkalemia. The initial findings on ECG are tall-peaked T waves as the serum K+ exceeds 6.0 to 6.5 mEq/L (Figure1). As serum K+ increases to 6.5 to 7.5 mEq/L, the PR interval is progressively prolonged and the P wave is flattened. When the serum K+ exceeds 8.0 mEq/L, the QRS complex may become prolonged and widened, and can merge with the T wave to form a sine-wave pattern, with impending cardiac arrest (Figure 1).37

  • View full-size image.
  • Figure 1. 

    Life-threatening ECG changes in hyperkalemia. a, Tented T waves, loss of P waves, and a wide QRS complex in a patient presenting with paralysis and acute renal failure (serum K+=9.3 mmol/L). b, Sine-wave pattern in a patient with acute renal failure and digoxin toxicity (serum K+=9.3 mmol/L). c, Severe bradycardia at a rate of 28 beats/min in a patient on hemodialysis presenting with syncope (serum K+= 8.1 mmol/L). d, Ventricular tachycardia in a patient on hemodialysis presenting with generalized weakness (serum K+=9.1 mmol/L).

  • Reproduced with permission from Alfonzo et al.37

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Treatment of Hyperkalemia 

Hyperkalemia should be approached in terms of acute and long-term interventions (Table 2). Drugs that increase membrane stabilization and those that move K+ from the plasma space to the intracellular cytosol have a rapid onset of action and play a major role in acute treatment. Drugs that induce potassium excretion via renal or gastrointestinal means take longer to act and are used primarily for chronic hyperkalemia.

Table 2. Modalities to Treat Hyperkalemia in the Acute and Subacute Settings
Mode of TherapyTime of OnsetMechanism of Action to Reduce Serum K+
Calcium gluconateRapidAntagonizes membrane excitation of K+
Insulin and glucoseIntermediateMoves K+ from plasma into cells
β-Adrenergic agonistsIntermediateMoves K+ from plasma into cells
Sodium bicarbonateIntermediateMoves K+ from plasma into cells
Loop or thiazide diureticsDelayedEnhances urinary K+ excretion
Cation-exchange resinsDelayedEnhances gastrointestinal K+ excretion
DialysisDelayedExtracorporeal K+ removal

Acute Treatment 

Calcium gluconate, administered parenterally, has the fastest onset of action among drugs used for the treatment of hyperkalemia and is used when ECG changes (Figure 1) are present. Calcium gluconate acts by antagonizing the effects of K+ at the level of the cell membrane and does not affect the plasma K+ concentration.38 The protective effects of calcium are limited to less than 60 minutes, so other measures to decrease plasma potassium should be initiated at the time that parenteral calcium is administered.

Insulin, usually administered as 10 units of an immediate-acting formulation, with 50 g of parenteral dextrose to prevent hypoglycemia, acts by increasing Na-K-ATPase activity, which drives K+ from the plasma into the cellular cytosol.39 Insulin may decrease plasma K+ by 0.5 to 1.5 mEq/L and has an effect lasting for 4 to 6 hours.40

β-Adrenergic agonists also activate Na-K-ATPase, driving K+ intracellularly.41 For example, albuterol (20 mg by nebulizer in 4 mL of saline for 10 minutes) decreases plasma K+ by 0.5 to 1.5 mEq/L.42 The effects of β-adrenergic agonists are limited to 2 to 4 hours.

Sodium bicarbonate, infused parenterally (44 meq) for 5 minutes, facilitates the movement of K+ from the plasma into the cell. Bicarbonate will not effectively decrease serum K+ in the absence of metabolic acidosis.43 In addition, this treatment generates a large sodium load, often a major factor limiting its use in patients with heart failure.

Cation-exchange resins are commonly given orally as 60 g of sodium polystyrene sulfonate in 20% sorbitol. In the gastrointestinal tract, this resin takes up K+, releases Na+, and often induces diarrhea. These resins are relatively slow acting, and a significant reduction in serum K+ may not be observed for 4 to 6 hours.44 In patients with life-threatening hyperkalemia, more rapid-acting measures should be initiated first, followed by the cation-exchange resin to maintain a lower plasma K+ concentration for a longer period of time.

In instances of life-threatening hyperkalemia in the presence of renal failure, or with rhabdomyolysis in which there is persistent and marked potassium leaking from cellular necrosis, dialysis may be the most appropriate course of treatment. Hemodialysis is typically more effective than peritoneal dialysis for potassium removal.45

Long-term Treatment 

The first step in the longer-term management of hyperkalemia is to carefully review the patient's medication profile and discontinue drugs that may increase retention of potassium (eg, NSAIDs, potassium-sparing diuretics), when possible. A detailed dietary history also should be obtained. The use of salt substitutes containing potassium should be strongly discouraged.46 Potassium-rich foods should be consumed only in moderation.

Diuretics are often effective for the prevention of hyperkalemia and allow patients to increase their sodium intake, which also assists in potassium excretion in the distal nephron.47 In patients with preserved renal function, thiazide diuretics are the preferred agents in this category. When the GFR is less than 40 mL/min, thiazide diuretics might prove ineffective and a loop diuretic such as furosemide or torsemide should be initiated.48

Because patients with chronic kidney disease often have metabolic acidosis, the daily administration of sodium bicarbonate may be effective for hyperkalemia.49 Sodium bicarbonate will shift K+ into the cells as the acidosis is corrected. Precaution should be taken not to induce volume overload from administration of the salt, and patients can require an increased dose of diuretic to offset this side effect.

For patients taking RAAS blocking agents alone or in combination, it is prudent to initiate patients on low doses. If the potassium is less than 5.5 mEq/L or there is a more than 30% increase in serum creatinine from baseline, no further investigation is needed and patients should be maintained on an ARB or ACE inhibitor.50 For greater increases, an evaluation for renovascular disease should be pursued, along with discontinuation of the RAAS-blocking drug. Revascularization may result in careful reintroduction of the RAAS blocker without adverse renal effects.

Reevaluation of the Case 

For our patient with cardiovascular disease, the serum potassium has varied from high normal to one of clinical concern. A common underlying possibility is hyporeninemic hypoaldosteronism in this older patient with diabetes.17 β-blockers can worsen hyperkalemia by reducing cellular uptake of K+. In addition, ACE inhibitors and aldosterone blockers are agents known to interfere with potassium excretion. Nevertheless, her underlying conditions of diabetes and heart failure warrant blockade of the RAS.

It is advisable for the patient to have the serum potassium decreased to a safer level. Because she has no ECG abnormalities, this can be accomplished with the cation-exchange resin, sodium polystyrene (Kayexalate; Sanofi-Aventis, Bridgewater, NJ), 30 to 45 g, 6 to 12 hours apart. Subsequently, the patient can be managed with modestly increasing dietary sodium intake, more aggressively restricting dietary potassium, and changing the thiazide to a loop diuretic to enhance potassium excretion. If this is not successful in reducing the serum potassium to less than 5.5 meq/L, one would have to consider discontinuation of spironolactone or maintenance of the cation-exchange resin once or twice per week.

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Conclusions 

Hyperkalemia is being observed with increasing prevalence in patients with cardiovascular disease on RAAS blockade. Appropriate adjustment of the treatment regimen and, if necessary, use of drugs to offset hyperkalemia might allow clinicians to continue administering these agents to patients. In view of the long-term benefits proven for RAAS-blocking therapies, intervention to manage hyperkalemia makes more sense than avoidance of the drugs in patients with high-risk hypertension and cardiovascular diseases.

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 Funding: This work was supported in part by funding from US Department of Defense DAMDW81XWH-05-10060, NIH R01 AG022092, and an unrestricted educational grant from Boehringer-Ingelheim Pharmaceuticals.

 Conflict of Interest: Dr White discloses that he has received research funding during the previous 12 months from the National Institutes of Health, the Catherine and Patrick Donaghue Foundation, Astra-Zeneca Pharmaceuticals, Inc, Boehringer-Ingelheim Pharmaceuticals, Inc, Novartis, Inc, and Pfizer, Inc. Dr White serves as a safety consultant to Gilead, Inc, Nicox, Inc, Palatin Technologies, Takeda Research Development Group, and Teva Neurosciences, Inc. Dr Khanna discloses he has received an unrestricted educational grant from Boehringer-Ingelheim Pharmaceuticals.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(08)01119-4

doi:10.1016/j.amjmed.2008.10.028

The American Journal of Medicine
Volume 122, Issue 3 , Pages 215-221, March 2009

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