REVIEWThe Management of Hyperkalemia in Patients withCardiovascular DiseaseApurv Khanna, MD, William B. White, MDDivision ...
216                                                             The American Journal of Medicine, Vol 122, No 3, March 200...
Khanna and White      Hyperkalemia in Cardiovascular Diseases                                                             ...
The management of hyperkalemia in patients with cardiovascular disease
The management of hyperkalemia in patients with cardiovascular disease
The management of hyperkalemia in patients with cardiovascular disease
The management of hyperkalemia in patients with cardiovascular disease
Upcoming SlideShare
Loading in …5

The management of hyperkalemia in patients with cardiovascular disease


Published on

Published in: Education
1 Like
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

The management of hyperkalemia in patients with cardiovascular disease

  1. 1. REVIEWThe Management of Hyperkalemia in Patients withCardiovascular DiseaseApurv Khanna, MD, William B. White, MDDivision of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School ofMedicine, Farmington, Conn. 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. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 215-221 KEYWORDS: Antihypertensive drug therapy; Cardiovascular disease; Chronic kidney disease; HyperkalemiaThe benefits of angiotensin-converting enzyme (ACE) in- patients who lack preexisting factors for its development. Inhibitors and angiotensin receptor blockers (ARBs) are es- contrast, patients with heart disease, congestive heart fail-tablished in patients with hypertension, congestive heart ure, severe hypertension, and diabetes often have renalfailure, coronary artery disease, and diabetic nephropa- insufficiency, putting them at increased risk for hyperkale-thy.1-3 Hyperkalemia caused by therapy with agents that mia.1 Renal insufficiency also is recognized as a robustinterfere with the renin-angiotensin-aldosterone system independent predictor of death in patients with cardiovas-(RAAS), including ACE inhibitors, ARBs, aldosterone an- cular disease.4 Thus, the typical patients who might derivetagonists, and direct renin inhibitors, occurs infrequently in the most benefit from use of a RAAS-blocking agent are those at enhanced risk for development of hyperkalemia. Because of the increasingly common use of antihyper- Funding: This work was supported in part by funding from US De- tensive and cardiovascular treatment strategies that oftenpartment of Defense DAMDW81XWH-05-10060, NIH R01 AG022092,and an unrestricted educational grant from Boehringer-Ingelheim Pharma- include multiple levels of blockade of the RAAS, weceuticals. present a current review on the evaluation and management Conflict of Interest: Dr White discloses that he has received research of hyperkalemia in patients with underlying cardiovascularfunding during the previous 12 months from the National Institutes of disease.Health, the Catherine and Patrick Donaghue Foundation, Astra-ZenecaPharmaceuticals, Inc, Boehringer-Ingelheim Pharmaceuticals, Inc, Novar-tis, Inc, and Pfizer, Inc. Dr White serves as a safety consultant to Gilead, CASE PRESENTATIONInc, Nicox, Inc, Palatin Technologies, Takeda Research Development A 73-year-old woman with hypertension, type 2 diabetesGroup, and Teva Neurosciences, Inc. Dr Khanna discloses he has receivedan unrestricted educational grant from Boehringer-Ingelheim Pharmaceu- mellitus, and chronic heart failure was determined to have aticals. serum potassium of 6.1 mEq/L at an outpatient visit. Her Authorship: All authors had access to the data and played a role in medications included hydrochlorothiazide 25 mg daily,writing this manuscript. metoprolol XL 100 mg daily, perindopril 8 mg daily, and Requests for reprints should be addressed to Apurv Khanna, MD, spironolactone 25 mg daily. Three months earlier on theDivision of Hypertension and Clinical Pharmacology, Pat and Jim CalhounCardiology Center, University of Connecticut Health Center, 263 Farm- very same regimen, her serum potassium had been 4.8ington Avenue, Farmington, CT 06030-3940. mEq/L. On examination, her seated blood pressure was E-mail address: 128/76 mm Hg. Repeated serum potassium was 6.2 mEq/L,0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved.doi:10.1016/j.amjmed.2008.10.028
  2. 2. 216 The American Journal of Medicine, Vol 122, No 3, March 2009serum creatinine was 1.0 mg/dL, estimated glomerular fil- manifested by only minor elevations in the serum Kϩ,tration rate (GFR) was 43 mL/min, and urinalysis showed because the kidney is usually able to compensate by increas-normal results. The electrocardiogram demonstrated sinus ing urinary excretion of potassium.11 This effect can berhythm at 64 beats/min, with normal conduction intervals problematic in patients with chronic kidney disease or whenand normal morphology of the P and T waves. there is concomitant use of other RAAS blockers. ␤1- Questions of clinical importance Selective adrenergic blockersfor this patient include the follow- are less likely to reduce cellularing: What are the likely causes of uptake of Kϩ than nonselective CLINICAL SIGNIFICANCEhyperkalemia in this patient? How ␤-blockers when used in lowshould the hyperkalemia observed ● Hyperkalemia is increasingly common be- doses.12in this patient be managed acutely? cause of the use of drugs affecting theHow should the hyperkalemia ob- renin-angiotensin-aldosterone system. Digoxin Toxicityserved in this patient be managed The Naϩ-Kϩ ATPase receptorover the long term? ● The use of these drugs is, however, of has been found to be highly spe- proved benefit in patients with congestive cific for digoxin, which inhibitsREGULATION OF heart failure and chronic kidney disease. the activity of the pump in a ● Hyperkalemia can be safely managed in dose-dependent manner.13 ThePOTASSIUM HOMEOSTASIS increase in plasma Kϩ associatedPotassium stores in the adult are patients by dietary restriction, regular with digoxin on this mechanism ofapproximately 3500 mEq, making review of medication lists, and use of cellular transport is usually not atit the most abundant cation in diuretics, cation-exchange resins, and levels of clinical importance. How- 5the human body. Potassium is sodium bicarbonate. ever, after ingestion of largemainly distributed in the intra- amounts of digoxin, severe hyper-cellular space. This intracellular- ϩ kalemia has been reported.14extracellular K gradient is main-tained by the Naϩ-Kϩ adenosine triphosphatase (ATPase)pump, which transports 3 Naϩ ions out of the cell in ex-change for 2 Kϩ ions into the cell.6 Potassium stores are Table 1 Common Foods Rich in Potassiumdetermined by dietary intake and renal excretion of potas-sium. Most potassium filtered in the glomeruli is reabsorbed Fruitsat the proximal tubule. The distal nephron accounts for only Apricot ϩ Avocadoa small percentage of the K reabsorbed, but the secretion ϩ Bananaof K distally is under the control of the RAAS and becomes ϩ 7 Cantaloupethe major determinant of plasma K concentration. Grapefruit Hyperkalemia can occur as the result of 1 or more of 3 Orangeprocesses: increased potassium intake; impaired movement Prunesof potassium from the extracellular to the intracellular Raisinsspace; or impaired renal excretion of potassium. Vegetables Acorns Baked beansINCREASED POTASSIUM INTAKE CarrotsIncreased potassium intake is an uncommon cause of hy- Lentilsperkalemia unless it is accompanied by an underlying im- Legumespairment of renal function. Oral intake of large amounts of Potatoespotassium in a single dose (eg, Ͼ160 mEq of Kϩ) can Pumpkinsincrease plasma Kϩ concentrations to more than 7.0 to 8.0 Spinachmmol/L, even in patients with a normal GFR.8 Excessive Tomatoespotassium intake also can occur as the result of blood Other Foods Brantransfusions, potassium-containing “salt substitutes,”9 and Chocolatelow-sodium foods that may contain potassium (Table 1).10 Milk Nuts and seeds Peanut butterIMPAIRED MOVEMENT OF POTASSIUM Salt substitutesINTO CELLS Yogurt Snuff␤-Adrenergic Blockade Adapted from the National Kidney Foundation website, http://www.␤-Adrenergic– blocking drugs can induce hyperkalemia by Accessed October 14, 2008.reducing the cellular uptake of Kϩ. This process is typically
  3. 3. Khanna and White Hyperkalemia in Cardiovascular Diseases 217Cardiopulmonary Bypass Renin-angiotensin BlockersHyperkalemia has been described during cardiopulmonary Administration of ACE inhibitors or ARBs does not typi-bypass using warm blood cardioplegia15 and is caused by cally result in hyperkalemia in most patients.15 The meanwashout of ischemic areas of the myocardium that were increase in plasma Kϩ concentration after ACE inhibition ispreviously underperfused and develop restoration of blood less than 0.3 to 0.4 mEq/L if renal function is normal.22flow. Clinically important hyperkalemia could occur if patients are coadministered Kϩ supplements or aldosterone antago- nists, or have chronic kidney disease.22,23Metabolic AcidosisIn metabolic acidosis, there is Kϩ movement into the extra-cellular compartment. This movement occurs to preserve elec- Aldosterone Antagoniststroneutrality in exchange for excess Hϩ ions, which then Aldosterone antagonists induce hyperkalemia by impairingmoves back across cell membranes into the cytosol. The in- the ability of the distal nephron to excrete potassium. Drugscrease in the plasma Kϩ concentration ranges from 0.2 to 1.7 such as spironolactone and eplerenone block the interactionmEq/L for every 0.1 unit reduction in the arterial pH.16 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 hyperkalemiaTYPES OF IMPAIRED EXCRETION OF POTASSIUM (serum Kϩ Ն 5.5 meq/L) for patients receiving an ACE inhibitor versus those receiving both the ACE inhibitor andChronic Kidney Disease an aldosterone antagonist over a period of several years. InThe kidney has a great capacity for excreting potassium; all, 16 patients receiving the combination treatment devel-consequently, in a non-oliguric patient, hyperkalemia is oped a serum Kϩ more than 5.5 mEq/L versus 1 patientmanifested only with a GFR less than 15 mL/min. However, receiving the ACE inhibitor alone. The proportion whoin patients who have oliguria with concurrent use of RAAS developed a serum Kϩ greater than 6.0 meq/L in patientsblockade, elevated plasma Kϩ levels may be induced in taking spironolactone was 14% versus 0% for patients tak-earlier stages of chronic kidney disease.17 The retention of ing ACE inhibitors alone.Kϩ in chronic kidney disease occurs because of an inade-quate number of nephrons.18 Other Potassium-Sparing Diuretics The potassium-sparing diuretics amiloride and triamtereneCongestive Heart Failure impair distal Kϩ secretion by closing the Naϩ channel in the luminal membrane of the collecting tubular cell.26 DataDecreases in cardiac output lead to diminished renal perfu- from case-control studies in older patients show that thosesion and urinary excretion of potassium. In addition to renal admitted to the hospital because of hyperkalemia were 20dysfunction in patients with heart failure, the risk of hyper- times more likely to be taking a potassium-sparing diuretickalemia is increased because most of these patients also are in combination with an ACE inhibitor than those taking anmaintained on RAAS blockers. In a case-control study ACE inhibitor alone.27involving 938 patients with heart failure, Ramadan andcolleagues19 showed that diabetes mellitus (odds ratio[OR] ϭ 2.42), reduced creatinine clearance (OR ϭ 8.36), Heparinuse of spironolactone (OR ϭ 4.18), and use of ACE inhib- Heparin can lead to decreased renal excretion of potassiumitors (OR ϭ 2.55) were all independent risk factors for the in patients with underlying chronic kidney disease. Hyper-development of hyperkalemia. kalemia occurs in approximately 7% of patients who receive Inhibition of aldosterone as a cause of hyperkalemia has long-term heparin. Heparin is a potent inhibitor of aldoste-assumed increasing relevance after the Randomized Aldac- rone secretion via attenuation of the affinity and number oftone Evaluation Study (RALES) demonstrated that spirono- angiotensin II receptors.28 It is recommended that monitor-lactone improved outcomes in patients with chronic heart ing for hyperkalemia be performed at 3- to 4-day intervalsfailure.20 The incidence of hyperkalemia in patients ran- in patients receiving prolonged heparin, including deep ve-domized to spironolactone in RALES was 2%, but patients nous thrombosis prophylaxis.with serum creatinine more than 2.5 mg/dL and serum Kϩconcentration more than 5 mmol/L were excluded. Nonsteroidal Anti-inflammatory Drugs A prospective cohort study of more than 1000 patients Nonsteroidal anti-inflammatory drugs (NSAIDs) mightwith heart failure done after publication of the RALES trial cause hyperkalemia and renal insufficiency, particularly inshowed that spironolactone had a survival benefit (relative patients with underlying chronic kidney disease and heartrisk 0.09; confidence interval 0.02-0.39) even in a popula- failure.29 By inhibiting both prostaglandin E and prostacy-tion in whom 78% of the patients did not meet RALES clin synthesis, NSAIDs decrease renin secretion and renaleligibility criteria. However, 25% of patients had spirono- blood flow, and impair natriuresis.30 In patients with normallactone withdrawn because of side effects. Only 1 patient kidney function, the mean increase in plasma Kϩ is typi-developed serum Kϩ greater than 6 mmol/L.21 cally on the order of 0.2 mEq/L. However, in patients with