POTASSIUM TOLERABLE UPPER INTAKE LEVELS IN THE 2005 DRI REPORT

A potassium UL was not established in the 2005 DRI Report. Potential indicators reviewed included gastrointestinal discomfort from certain forms of potassium supplements and arrhythmia from hyperkalemia. Available evidence indicated that, in generally healthy individuals, excess potassium is excreted in the urine. Because they may have impaired potassium excretion, individuals with certain conditions (e.g., chronic kidney disease, end-stage renal disease, diabetes, severe heart failure, adrenal insufficiency) and individuals who use certain medications (e.g., angiotensin-converting enzyme inhibitors [ACE-Is] and angiotensin-receptor blockers [ARBs]) were identified as potentially vulnerable subpopulations in which potassium intakes at the AI may not be appropriate (IOM, 2005).

REVIEW OF POTENTIAL INDICATORS OF TOXICOLOGICAL ADVERSE EFFECTS OF EXCESSIVE POTASSIUM INTAKE

Although dietary potassium intake can be increased through behavioral change, there is a self-limiting aspect to such changes that makes toxic adverse effects from increases in dietary potassium intake unlikely. Reports and studies evaluating potassium supplements were therefore considered most useful to determine whether a potassium intake level that could lead to toxicity could be quantified. For ethical reasons, trials cannot be designed to evaluate whether an intervention will increase the incidence of adverse effects. Consequently, adverse effect data in trials are almost always secondary outcomes. These data, particularly if systematically and carefully reported, can provide useful information for evaluating the likelihood of adverse effects. However, as secondary outcomes, these trials may not be adequately powered to identify a statistically significant occurrence of an adverse effect. These strengths and limitations need to be taken into account when using data from trials for evaluating the potential for adverse effects.

Guided by the first step of the DRI organizing framework, the committee sought to identify potential indicators of toxicological adverse effects from excessive potassium intake. The section that follows describes the evidence the committee reviewed to identify indicators that could potentially inform the derivation of the potassium UL.

Evidence Reviewed to Identify Potential Toxicological Indicators

The committee conducted a literature scan to identify potential indicators that may be informative for the potassium DRIs (see Appendix D). Among the identified indicators were blood lipid concentrations and catecholamines. Based on the committee's supplemental literature search (see Appendix E), a systematic review was identified that compiled evidence from randomized controlled trials on these measures (Aburto et al., 2013). Meta-analyses of randomized controlled trial data found that increasing potassium intake did not increase blood lipids, plasma adrenaline, or plasma noradrenaline concentrations among adults (Aburto et al., 2013). No other potential indicator of potassium toxicity was identified from the committee's literature scan.

Additional exploration of systematic reviews and case reports on toxicity, adverse effects, and poisonings from potassium intake were undertaken in an effort to identify potential toxicological adverse effects. From these efforts, the committee identified a collection of case reports on deaths and sublethal symptomology attributed to high levels of potassium intake. The committee also compiled reported adverse effects of the potassium trials included in the Agency for Healthcare Research and Quality systematic review, Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks (AHRQ Systematic Review) (Newberry et al., 2018), and the committee's supplemental literature searches. The committee notes that the doses used in trials are generally not high enough to cause serious adverse effects, as it would be unethical to randomize participants to such an exposure. The intent of these evidence searches was to identify specific indicators that could potentially inform the potassium UL. The evidence that was compiled is described below.

Case Reports of Death and Sublethal Symptomology

High, acute potassium intakes have been associated with symptoms related to neuromuscular dysfunction, including weakness, paralysis, nausea, vomiting, and diarrhea. These symptoms, however, do not consistently develop prior to life-threatening cardiac arrhythmias. Furthermore, consistent evidence to quantify potassium exposure that leads to these symptoms is lacking. Acute potassium intoxications and associated hyperkalemia have been consistently linked with cardiac conduction system abnormalities, which may be fatal. These include bradycardia, peaking of T waves and widening of the QRS complex on surface electrocardiography, wide complex arrhythmias, and ultimately asystole and death. These cardiac adverse effects are mediated through higher serum potassium concentrations influencing the electrical potential on cardiac tissues.

Several case reports of potassium intoxication have been published and summarized in the literature (Guillermo et al., 2014; Ray et al., 1999). Some of the case reports include death resulting from an overdose of potassium chloride tablets. For instance, a 32-year-old female who was consuming a liquid protein diet reportedly died after ingesting approximately 47 extended-release potassium chloride tablets (Wetli and Davis, 1978). In a summary of cases reported in the literature, a report was outlined of a 26-year-old male who died after consuming an estimated 12,500 mg (320 mmol) of potassium from extended-release potassium chloride tablets (Guillermo et al., 2014); there was also co-ingestion of dextropropoxyphene-acetaminophen in this case, which complicates the interpretation.

Death is a particularly severe endpoint to use to establish a UL. As such, the committee sought to define doses of potassium supplementation associated with signs and symptoms that preceded death and thus could serve as early warning signs of toxicity. A case report described a 17-year-old male developing nausea, vomiting, and diarrhea in conjunction with hyperkalemia after consuming between 7,800 and 11,730 mg (200 and 300 mmol) of potassium from sustained-release potassium chloride tablets (Su et al., 2001). Another case report described a 67-year-old male who was revived from cardiac arrest after consuming approximately 2,730 mg/d (70 mmol/d) of potassium from a salt substitute for 1 week (Ray et al., 1999). The individual in this case report had recently increased the dose of an ACE-I and had mild acute kidney injury at the time of presentation, which could have influenced his ability to excrete excess potassium. Although not quantified, this individual reportedly consumed a high-potassium diet, in addition to the salt substitute.

Case reports of acute intoxications from potassium supplements are not suitable for establishing a potassium UL. Such reports generally do not evaluate habitual dietary intakes, are often confounded by concurrent medical conditions, and often can only provide estimates of the number of supplements or quantity of potassium consumed based on patient self-report or reports from others who witnessed the event. The accuracy of the dose of potassium in relation to clinical signs and symptoms may be suspect. Nevertheless, the case reports demonstrate that excessive potassium supplement intake can lead to adverse events and death, even in the absence of comorbid conditions that compromise potassium excretion.

Of note is the case report of adverse effects from salt-substitute intake (Ray et al., 1999). Although total potassium intake was not quantified, the amount reportedly consumed from the salt substitute is a level of intake that has been repeatedly studied in potassium supplement trials, wherein the risk of adverse events appears to be low among generally healthy populations (described below). The 2,730 mg/d (70 mmol/d) dose of salt substitute is likely too low to inform a potassium UL for the generally healthy population. However, this case report provides evidence that certain subpopulations are susceptible to adverse effects from elevated potassium intakes.

Adverse Events Reported in Potassium Supplementation Trials

The AHRQ Systematic Review did not have a key question regarding adverse events in potassium trials, but it provided a brief summary of commonly reported adverse events, including gastrointestinal discomfort. Building on this work, the committee reviewed descriptions of adverse events reported in trials meeting the inclusion criteria for the AHRQ Systematic Review and the committee's supplemental literature searches (see Table 5-1); trials that only assessed dietary interventions are omitted from the table. Because carefully designed feeding studies demonstrate that consuming diets high in potassium induces small but detectable increases in serum potassium concentrations in healthy individuals (Macdonald-Clarke et al., 2016), the committee's review also summarizes changes or groupwise differences in serum or plasma potassium concentrations reported in these trials.

TABLE 5-1

Potassium Supplementation Trials Included in the AHRQ Systematic Review and the Committee's Supplemental Literature Search That Provided a Description of Adverse Events or Blood Potassium Concentrations.

The potassium supplement dose was frequently the same across trials, at or near 2,500 mg/d (64 mmol/d). The similarity in doses studied makes it challenging to identify intake–response relationships. These studies also systematically excluded individuals at risk for potassium toxicity, such as persons with chronic kidney disease, prior evidence of hyperkalemia, and in some instances individuals with diabetes or using antihypertensive medications. The duration of exposure was typically short term, 4 to 16 weeks, although there are some trials that lasted 1 year or longer. Under these conditions, only one study provided evidence on hyperkalemia and reported higher prevalence among those in the placebo group than in the potassium supplement group. The committee's findings on changes in blood potassium concentrations are augmented by a meta-analysis of potassium supplementation trials; it found that among relatively healthy individuals there were small increases in plasma or serum potassium concentrations (weighted mean difference: 0.14 mmol/L [95% confidence interval: 0.09, 0.19], I² = 57 percent) with moderate potassium supplementation (Cappuccio et al., 2016).¹ The meta-analysis, however, did not find evidence of a relationship of potassium dose or duration with circulating potassium concentrations. Although there were occasional reports of nausea or gastrointestinal upset, these were rare, and it was not possible to identify a potassium dose at which these symptoms develop.

The committee's review of potassium supplementation trials were limited in facilitating establishment of a UL for potassium owing to a lack of variability in doses of potassium that were studied. The adverse reports included in potassium supplementation trials did not reveal a specific indicator on which to base a potassium UL.

THE COMMITTEE'S CONCLUSION REGARDING THE TOLERABLE UPPER INTAKE LEVEL FOR POTASSIUM

Short-term potassium supplementation of approximately 2,500 mg/d (64 mmol/d) on the background of a usual diet appears to be safe for generally healthy individuals. This level of potassium intake would likely be below the UL for individuals without kidney disease, diabetes, heart failure, adrenal insufficiency, or individuals using ACE-Is, ARBs, or other medications that may raise blood potassium concentrations to levels that could lead to adverse effects. There is evidence that very high doses of supplemental potassium ingestion can lead to adverse events, and in extreme cases has led to death, even in the absence of kidney disease or other factors that alter potassium excretion. However, without a specific indicator of a toxicological effect of high potassium intake, a potassium UL cannot be established.

The committee concludes that there is insufficient evidence of potassium toxicity risk within the apparently healthy population to establish a potassium Tolerable Upper Intake Level (UL).

The limitations that exist in the evidence highlight the need for future monitoring and research opportunities (see Chapter 12). Given the relatively high prevalence of chronic kidney disease, diabetes, heart failure, and use of ACE-Is and ARBs in the U.S. and Canadian populations, these groups represent subpopulations in which potassium excess may be of concern (see Chapter 7).

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