Hypokalemia in Diabetes Mellitus Setting Ⅲ

3. Symptoms, Exams, and Diagnosis of Hypokalemia 

As the ion K+ plays a large role in the physiology of various tissues, organs, and systems, its deficiency can lead to changes in cardiovascular functioning, skeletal muscles, the kidneys, and even in the release and effect of certain hormones [10]. The direct correlation between K+ levels and the appearance of signs and symptoms is not linear, depending on intrinsic factors and the clinical status of each individual, highlighting diabetic patients, in which it may vary according to both K+ levels and the presence of other pre-existing comorbidities. Nevertheless, mild hypokalemia can be often asymptomatic [40]. Although chronic or persistent hypokalemia may be asymptomatic in some individuals, patients with DM may have this condition worsened by diarrhea or vomiting, which can occur during acute complications of DM. Nocturia and polyuria can also be exacerbated, especially in individuals predisposed to persistent hypokalemia, as in Bartter and Gitelman syndromes. Hypokalemia-induced polyuria is related to an impairment of vasopressin action in collecting ducts. In addition, insulin treatment can also promote K+ shift into cells. Therefore, hypokalemia can have worse consequences in diabetic patients, which puts these individuals at greater risk of chronic hypokalemia. In this group of patients, cardiovascular diseases are found more often, making them more vulnerable to cardiac arrhythmias, fluid depletion, and worsening neuropathy from muscle weakness [41,42]. To note, KATP channels may not function properly in the DM setting because their expression is reduced in myocardium cells and aortic smooth muscle cells, resulting in impaired heart and vascular function [43]. Consequently, hypokalemia may affect the membrane potential and pose a decreased response to stress conditions, such as hypoxia and oxidative stress. Importantly, as hypokalemia may lead to hyperglycemia due to the impairment of insulin secretion and peripheral glucose utilization, a vicious circle is triggered where hypokalemia worsens glucose control and vice-versa.

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NEW HERBAL FORMULATION FOR  HYPOKALEMIA

3.1. Cardiovascular Effects 

The main cardiovascular changes caused by hypokalemia are cardiac arrhythmias [10]. Low K+ concentration increases cardiac muscle excitability and delays its repolarization, which can induce both atrial and ventricular arrhythmias [44]. The most commonly observed ECG changes are shown in Figure 2, which include T wave flattening, ST-T segment depression, an extension of the QT interval [44], the presence of U waves, and multiple ventricular extrasystoles, which can be seen in up to 20% of patients with severe hypokalemia (>2.6 mmol/L) [_bookmark3138]. Patients at greatest risk for developing life-threatening arrhythmias are the elderly or those with underlying ischemic heart disease. Hypertensive patients using hydrochlorothiazide seem to have a higher risk for the incidence of sudden death [10]. The main serious arrhythmias induced by hypokalemia are ventricular fibrillation, ventricular tachycardia, and torsades des pointes. 

Figure 2. Drawing of an ECG showing the main changes during hypokalemia: Extension of QT interval, T wave flattening with ST-T depression, and U waves. 

3.2. Muscular Effects 

In contrast to cardiac musculature, hypokalemia can induce hyperpolarization of skeletal muscle, compromising its ability to depolarize and contract. Additionally, dehydration (e.g., during diabetic ketoacidosis) can reduce blood supply to the musculature and induce rhabdomyolysis. Together, these processes can lead to muscle weakness and fatigue. In severe cases, hypokalemia can cause respiratory muscle weakness and even lead to respiratory acidosis [44]. 3.3. Kidney Effects The most common renal complication of hypokalemia is metabolic alkalosis, which can occur through multiple pathways: The low serum K+ concentration promotes H+ secretion through the H+ -K+ -ATPase pump in the collecting ducts. Furthermore, it stimulates the absorption of HCO3 − in the proximal tubule, NH4+ synthesis, and reduction in urinary citrate secretion. Another effect of hypokalemia in the kidneys is the impairment of the urinary concentration capacity, apparently through defective activation of the enzyme adenylate cyclase in the tubular cells of the distal nephron, preventing the activity of the antidiuretic hormone. In addition, fluid intake is stimulated due to an increase in the level of angiotensin II in the central nervous system. This hypokalemic-induced nephrogenic diabetes insipidus can lead to polyuria, with loss of up to 3 L of water per day. When associated with hyperaldosteronism, hypokalemia can also lead to cystic kidney disease, originating from the collecting duct epithelium [10]. 3.4. Hormonal Effects In diabetic patients, the effects of low K+ concentration on insulin have great importance. Hypokalemia leads to both a reduction in pancreatic insulin release and its activity in target cells. The combination of these effects can worsen hyperglycemia and diabetic control [44], having devastating effects on individuals in DKA or HHS states. 

3.5. Diagnosis of Hypokalemia 

In the presence of the aforementioned signs and symptoms and after the identification of serum K+ < 3 mmol/L, it is important to perform a sequential analysis of the possible causes and mechanisms behind hypokalemia. The first step is to assess any possible renal K + losses, differentiating them from possible gastrointestinal losses. Some measurements can be used to identify whether the causes are of renal or extrarenal origin, such as the trans tubular potassium gradient (TTKG), the urinary potassium excretion fraction, or the potassium value obtained in an isolated urine sample, which can be normalized by creatinine (K/Cr ratio) [45]. It is important to keep in mind that each of these measurements has its due limitations, for example, not very sensitive to losses due to mineralocorticoid activity. Additionally, because they are fixed values, they can be influenced by other variables, such as volume and electrolyte intake, urinary flow, and GFR. Furthermore, TTKG is more sensitive in detecting inappropriate K+ secretion in hyperkalemia [44]. 

3.5.1. Fractional Excretion of Potassium (FEK)

If a urine creatinine measurement is not available, one can often use the UK alone, in a random urine specimen, to differentiate between renal and extrarenal causes of hy hypokalemia: UK > 20 mEq/L suggests a renal etiology, whereas UK < 20 mEq/L suggests extrarenal etiology.

3.5.2. Transtubular Potassium Gradient (TTKG)

The trans tubular potassium gradient estimates the potassium gradient between the urine and the blood in the distal nephron. TTKG is a measurement of net K+secretion by the distal nephron, after correcting for changes in urine osmolality. In a normal individual under normal circumstances, the TTKG is about 6 to 12. 

UK: Urinary potassium; UOsm: Urinary osmolality; POsm: Plasma osmolality; PK: Plasmatic potassium; UCr: Urinary Creatinine.

In the hypokalemia setting, a high TTKG suggests excessive renal K+ losses, whereas hypokalemia with a low TTKG suggests an extrarenal etiology. The Uosm/Posm term is included to correct for the rise in the UK that is due purely to water abstraction and concentration of the urine. Several factors limit the utility of the FEK and TTKG in the differential diagnosis of K+ disorders, so the FEK and TTKG are increased when K+ intake is increased, and they are decreased when K+ intake is decreased. In patients with kidney function impairment, there is an adaptive increase in K+ excretion per functioning nephron, and FEK and TTKG may increase accordingly. Figure 3 describes a flowchart to guide the etiological diagnosis of hypokalemia. 

Figure 3. Hypokalemia diagnostic flowchart. UK: Urinary Potassium; TTKG: Transtubular Potassium Gradient; UCr: Urinary Creatinine; BP: Blood Pressure; DKA: Diabetic Ketoacidosis; PAldosterone: Plasmatic Aldosterone; PRA: Plasmatic Renin Activity; RTA: Renal Tubular Acidosis; UCl−: Urinary Chloride. 

3.6. Management of Hypokalemia

For the optimal treatment of hypokalemia, it is necessary that underlying causes have already been identified and associated disorders are being managed. Significant potassium losses, for example, due to vomiting, diarrhea, or excessive diuresis, need to be ceased. In most cases, K+ disturbances are accompanied by acid-base disturbances, and, for this reason, the acid-base status should be constantly monitored [44]. If metabolic acidosis is present, for example, due to diabetic ketoacidosis or type I tubular acidosis, correction of hypokalemia should be performed before administration of bicarbonate. Before starting K+ replacement, hypomagnesemia, if present, should be promptly corrected with intravenous administration of magnesium sulfate, as Mg2+ deficiency may prevent the correction of hypokalemia [40]. The next step is the administration of K+, which can be achieved orally (in liquid or tablet form), or intravenously (KCl solution is the most frequent). 

The amount of potassium that should be administered depends on the total K+ deficit, which can be calculated based on the serum potassium concentration. A commonly used equation is: 

Kde f it: Serum potassium deficit (in mmol); Klower limit∗ : Serum potassium lower limit under normal conditions; Kmeasured: Serum potassium measured concentration; Weight (Kg): Bodyweight (in Kilograms). * Potassium's normal lower limit ranges from 3.0 to 3.5 mmol/L. Without any stimulus for transcellular shifts, a 0.1 mmol/L reduction in K+ concentration, on average, equates to a total body deficit of approximately 35 mmol. 

If the replacement route of choice is intravenous, the potassium administration rate should not exceed 20 mmol/h (increases the serum K+ by about 0.25 mmol/L), to avoid the onset of hyperkalemia, and in cases of associated periodic paralysis hypokalemia, this rate should not exceed 10 mmol/h, due to a spontaneous improvement in these conditions [44].

If faster replacement is required, 20 or 40 mmol/h can be given via a central venous catheter due to the risk of phlebitis if a peripheral vein is cannulated for this purpose. Importantly, continuous ECG monitoring should be used under these circumstances. In DKA and HHS, serum K+ can be normal or elevated on admission despite total body K+ depletion, which is more severe in HHS compared to DKA (Table 1) [13,36]. Osmotic-induced intracellular dehydration results in K+ efflux from the cells. Since insulin causes a shift of K+ into the cell, via an indirect effect on Na+ -K+ ATPase, one should correct the K+ level to >3.3 mEq/L before starting insulin therapy. In that case, insulin must be held. If K+ is between 3.3 and 5.3 mEq/L, 20–30 mEq of K+ should be given in each liter of intravenous fluid to keep serum K+ between 4 to 5 mEq/L [37]. Potassium should be monitored if >5.3 mEq/L. Magnesium should be checked and given intravenously whether necessary, as this approach is important to prevent renal wasting of K+ with exacerbation of hypokalemia. Routine administration of phosphate is not recommended. However, careful phosphate replacement can be considered in patients with very low levels (<1 mEq/L) due to the risk of cardiac dysfunction or respiratory distress [46].

In the DKA setting, major guidelines for K+ replacement emphasize the importance of blood gas and renal function tests for profiling replacement [47–50]. Initial rehabilitation with saline solution is recommended until serum K+ levels normalize. Insulin should be withheld if blood K+ is below 3.3 mmol/L to avoid insulin-induced hypokalemia [46].

There are four main types of potassium-containing preparations: potassium chloride (KCl), potassium bicarbonate, potassium citrate, and potassium phosphate. Potassium phosphate solution is particularly useful when hypophosphatemia is associated, and citrate or bicarbonate solutions, when acidosis is installed [40]. In most situations, however, the solution of choice is potassium chloride. An adverse effect of oral KCl tablets (usually containing 8 mmol K+ ) is the irritation of the gastrointestinal tract mucosa, which can even lead to ulcerations or bleeding. For this reason, tablet ingestion must be accompanied by a large volume of fluid. The use of potassium-sparing diuretics during K+ replacement treatment can ease the onset of hyperkalemia, especially in diabetic patients with reduced GFR, using non-steroidal anti-inflammatory drugs, ACEi, or ARBs [44]. An interesting approach in diabetic patients prone to hypokalemia is to encourage the intake of potassium-rich foods, such as bananas, tomatoes, lentils, nuts, fish meat, etc., always keeping in mind the glycemic load of each item.

4. Conclusions

indicated and K+ intake should be addressed.

Funding: This work was supported by grants from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo/São Paulo Research Foundation; No. 2021/02216-7) and EFSD (European Foundation for the Study of Diabetes)/Sanofi to Rangel, É.B.R.

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