Treatment Strategies of Hypokalemia in Heart Failure

Abstract

Sudden cardiac death is estimated to affect approximately three million people worldwide each year. Substrates and triggers often play a complex role in these deaths. Among the heart cells, disturbed potassium homeostasis is one such trigger. Hypokalemia and transient drops in potassium concentration are significant issues. Heart failure (HF) therapy is increasingly complicated by maintaining normal serum potassium (K+) homeostasis. As a result of the use of loop diuretics hypokalemia has become a severe and feared side effect of treatment. Hypokalemia in HF also indicates greater neurohormonal activity and progression of disease. Personalized drug use and monitoring of electrolytes are crucial for successful treatment. The lowest dose of diuretic necessary to maintain euvolemia should be prescribed to HF patients with symptoms (New York Heart Association Class III-IV). Aldosterone receptor antagonists, spironolactone can be used to treat mild hypokalemia. For more severe, K + supplement is recommended. Levels should be routinely monitored and kept between 4.0 and 5.5 mEq/l.

INTRODUCTION

Potassium (K+) is the primary intracellular cations critical for all living cells. The optimal level lies between 3.5 and 5 mEq/L. Hypokalemia refers to the serum potassium concentration below 3.5 mmol/L, result from excessive potassium losses from the gut, renal and transcellular shifts.[¹] Almost 20% of hospitalized patients suffer from hypokalemia, especially with heart failure (HF) and multi-organ failure.[^1,2,3] Increasing the transmembrane potential of myocardial cells cause them to hyperpolarize and become more excitable with low potassium levels and leads to higher risk of ventricular arrhythmia, resulting in sudden cardiac death. Raised level may be particularly relevant for HF patients with structural heart disease.[³] Drugs particularly loop diuretics are known to cause hypokalemia, despite the presence of inhibitors of renin-angiotensin-aldosterone system (RAAS) system.[⁴]

Furosemide, the potent diuretic used to treat HF and edema. Loop diuretics, like furosemide, cause potassium loss in the urine, potassium depletion, increased mortality through mechanisms such as ventricular ectopy.[^5,6] The 2000 National Council on Potassium in Clinical Practice recommends routinely considering potassium supplementation to treat hypertension in patients on a potassium diuretic that does not spare the kidneys, as well as HF in patients with normal potassium levels.[⁷] It is also essential to routinely monitor potassium levels and to administer potassium supplements through oral or parenteral routes to maintain the optimum levels.[⁸] Mineralocorticoids have been shown to decrease mortality and hospitalizations associated with HF and myocardial infarction.[⁹]

POTASSIUM HEMOSTASIS

Physiology of potassium homeostasis

Potassium role in cellular functions

Potassium plays a vital role in the regulation of normal cell function.[¹⁰] Since potassium is the dominant intracellular cation, almost all cells have the pump called “Na+[FIGURE DASH]K+[FIGURE DASH]ATPase”, which pumps sodium out of the cell and potassium into the cell leading to K + gradient across the membrane and is partially responsible for maintaining the potential difference across the membrane. Many cell functions rely on this potential difference, such as nerve and muscle. Potassium is present at a concentration of 4 mEq/L and 2% of K + exists in the extracellular fluid (ECF).[¹¹] Cell division and growth as well as enzyme activities are catalyzed by potassium and are affected by its alterations and concentrations.

Intracellular K + also participates in regulating acid-base balance through the exchange for extracellular hydrogen ions (H+).[¹²] Disruption of potassium balance leads to disruption of normal electrical conduction of the heart, dysrhythmias, and even sudden death.[¹³]

Potassium balance

The kidney is responsible for maintaining homeostasis for K +. The intake of potassium equals the excretion of potassium in the steady-state. Hence, K + concentration in extracellular space should be regulated since it can enter or exit skeletal muscles. Thus, this prevents extracellular K + concentration shifts. Insulin and catecholamines regulate the movement of potassium.[¹⁴]

Catecholamines exert the same effect by activating β² receptors and by activating the Na+[FIGURE DASH]K+[FIGURE DASH]ATPase pump. Insulin shifts cellular K + via the Na+[FIGURE DASH]K+[FIGURE DASH]ATPase pump. The effect of mineral acidosis on the Na+/H + exchanger in skeletal muscles causes potassium to exit the cells and increase extracellular K + levels.[¹⁵] The distribution of potassium had a minimal effect on organic acidosis and respiratory acidosis. Osmolality rises because water moves from the cells to the extracellular space and subsequent efflux of K + increases extracellular K +.[¹⁶]

Classification of hypokalemia

Hypokalemia is a common electrolyte imbalance that occurs in patients who are on diuretic therapy. Various stages of hypokalemia and their distinguishing symptoms are described in [Table 1].[¹⁹] It has been estimated that around 50% of patients who receive diuretics have plasma concentrations <3.5 mEq/L. Patients with a history of heart disease are prone to have an electrolyte abnormality and are associated with the worst clinical outcomes and mortality rate.

Table 1: Severity, levels, and symptoms of hypokalemia

Etiopathophysiology of hypokalemia in heart failure

One of the major challenges in patients with HF is the maintenance of electrolyte imbalances. Diuretic therapy can lower serum potassium levels, resulting in complications such as ventricular arrhythmias and slowly changing dimension.[^17,18]

The principal causes of hypokalemia in patients diagnosed with HF are the use of drugs to reduce congestion (diuretics) and the activation of the RAAS that causes loss of K + through urine. HF leads to an intracellular shift in K + with catecholamines, while volume overload causes dilutional effects.[²⁰]

Hypokalemia interferes with the polarity of the cell. It causes cellular hyperpolarized, increased resting potential accelerates depolarization, and increases automaticity and excitability. As cardiac repolarization is dependent on K + influx, hypokalemia leads to a longer action potential duration as well as a larger QT dispersion indicating electrical inhomogeneity in the myocardium. Most HF patients have increased ventricular ectopy, and about 50% exhibit nonsustained ventricular tachycardia. A total of 50% of cardiac deaths are sudden and unexpected, presumably due to arrhythmias. Myocardial potassium levels are significantly lower in victims of sudden cardiac death than in controls, and survivors are often hypokalemic. The all-cause and cardiac mortality rates are higher in those taking non-K +[FIGURE DASH]sparing diuretics for HF. The incidence of death due to arrhythmia is significantly and independently related to the use of non-K +[FIGURE DASH]sparing diuretics. Additionally, hypokalemia predisposes a patient to digoxin toxicity by decreasing renal clearance and encouraging myocardial binding of the drug. This, in turn, produces increased automaticity and ventricular arrhythmias. K + depletion exacerbates diastolic dysfunction in animal and human models.[²¹]

TREATMENT OF HYPOKALEMIA IN HEART FAILURE

When selecting a suitable pharmacotherapy to normalize potassium, we must consider five factors:

1. The patient's usual baseline potassium concentration.
2. Other medical conditions that affect potassium balance.
3. Medications used for other comorbid conditions which may affect potassium balance.
4. The patient's dietary and salt intake
5. The ability of the patient to comply with the therapeutic drug regime.

The only way to detect hypokalemia is through routine blood tests. It is essential to monitor patients during treatment, as potassium supplements can cause hyperkalemia in hospitalized patients.[²²] Because serum potassium concentration drops approximately 0.3 mEq/L (0.3 mmol/L) for every 100-mEq (100-mmol) reduction in total body potassium, Similarly, a decrease in serum potassium of 3.8 mEq (3.8 mmol)/L roughly corresponds to a reduction of 300 mEq (300 mmol) in total body potassium. Concomitant hypomagnesemia should be corrected concurrently to avoid the progression of preexisting hypokalemia.[²³]

HF is one of the global pandemics affecting up to 37.7 million people worldwide,[²⁴] with a prevalence data of approximately 1%–2% of the adult population in developed countries, rising to more than 10% among people older than 70 years of age. Constipation, muscle weakness, and worsening ectopy are signs that one should be concerned about. Arrhythmias of higher grades could also be symptoms. In congestive HF, even mild hypokalemia may worsen ventricular arrhythmias.[²⁵]

Diuretics remain the mainstay of pharmacological therapy for HF. The dose of diuretics used commonly in HF is given in Table 2. In addition to diuretics, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors, and angiotensin II-receptor blockers often affects the serum potassium HF patients. Among these Diuretic use is the critical cause of hypokalemia, and HF patients with chronic kidney disease (CKD) are more likely to use diuretics.[²⁶]

Table 2: Dose of diuretics used in heart failure

Low serum potassium is associated with a poor outcome in patients with HF. Further in patients with chronic HF, decreased serum potassium may also lead to sudden cardiac death.[²⁷]

Serum potassium concentrations were lower and potassium supplementation was imperative in patients taking diuretics for HF. Routine use of diuretics, the intensity of diuretic therapy, and neurohumoral activation, renal function are well known to influence serum potassium concentrations, among HF patients contributing to the increased risk of ventricular arrhythmias and cardiac death in HF, hence, the need for potassium supplementation is essential Figure 1 represents the General principles of hypokalemia management

Figure 1: General principles of hypokalemia management. In many cases of hypokalemia, these steps should be helpful, although clinical judgment should be exercised based on the individual patient's circumstances. Generally, it is not recommended to check serum potassium concentration until 1 h after an intravenous dose has been given (2 h after an oral dose). Whenever possible, oral potassium preparations should be used in place of intravenous potassium, except in the urgent cases listed above. Particularly in patients with kidney and cardiac diseases, potassium levels should be carefully monitored. Abbreviation: KCl, potassium chloride

In patients receiving a loop diuretic, empirical supplementation of potassium may contribute to improved survival; with the increase in diuretic dose, the degree of benefit also increases. Mortality was about 9%/year, especially in those receiving higher doses of furosemide.[⁵] In addition to that salt, substitutes are available to correct diuretic-induced hypokalemia in hospitalized patients. Compared to prescription potassium supplements, salt substitutes are an effective, safe, and economical alternative.[²⁸] The route of administration of potassium depends on the severity of the hypokalemia.[²⁸] Table 3 represents the correction of hypokalemia in HF patients.

Table 3: Correction of hypokalemia in heart failure patients

In euvolemic patients with New York Heart Association (NYHA) Class I and II, diuretics should be avoided and should be administered with the appropriate neurohormonal blockade. In the case of patients with NYHA Class III and IV with symptoms of fluid overload, who must be treated with diuretics, mineralocorticoid receptor antagonist-spironolactone may be used to antagonize the aldosterone effects and also to prevent hypokalemia. Also in those patients, carefully monitoring serum potassium levels is essential to avoid the incidence of hyperkalemia.[^29,30]

Intravenous (i.v.) potassium should be given, if potassium levels are < 2.5 mEq/L, with close follow-up, continuous monitoring of electrocardiography (ECG), and potassium levels. The iv. route should also be a precise choice in patients with severe nausea, vomiting, or abdominal distress. with close follow-up, continuous ECG monitoring, and serial potassium levels measurements. The IV route is also a better choice in patients with severe nausea, vomiting, or abdominal distress.[³¹] Most patients are treated with potassium chloride (KCl) [Table 4].[³²]

Table 4: Comparison of different potassium salts

Patients unable to take oral medications or those with significant deficits of K + may require intravenously administered K +. In these cases, K + is given intravenously to prevent cardiac arrhythmias, respiratory paralysis, and rhabdomyolysis. KCl must be administered intravenously at a rate not exceeding 20 mEq/h and a concentration not exceeding 40 mEq/L. Excessive concentrations can cause phlebitis. Patients who are academic should take K + before HCO3. Because correction of metabolic acidosis will shift intracellular K + levels, consequently, ECF concentration decreases further. Combined administration of HCO3 and K + can be used to treat metabolic acidosis after the patient is stabilized. The administration of IV K + during severe manifestations, such as paralysis and respiratory failure, must be done with a solution containing no sugar (due to insulin counter-regulation) or HCO3 (to avoid rapid shifts into the intracellular compartment). Potassium supplements should be taken by mouth whenever possible. Potassium can be supplemented orally with three salts: chloride, phosphate, and bicarbonate. Tablets and liquid forms of potassium chloride are available [Table 5]. Liquid potassium chloride is usually inexpensive; however, patient compliance can be poor because of their strong, disagreeable taste.[³³]

Table 5: Differentiation of available potassium supplements

Potassium-sparing diuretic therapy is an alternative to exogenous potassium supplementation in patients receiving concomitant potassium-depleting drugs (e.g., diuretics or amphotericin B). The examples of potassium-sparing diuretics are mentioned in Table 6.[^34,35]

Table 6: Potassium-sparing diuretics

Use of finerenone in heart failure patients with hypokalemia

Using a steroidal mineralocorticoid antagonist (eplerenone, spironolactone, etc.) can greatly improve the prognosis and quality of life of patients with HF, reduce hospitalizations, and lower deaths.[^36,37,38]

Nonetheless, mineralocorticoid antagonists have low selectivity and may result in increased serum potassium,[^39,40] male breast growth, female menstrual disorders,[⁴¹] and other adverse effects[⁴²] that limit their clinical use. BAY 94-8862 (finerenone), a nonsteroidal mineralocorticoid antagonist developed by Bayer Company of Germany, is currently in Phase III clinical trials. The pharmacophore's selectivity is better than spironolactone, and its affinity is better than eplerenone. According to studies, finerenone is highly selective for the mineralocorticoid receptor (MR), and its half-maximal inhibitory concentration was only 17.8 nmol/L (spironolactone IC50 = 24.2 nmol/L, eplerenone IC50 = 990 nmol/L). It has a much higher selectivity for MRs (>500 folds) than for glucocorticoid receptors, androgen receptors, and progesterone receptors.[⁴³]

The nonsteroidal selective MRA finerenone showed efficacy in delaying the progression of CKD in patients with CKD and Type 2 diabetes mellitus as well as reducing cardiovascular events in patients with CKD and diabetes mellitus.[⁴⁴]

Among its target tissues and cells are the heart, kidneys, blood vessels, and immune cells, where Finerenone binds to the MR. It blocks the effects of the MR's natural hormone ligands, aldosterone and cortisol. MR blockade at the collecting duct and distal nephron in the kidneys has beneficial effects on inflammation and fibrosis, as well as reducing sodium reabsorption and consequently decreasing potassium excretion into the urine. Due to this, finerenone cannot be used without causing serum potassium levels to increase.[^45,46]

The effects of finerenone on blood potassium and estimated glomerular filtration rate are less unfavorable than those of spironolactone and eplerenone. Perhaps this is primarily due to the distinct differences in their pharmacological properties in metabolism and tissue distribution. The finerenone concentration in the heart and kidneys is the same, but eplerenone levels in the kidneys are at least three times higher. This may explain why finerenone induces hyperkalemia at a lower rate than spironolactone at a relatively low dose, and why the cardiac effect of finerenone is low at lower doses.[⁴⁷]

PREVENTION OF HYPOKALEMIA IN HEART FAILURE

Proper monitoring during treatment is crucial as supplemental potassium is a common cause of hyperkalemia in hospitalized patients.[²²] Diuretics and gastric drainage can be used to prevent potassium depletion. Potassium depletion can be avoided by preventing metabolic alkalosis in these settings, where profound potassium depletion is almost exclusively the result of alkalosis. In order to prevent developing a chloride deficit, special attention must be paid to providing a sufficient supply of chloride to these patients. In most cases, potassium chloride will be given. It is necessary to reexamine the need for diuretics in patients with diuretic-induced hypokalemia. Sodium intake should be assessed if continuous use is necessary. Diabetic-induced hypokalemia may be exacerbated by excessive sodium intake. A potassium-sparing diuretic such as amiloride, triamterene, or spironolactone can also be used to prevent potassium deficiency and alkalosis that accompany diuretic therapy in edematous patients. In addition to beta-blockers or angiotensin-converting enzyme inhibitors, other health conditions may warrant their use to maintain potassium levels. H2 receptor blockers and proton pump inhibitors can prevent both alkalosis and potassium deficiency in patients undergoing gastric drainage. By raising the pH of gastric fluid to 3 or 4, significant acid loss is avoided, as well as the development of alkalosis and potassium depletion.[⁴⁸]

CONCLUSION

In light of the fact that plasma potassium dynamics and hypokalemia are common, it may be beneficial to pay more attention to hypokalemia and maintain a plasma potassium level within the ideal range. Dyskalemia can be life-threatening if not adequately managed, directly or indirectly through the provision of optimal medical care. In patients taking nonpotassium-sparing diuretics, beta-adrenoreceptor agonists, or insulin, it is crucial to distinguish between HF, arrhythmia, and hypertension. It is essential that patients with HF have their serum potassium levels checked regularly, and they should have a level between 4 and 5 mEq/L.

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Conflicts of interest

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