Controversial issues in the treatment of hyperkalaemia

Kamel S. Kamel1 and Charles Wei2

1Renal Division, St Michael’s Hospital, University of Toronto, Toronto and 2Renal Division, Lakeridge Health Corporation, Oshawa, Canada

Correspondence and offprint requests to: K. S. Kamel, MD, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. Email: kamel.kamel{at}utoronto.ca

Keywords: ß2-adrenergic agents; cation-exchange resins; hyperkalaemia; insulin; sodium bicarbonate; treatment

Introduction

Hyperkalaemia is a frequent medical emergency that can cause life-threatening cardiac arrhythmias [1]. Its management remains controversial [2]. We shall examine the clinical evidence for therapies used to induce a shift of potassium (K+) into cells and the role of cation-exchange resins.

Insulin

Several clinical studies support the use of insulin for the treatment of acute hyperkalaemia in patients with end-stage renal disease (ESRD) [37]. Blumberg et al. [3] showed that the administration of close to 20 units of regular insulin with glucose caused the plasma potassium (PK) to fall rapidly; a drop of close to 1 mM was observed at 60 min. Supraphysiological levels of insulin in plasma are required for maximal K+ shift. Hypoglycaemia is a frequent complication [3]. Supplementary parenteral glucose and blood glucose monitoring are essential.

Although some advocate treating non-diabetic hyperkalaemic patients with glucose without insulin, we feel that this is unwise because the high levels of insulin required might not be achieved. Also, hypertonic glucose may cause K+ to shift out of cells in patients with inadequate insulin reserves, leading to a rise in PK [8].

ß2-adrenergic agonists

The ability of ß2-adrenergic stimulation to lower PK in patients with ESRD has been demonstrated [4,6,914]. Allon et al. [12] treated patients on haemodialysis who had hyperkalaemia with 10 or 20 mg of nebulized albuterol or placebo on three separate occasions. The administration of albuterol caused a decrease in PK within 30 min and the effect was sustained for at least 2 h. The mean maximum decrease in PK was 0.6 mM with the 10 mg dose and 1.0 mM with 20 mg. Two out of the 10 patients studied were resistant to the hypokalaemic effects of albuterol. There was a minimal increase in heart rate and a notable absence of cardiovascular side effects.

Nonetheless, we have reservations about the use of ß2 agonists as a first-line therapy in emergency treatment of hyperkalaemia. First, 20–40% of patients studied have a decline in PK of <0.5 mM and it is not possible to predict who will fail to respond. Secondly, there are safety concerns because the doses used are 4–8 times those prescribed for the treatment of acute asthma. Although no severe adverse events were reported, most of these studies were performed in stable patients. Some of these studies excluded patients on ß-blockers and those with significant coronary heart disease or unstable heart rhythms. Therefore, the safety of these agents was determined in a group of patients that may not resemble the general ESRD population.

Allon and Copkney [4] examined whether the effect of nebulized ß2 agonists is additive to that of insulin. There was a similar decrease in PK with insulin (0.65 mM) or albuterol (0.66 mM). There was a substantially greater fall in PK with the combined regimen (1.2 mM). The dose of intravenous regular insulin used in this study was only 10 units, and PK fell less than in studies when higher doses of insulin were used [3]. Thus, it remains uncertain whether ß2 agonists would have a PK-lowering effect additive to that of insulin if insulin were given at the higher doses.

NaHCO3

The administration of NaHCO3 decreases the concentration of H+ in the extracellular fluid (ECF) compartment. In theory, if the Na+/H+ exchanger (NHE) were in an active mode, and if the administration of NaHCO3 were to favour the movement of H+ out of cells via the NHE, more Na+ would enter the cell in an electroneutral manner. The subsequent electrogenic exit of Na+ via the Na-K-ATPase would render the cell interior voltage more negative and allow a shift of K+ into the cell [15]. It appears that the NHE is normally inactive because the concentrations of its substrates [Na+ in the ECF compartment and H+ in the intracellular fluid (ICF) compartment] are considerably lower than that of its products (Na+ in the ICF compartment and H+ in the ECF compartment) in steady state. A major activator of the NHE is intracellular acidosis.

Several studies have found NaHCO3 therapy to be ineffective in the acute treatment of hyperkalaemia [3,16,17]. Blumberg et al. [3] gave 100–215 mmol of intravenous isotonic or hypertonic NaHCO3 to haemodialysis patients who had mild hyperkalaemia. Although the mean plasma HCO3 concentration (PHCO3) rose from 21 to 34 mM, there was no change in PK after 60 min. A subsequent study [16] found a moderate decline in PK, but only after 4 h of NaHCO3 infusion. Most of the decline was attributed to the volume of infused NaHCO3.

The above studies that found a lack of effect of NaHCO3 were performed in stable haemodialysis patients who did not have significant acidosis and therefore when the NHE was presumably in an inactive mode. The question remains as to whether NaHCO3 would be effective in patients with a more significant degree of acidosis. There are limited data in the literature to answer this question. A report by Schwarz et al. [18] described four uraemic patients with PK values ranging from 5.9 to 8.5 mM associated with ECG changes and a profound degree of acidosis (PHCO3 of 1.3–7.3 mM). With an infusion of between 150 and 400 mmol of NaHCO3, all four patients had a significant reduction in PK and improvement in ECG.

It is difficult to draw a definite conclusion from the available data in the literature. Given this uncertainty, we still use NaHCO3 to treat acute hyperkalaemia in patients with a significant degree of acidosis, but not as the only emergency therapy to shift K+ into cells. Caution is warranted, as excessive administration of NaHCO3 can induce hypernatraemia, ECF volume expansion, carbon dioxide retention and a fall in ionized serum calcium levels.

Studies that examined the combined use of NaHCO3 with insulin had conflicting results. Allon and Shanklin [5] found that the addition of NaHCO3 did not enhance the PK-lowering effect of insulin. In contrast, Kim [7] found a synergistic effect of NaHCO3 with insulin. It should be noted, however, that the patients studied by Allon and Shanklin [5] were not hyperkalaemic (mean PK 4.5 mM).

Cation-exchange resins

A cation-exchange resin is a cross-linked polymer with negatively charged structural units. The resin can exchange bound Na+ (Kayexalate) or Ca2+ (calcium resonium) for cations including K+.

Kayexalate contains 4 mEq of Na+ per gram. This Na+ is theoretically exchangeable for 4 mEq of K+. Thus, 30 g of Kayexalate could possibly remove 120 mEq of K+. However, this degree of exchange does not occur at the Na+ and K+ concentrations found in the gastrointestinal tract. Based on in vitro binding characteristics of Kayexalate, it seems that the Na+ and K+ concentrations at which 50% of the initial Na+ would be exchanged for K+ were 65 and 40 mM, respectively [19]. With a higher concentration of Na+ and/or a lower concentration of K+, less exchange would be expected to take place. In the duodenum, Na+ concentration is ~140 mM and K+ is close to 5 mM. In the distal ileum, Na+ concentration is ~125 mM and K+ concentration is 9 mM. Na+ concentration decreases in the colon to ~40 mM and the concentration of K+ rises to 90 mM [20]. It seems that the only favourable location for the exchange of Na+ for K+ is in the lumen of the colon. Data from patients with ileostomia, however, indicate that the amount of K+ that is not absorbed in the small intestine and hence would have been delivered to the colon and be available for that exchange is only ~5 mmol per day [21,22].

In humans, active secretion of K+ in the gastrointestinal tract occurs in the recto sigmoid portion of the colon. One possible theoretical benefit to the use of cation-exchange resins is that, if they were to lower the K+ concentration in luminal feacal water, the net secretion of K+ by the colon would be enhanced. A number of other cations are available in the colon to exchange for resin-bound Na+, including NH4+, Ca2+ and Mg2+. The concentration of NH4+ in stool water may be high in patients with ESRD. Ca2+ and Mg2+ have an even greater affinity for the resin than K+ because of their divalent positive charge.

Colonic secretion of K+ in normal subjects is ~4 mmol per day [21]. It has been suggested that patients with ESRD have an enhanced colonic secretion of K+ that is perhaps mediated by aldosterone [23,24]. Balance data are conflicting, and the evidence that there is a substantial increase in K+ excretion by the gastrointestinal tract in patients with ESRD is not convincing [25]. Even if there was an adaptive increase in colonic K+ secretion, stool volume would be limiting. If one assumes a lumen negative transepithelial voltage of as high as 90 mV (measured values are significantly lower, close to 40 mV [23]) and a plasma K+ of 5 mM, the concentration of K+ in stool water would be 100 mM. With a usual stool weight of 125 g, of which 75% is water, only 10 mmol of K+ would be excreted. In experiments where dialysis bags were placed into the rectum of subjects with chronic renal failure, the rate of net K+ secretion was 1.5 µmol/h/cm2 of rectal surface area [24,25]. Agarwal et al. [25] pointed out that a subject with an average rectal surface area of 100 cm2 would only be able to have a net secretion of 4 mmol of K+ per day. If, however, this high rate of K+ secretion was to be present unabated throughout the entire colon, faecal K+ excretion would be as high as 70 mmol per day, if stool volume was not limiting. It is also notable that these studies have likely significantly overestimated the rate of K+ secretion by the rectum, since they were conducted with a low K+ concentration in the bags.

Two reports are commonly cited to support the use of resins for treatment of hyperkalaemia [26,27]. Although both studies concluded that resins were useful for treating hyperkalaemia, it should be noted that several doses were given, sometimes for a number of days, and that the effect on PK was noted after 1–5 days. Furthermore, it is not clear whether the effect was due to the resin or merely to the induction of diarrhoea with hypertonic glucose or other cathartics.

Two recent studies have re-examined the effect of cathartics and/or resins on faecal K+ excretion [19,28]. Emmett et al. [19] showed that, in normal subjects, the addition of the resin to sorbitol or sodium sulphate did not significantly increase stool K+ excretion compared to either laxative alone. Phenolphthalein resulted in the highest stool K+ excretion rate compared to the other laxatives; the addition of Kayexalate to phenolphthalein increased K+ excretion only modestly.

Gruy-Kapral et al. [28] studied the effect of a single dose of cathartic and/or resin on faecal K+ excretion and PK in ESRD patients. Their results show that resins do not contribute to faecal K+ excretion above the effect of cathartics alone. Although the patients were not initially hyperkalaemic, none of the regimens used reduced PK.

In summary, we do not use resins for treatment of acute hyperkalaemia. In the setting of chronic hyperkalaemia, it seems that the addition of resins to cathartics adds little to the induction of diarrhoea alone.

Conclusions

Evidence supports the use of insulin with glucose as the first-line therapy to induce a shift of K+ in the emergency management of hyperkalaemia. ß2 agonists lower plasma K+ concentration to a similar degree as insulin but are ineffective in a significant number of patients, and questions remain about their safety. We continue to use NaHCO3 in patients with a significant degree of acidosis, but not as the only therapy. Cation-exchange resins are not effective in the treatment of acute hyperkalaemia. The addition of resins does not significantly enhance the excretion of K+ beyond the effect of diarrhoea induced by osmotic or secretory cathartics.

Conflict of interest statement. None declared.

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