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Hyperkalemia is a common clinical condition that can induce deadly cardiac arrhythmias. Electrocardiographic manifestations of hyperkalemia vary from the classic sine-wave rhythm, which occurs in severe hyperkalemia, to nonspecific repolarization abnormalities seen with mild elevations of serum potassium. We present a case of hyperkalemia, initially diagnosed as ventricular tachycardia, to demonstrate how difficult hyperkalemia can be to diagnose. An in-depth review of hyperkalemia is presented, examining the electrophysiologic and electrocardiographic changes that occur as serum potassium levels increase. The treatment for hyperkalemia is then discussed, with an emphasis on the mechanisms by which each intervention lowers serum potassium levels. An extensive literature review has been performed to present a comprehensive review of the causes and treatment of hyperkalemia.
Hyperkalemia is a common clinical condition that can induce deadly cardiac arrhythmias. Electrocardiographic manifestations of hyperkalemia vary from the classic sine-wave rhythm, which occurs in severe hyperkalemia, to nonspecific repolarization abnormalities seen with mild elevations of serum potassium. Herein, we describe the clinical electrocardiographic abnormalities associated with hyperkalemia and present an in-depth review of the literature regarding its treatment.
A 69-year-old woman with end-stage renal disease experienced the sudden onset of crampy abdominal pain and emesis several hours after a routine hemodialysis treatment. Severe fatigue and dysphoria followed, which prompted her to summon emergency medical personnel for assistance. She was taken to the local emergency department, where she continued to have severe fatigue but denied chest pain, palpitations, dyspnea, pre-syncopal symptoms, fever, or additional gastrointestinal discomfort. The patient's medications at the time of admission included omeprazole, glipizide, labetalol, doxepin, quinine, phenergan, lactulose, aspirin, and sevelamer. Her medical history included long-standing diabetes mellitus, hypertension, and end-stage renal disease that had necessitated dialysis for the past 4 years.
Physical examination of the patient in the emergency department revealed a woman with ashen skin who was in moderate distress. Her blood pressure was 141/87 mmHg with a pulse of 100 beats/min. She was breathing 32 times/min with an oxygen saturation of 97% on 3 liters of oxygen via nasal cannula. On cardiovascular examination, heart sounds were inaudible. Her lung fields were clear to auscultation bilaterally, and results of the abdominal examination were normal. The extremities were without cyanosis or edema. Neurologically, she was alert and oriented, with diminished deep tendon reflexes.
Results of multiple 12-lead electrocardiograms revealed a wide QRS complex rhythm with a rate of 70 to 100 beats/min and a QRS duration of 238 msec, which led to a diagnosis of ventricular tachycardia (Fig. 1). The patient was subsequently treated with a lidocaine bolus and infusion. Because her arrhythmia continued unabated, we initiated a procainamide infusion and discontinued the lidocaine. One hour after admission, the patient's serum potassium level was found to be at 10.0 mEq/L. The procainamide infusion was discontinued; and calcium, insulin, glucose, and bicarbonate were given intravenously. She then underwent emergent dialysis and her potassium level gradually returned to normal.
After dialysis, her electrocardiographic results returned to baseline, with a QRS duration of 95 msec (compared with 238 msec at presentation; see Fig. 2), and her cardiac enzymes were found to be within normal limits. A transthoracic echocardiogram revealed normal left ventricular systolic function, and she was discharged from the hospital in stable condition with no further arrhythmias. The cause of her hyperkalemia was never ascertained; however, it was postulated that there might have been an inappropriate potassium concentration in her dialysis fluid.
Extracellular potassium concentration is normally maintained between 4.0 and 4.5 mEq/L by a complex interplay of potassium excretion and consumption. Ninety-five percent of total body potassium is intracellular; only 2% is extracellular. A 70-kg man, for instance, has about 3,920 mEq of potassium in the intracellular space but only 59 mEq in the extracellular space.1 Given that the total daily intake of potassium from a normal diet can be up to 200 mEq, one can see how precisely and quickly the body must be able to respond to any given potassium load in order to prevent severe hyperkalemia.
Total body potassium levels are regulated mostly by the kidneys, with only 5% to 10% of ingested potassium excreted in the feces.1 Renal excretion of potassium is determined by the rate of potassium filtration across the glomerular basement membrane and by the rate of its secretion and resorption in the distal tubules of the nephron. When increased intake of potassium overwhelms the ability of the kidneys to excrete potassium, or when a decrease in renal function occurs, hyperkalemia may result. Because there are often no clinical signs or symptoms to suggest hyperkalemia, clinicians must frequently rely on clinical information (that is, a history of renal failure or the ingestion of medications known to cause hyperkalemia), laboratory data, and electrocardiographic changes to make the diagnosis.
Hyperkalemia is a common cause of the cardiac arrhythmias seen in clinical practice. The challenge in managing hyperkalemia comes from the fact that it can be difficult, if not impossible, to identify the condition solely on the basis of electrocardiographic information. Patients who present with hyperkalemia may have a normal electrocardiogram or have changes that are so subtle that physicians frequently have difficul-ty attributing these changes to increased potassium levels. In a study performed at the University of Pittsburgh Medical Center, only 46% of patients with potassium levels greater than 6.0 mEq/L had electro-cardiographic changes, and only 55% of patients with potassium levels greater than 6.8 mEq/L had changes consistent with hyperkalemia.2 In fact, there have been several reports in the literature of patients who had potassium levels greater than 7.5 mEq/L with no electrocardiographic manifestations of hyperkalemia.3–5 Even when there is evidence of hyperkalemia on a patient's electrocardiogram, physicians often miss the diagnosis. Wrenn and colleagues6 designed a study to determine the ability of physicians to predict the presence of hyperkalemia solely on the basis of their patients' electrocardiograms. The physicians in this study were able to predict hyperkalemia with a sensitivity of 35% to 43% and a specificity of 85% to 86%. This small study further emphasizes how difficult hyperkalemia can be to diagnose. Nevertheless, hyperkalemia can manifest with classic electrocardiographic changes that suggest its presence.
Potassium and sodium concentrations in the intracellular and extracellular compartments play a vital role in the electrophysiologic function of the myocardium. Concentration gradients are established across the myocyte membrane secondary to very high intracellular potassium concentrations and a relative paucity of potassium ions in the extracellular space. The opposite is true of sodium ions, which are abundant extracellularly and relatively few intracellularly. These concentration gradients are maintained by sodium-potassium adenosine triphosphatase (Na-K ATPase) pumps on the cellular wall, which actively pump sodium out of the myocyte and potassium inward. These concentration gradients establish an electrical potential across the cell membrane, leading to a resting membrane potential of −90mV. The potassium gradient across the cellular membrane is the most important factor in establishing this membrane potential; therefore, any changes in extracellular potassium concentration may have profound effects upon myocyte electrophysiologic function.7 For instance, as potassium levels increase in the extracellular space, the magnitude of the concentration gradient for potassium across the myocyte diminishes, thus decreasing the resting membrane potential (that is, –90 mV to –80 mV; see Fig. 3).
Phase 0 of the action potential occurs when voltage-gated sodium channels open and sodium enters the myocyte down its electrochemical gradient (Fig. 3). The rate of rise of phase 0 of the action potential (Vmax) is directly proportional to the value of the resting membrane potential at the onset of phase 0.7–9 This is because the membrane potential at the onset of depolarization determines the number of sodium channels activated during depolarization, which in turn determines the magnitude of the inward sodium current and the Vmax of the action potential. As illustrated in Figure 4, Vmax is greatest when the resting membrane potential at the onset of the action potential is approximately −75 mV, and does not increase as the membrane potential becomes more negative. Conversely, as the resting membrane potential becomes less negative (that is, −70 mV), as in the setting of hyperkalemia (Fig. 3), the percentage of available sodium channels decreases. This decrease leads to a decrement in the inward sodium current and a concurrent decrease in the Vmax; therefore, as the resting membrane potential becomes less negative in hyperkalemia, Vmax decreases. This decrease in Vmax causes a slow-ing of impulse conduction through the myocardium and a prolongation of membrane depolarization; as a result, the QRS duration is prolonged.
As previously discussed, increasing the extracellular potassium concentration results in a decrease in the resting membrane potential (that is, from −90 mV to −80 mV). In turn, the threshold potential decreases (that is, from −75 mV to −70 mV); this 5-mV decrease, however, is less than the decrease in resting potential. Therefore, the difference between the resting and threshold potentials decreases to approximately 10 mV (as opposed to 15 mV in a physiologic milieu). As potassium levels increase further, the resting membrane potential continues to become less negative, and thus progressively decreases Vmax. The changes in threshold potential now parallel the changes in resting potential, and the difference between the two reaches a constant value of approximately 15 mV. The decrease in Vmax levels causes a slowing of myocardial conduction, manifested by progressive prolongation of the P wave, PR interval, and QRS complex. In summary, the early effect of mild hyperkalemia on myocyte function is to increase myocyte excitability by shifting the resting membrane potential to a less negative value and thus closer to threshold potential; but as potassium levels continue to rise, myocyte depression occurs and Vmax continues to decrease.
Hyperkalemia also has profound effects upon phase 2 and phase 3 of the action potential. After the rapid influx of sodium across the cell membrane in phase 0, potassium ions leave the cell along its electrochemical gradient, which is reflected in phase 1 of the action potential. As the membrane potential reaches −40 to −45 mV during phase 0, calcium channels are stimulated, allowing calcium to enter the myocyte. The maximum conductance of these channels occurs approximately 50 msec after the initiation of phase 0 and is reflected in phase 2 of the action potential.7 During phase 2, potassium efflux and calcium in-flux offset one another so that the electrical charge across the cell membrane remains the same, and the so-called plateau phase of the action potential is created (Fig. 3). During phase 3, the calcium channels close, while the potassium channels continue to conduct potassium out of the cell; in this way, the electronegative membrane potential is restored.7 One of the potassium currents (Ikr), located on the myocyte cell membrane, is mostly responsible for the potassium efflux seen during phases 2 and 3 of the cardiac action potential.10 For reasons that are not well understood, these Ikr currents are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased so that more potassium leaves the myocyte in any given time period.10 This leads to an increase in the slope of phases 2 and 3 of the action potential in patients with hyperkalemia and therefore, to a shortening of the repolarization time. This is thought to be the mechanism responsible for some of the early electrocardiographic manifestations of hyperkalemia, such as ST-T segment depression, peaked T waves, and Q-T interval shortening.11,12
In experimental models, there is a very orderly progression of electrocardiographic changes induced by hyperkalemia.13,14 The earliest electrocardiographic manifestation of hyperkalemia is the appearance of narrow-based, peaked T waves. These T waves are of relatively short duration, approximately 150 to 250 msec, which helps distinguish them from the broad-based T waves typically seen in patients with myocardial infarction or intracerebral accidents.7 Peaked T waves are usually seen at potassium concentrations greater than 5.5 mEq/L and are best seen in leads II, III, and V2 through V4, but are present in only 22% of patients with hyperkalemia.8,11,15 It may be that increased myocyte excitability, shortening of the myocyte action potential, and an increase in the slope of phase 2 and 3 of the action potential account for the T wave peaking seen in mild hyperkalemia.11
As serum potassium levels increase to greater than 6.5 mEq/L, the rate of phase 0 of the action potential decreases, leading to a longer action potential and, in turn, a widened QRS complex and prolonged PR interval. Electrophysiologically, this appears as delayed intraventricular and atrioventricular conduction.7,11 As the intraventricular conduction delay worsens, the QRS complex may take on the appearance of a left or right bundle branch block configuration. A clue that these electrocardiographic changes are due to hyperkalemia, and not to bundle branch disease, is that in hyperkalemia the conduction delay persists throughout the QRS complex and not just in the initial or terminal portions, as seen in left and right bundle branch block, respectively.11,16 As potassium levels reach 8 to 9 mEq/L, sinoatrial (SA) node activity may stimulate the ventricles without evidence of atrial activity, producing a sinoventricular rhythm. This occurs because the SA node is less susceptible to the effects of hyperkalemia and can continue to stimulate the ventricles without evidence of atrial electrical activity.11,17 The electrocardiographic manifestations of continued SA node function in the absence of atrial activity may be very similar to those of ventricular tachycardia, given the absence of P waves and a widened QRS complex (Fig 1).
As the hyperkalemia worsens and the potassium levels reach 10 mEq/L, sinoatrial conduction no longer occurs, and passive junctional pacemakers take over the electrical stimulation of the myocardium (accelerated junctional rhythm).11,12,18 If hyperkalemia continues unabated, the QRS complex continues to widen and eventually blends with the T wave, producing the classic sine-wave electrocardiogram. Once this occurs, ventricular fibrillation and asystole are imminent.
In addition to the previously mentioned arrhythmias, many other electrocardiographic abnormalities have been associated with hyperkalemia. In patients with acutely elevated serum potassium levels, a pseudomyocardial infarction pattern has been reported to appear as massive ST-T segment elevation develops secondary to derangements in myocyte repolarization.19–23 Early stages of hyperkalemia may manifest with only shortening of the PR and QT interval.8 Sinus tachycardia and bradycardia, idioventricular rhythm, and 1st-, 2nd-, and 3rd-degree heart block have all been described on the presenting electrocardiograms of patients with hyperkalemia.7 Given the vast array of electrocardiographic manifestations of hyperkalemia, the difficulty in consistently identifying hyperkalemia on the basis of electrocardiographic abnormalities, and the fact that the electrocardiogram during hyperkalemia may progress from normal to that of ventricular tachycardia and asystole precipitously, physicians need to consider this diagnosis in patients at risk.8
Numerous causes of hyperkalemia are seen in clinical practice. The most common are renal disease and the ingestion of medications that predispose the patient to hyperkalemia.2 Medications known to cause hyperkalemia include angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, penicillin G, trimethoprim, spironolactone, succinylcholine, alternative medicines, and heparin, to name just a few.24–30 In their study in a university setting, Acker and colleagues2 reported that 75% of all patients with severe hyperkalemia had renal failure, and 67% were taking a drug that predisposed them to hyperkalemia. Other less common causes of hyperkalemia include massive crushing injury with resultant muscle damage, large burns, high-volume blood transfusions, human immunodeficiency virus infection, and tumor lysis syndrome.8,31–35 In many patients, the cause of hyperka-lemia is multifactorial and never clearly defined.
Although hyperkalemia is one of the deadliest electrolyte abnormalities, it is also one of the most treatable. As previously discussed, the diagnosis of hyperkalemia can be difficult if one relies solely on electrocardiographic criteria. Frequently, physicians must initiate treatment for hyperkalemia on the basis of a patient's clinical scenario (such as a cardiac arrest occurring in a chronic dialysis patient). More commonly, however, the patient is treated when laboratory data become available. Most authorities recommend treatment for hyperkalemia when electrocardiographic changes are present or when serum potassium levels are greater than 6.5 mEq/L, regardless of the electrocardiogram.36,37 The treatment for hyperkalemia can be thought of in 3 distinct steps. First, antagonize the effects of hyperkalemia at the cellular level (membrane stabilization). Second, decrease serum potassium levels by promoting the influx of potassium into cells throughout the body. Third, remove potassium from the body.
The initial treatment of hyperkalemia should be the infusion of calcium. Calcium antagonizes the effects of hyperkalemia at the cellular level through 3 major mechanisms. First, in the setting of hyperkalemia, the resting membrane potential is shifted to a less negative value, that is, from −90 mV to −80 mV, which in turn moves the resting membrane potential closer to the normal threshold potential of −75 mV, resulting in increased myocyte excitability. When calcium is given, the threshold potential shifts to a less negative value (that is, from −75 mV to −65 mV), so that the initial difference between the resting and threshold potentials of 15 mV can be restored.38 For example, if a myocyte has a normal resting membrane potential of −90 mV and a normal threshold potential of −75 mV, then 15 mV of depolarization is required before reaching the threshold potential. In the setting of hyperkalemia, the resting membrane potential may change to a new level (that is, −80 mV), so that now only 5 mV of depolarization must occur before reaching the threshold potential of −75 mV. When calcium is given, the threshold potential becomes less negative (that is, it changes from −75 mV to −65 mV). Thus the difference between the hyperkalemia-induced resting membrane potential of −80 mV and the calcium-induced threshold potential of −65 is now back to 15 mV, and myocyte excitability can return to normal.
Second, it has been shown in animal studies that increasing levels of calcium shift the curve relating Vmax to the resting membrane potential at the onset of action potential upward and to the right (Fig. 5).9 Therefore, at any given level of resting membrane potential, up to approximately −75 mV, the Vmax is increased when high calcium concentrations are present.39 This serves to return myocyte excitability back to normal in the setting of hyperkalemia, where myocyte depolarization is decreased secondary to decreased rates of Vmax.
Finally, in cells with calcium-dependent action potentials, such as SA and atrioventricular nodal cells, and in cells in which the sodium current is depressed, an increase in extracellular calcium concentration will increase the magnitude of the calcium inward current and the Vmax by increasing the electrochemical gradient across the myocyte. This would be expected to speed impulse propagation in such tissues, reversing the myocyte depression seen with severe hyperkalemia.40
The effects of intravenous calcium occur within 1 to 3 minutes but last for only 30 to 60 minutes. Therefore, further, more definitive treatment is needed to lower serum potassium levels. Calcium gluconate is the preferred preparation of intravenous calcium. The dose should be 10 mL of a 10% calcium gluconate solution infused over 2 to 3 minutes. Calcium chloride may also be used but provides about 3 times the amount of calcium per 10-mL dose, so the dose needs to be attenuated accordingly to avoid potential calcium toxicity.36 Because hypercalcemia can potentiate digitalis toxicity, calcium should be used in patients taking digitalis only if there is loss of P waves or a widened QRS complex.8 In this situation, calcium gluconate should be diluted in 100 mL of D5W (dextrose [5%] in water) and infused over 30 minutes.
Promotion of Potassium Influx into Cells. After the administration of calcium, the next goal of treatment is to shift potassium intracellularly. This is most frequently done by giving insulin. Insulin stimulates the Na-K ATPase pump, which moves potassium intracellularly in exchange for sodium in a 2:3 ratio; this effect is independent of insulin's effect on glucose.41 Ten units of intravenous insulin is typically given, followed by close monitoring of serum blood sugar. Fifty mL of 50% dextrose is frequently co-administered with insulin in normoglycemic patients to prevent hypoglycemia. If a patient is already hyperglycemic, supplemental glucose is not needed. The effect of the insulin is seen within 10 to 20 minutes of administration and can be expected to decrease potassium levels by 0.6 to 1.0 mEq/L.36,42,43
Growing evidence suggests that there may be a role for albuterol in the treatment of patients with severe hyperkalemia. Catecholamines activate Na-K ATPase pumps through β2 receptor stimulation in a manner that is additive to the effect of insulin.36,44 In a study by Montoliu and coworkers,41 0.5 mg of intravenous albuterol was given to patients with hyperkalemia, leading to a 1-mEq/L decrease in serum potassium levels with minimal adverse effects.41 Because there are no approved intravenous forms of β agonists available in the United States, studies have been performed to determine whether nebulized β agonists would have a similar effect on serum potassium levels. One such study found that albuterol, when given in very high doses (10–20 mg vs the normal 0.5 mg), decreased potassium levels by 0.62 to 0.98 mEq/L.45 The onset of action for inhaled albuterol was immediate and lasted for 1 to 2 hours. Although in these studies the effects varied among individuals, β2 agonist administration was found to be safe and was associated with a significant decrease in serum potassium levels. Therefore, β2 agonist therapy should be considered as an adjunctive treatment for patients with severe hyperkalemia.
Sodium bicarbonate infusion can shift potassium from the extracellular to intracellular space by increasing blood pH. However, routine bicarbonate therapy for the treatment of hyperkalemia is controversial.36,46–49 In a study by Blumberg and associates,50 12 dialysis patients with potassium levels of 5.25 to 8.15 mEq/L received 390 mmol of intravenous sodium bicarbonate over a 6-hour period. No change in potassium levels was seen until 4 hours after drug administration, when a decrease of 0.7 mEq/L was noted; at 6 hours, however, the decrease in potassi-um level was only 0.35 mEq/L.50 Due to the lack of a quick or sustained decrement in potassium levels, physicians should reserve the use of intravenous sodium bicarbonate for situations wherein severe acidemia is present or there is another indication for its administration (such as phenobarbital or tricyclic antidepressant overdose).
The final task in treating patients with severe hyperkalemia is to remove potassium from the patient's body. The quickest, most efficient way to do this is through the use of hemodialysis.42 In 1970, Morgan and colleagues51 reported the removal of 48 mEq/L of potassium using a Kiil dialyzer over a 10-hour period; others confirmed these findings.52,53 Because of the time, expense, and invasive nature of hemodialysis therapy, it is rarely used as a 1st-line treatment for hyperkalemia unless a patient is already on dialysis and has life-threatening hyperkalemia. For most patients, treatment with an exchange resin such as sodium polystyrene sulfonate is more appropriate.
Ion exchange resins can be administered orally or rectally and work by exchanging gut cations, most importantly potassium, for sodium ions that are released from the resin. Most studies have found exchange resins to decrease serum potassium levels by about 1 mEq/L over a 24-hour period.54 It should be emphasized that the extended time required for exchange resins to work exclude their use in the emergent treatment of hyperkalemia. Exchange resins can cause significant constipation and are typically given in combination with a laxative such as sorbitol. Not only does a laxative prevent constipation, but it also promotes the elimination of potassium from the gut once it binds to the resin. Although generally safe, the combination of a resin and sorbitol has been reported to cause intestinal necrosis, and as such should be used cautiously and only when necessary.36,55,56
As our case presentation illustrates, hyperkalemia can be very challenging to diagnose. Patients with severe hyperkalemia frequently have normal electrocardiograms or electrocardiographic abnormalities that are difficult to attribute to hyperkalemia. The diagnosis of hyperkalemia must be considered in any patient with clinical risk factors that would predispose them to its development. Most commonly, patients with hyperkalemia have underlying renal dysfunction or are taking a medication known to increase serum potassium concentrations. The treatment of hyperkalemia must be swift and appropriate to prevent the development of fatal cardiac arrhythmias. If a patient has electrocardiographic evidence of hyperkalemia, or the potassium level is greater than 6.5 mEq/L, the 1st drug to be administered should be calcium, because of its rapid onset of action and ability to stabilize myocyte electrical activity. Insulin, with or without glucose, and β2 agonists should then be quickly administered to decrease extracellular potassium levels. Exchange resins and hemodialysis are then used, in the appropriate clinical settings, to decrease systemic potassium levels. Sodium bicarbonate therapy has little use in the routine treatment of hyperkalemia unless severe metabolic acidosis is present. Finally, and as a matter of course, physicians should perform a thorough search to identify the cause of the hyperkalemia in their patient in order to prevent a recurrence.
Address for reprints: Walter A. Parham, MD, St. Louis University School of Medicine, Department of Internal Medicine, Division of Cardiology, 3635 Vista Ave., FDT 13, St. Louis, MO 63110