5
Potassium: Dietary Reference Intakes for Toxicity
The Tolerable Upper Intake Level (UL) specifies the highest average daily intake level of a nutrient, consumed on a habitual basis, that is likely to pose no risk of adverse health effects for nearly all apparently healthy individuals in a given Dietary Reference Intake (DRI) age, sex, and life-stage group. The potential for adverse health effects increases as intakes increase above the UL. The UL is intended to provide guidance on intake levels that are safe; it is not intended to serve as an intake goal. The Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease (Guiding Principles Report) recommended that the UL be retained in the expanded DRI model, but that it should characterize toxicological risk (NASEM, 2017). Although this conceptual revision narrows the scope of the UL, it allows for a more nuanced characterization of the different types of risk that can exist with intake of a nutrient or other food substance. This chapter presents the committee’s review of the evidence on the toxicological effects of excessive potassium intake and its conclusion regarding establishing a potassium UL. For context, the committee’s findings are preceded by a brief summary of the decision made regarding the potassium UL in the Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005 DRI Report) (IOM, 2005).
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. Build-
ing 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.
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.
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1 The dose of potassium supplement used in the trials included in the meta-analysis ranged from 860–5,474 mg/d (22–140 mmol/d).
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
| Reference | Duration, Weeksa | Participants | Intervention |
|---|---|---|---|
| Crossover Studies | |||
| Patki et al., 1990 | 8 | 37 Indian adults, mean age 49.9 ± 7.6 years, with mild hypertension who did not take antihypertensive medications throughout trial | Placebo 60 mmol/d liquid K supplement |
| Graham et al., 2014 | 6 | 43 British adults, 40–70 years of age, at moderate cardiovascular disease risk | Placebo 64 mmol/d KCl |
| Richards et al., 1984 | 4–6 | 12 New Zealand adults, 19–52 years of age, with mild hypertension | Control period 140 mmol/d K supplement |
| He et al., 2010 | 4 | 42 British adults, 18–75 years of age, with untreated mild hypertension | Placebo 64 mmol/d KCl 64 mmol/d KHCO3 |
| Vongpatanasin et al., 2016 | 4 | 30 U.S. adults, mean age 54 ± 12 years, with prehypertension or stage I hypertension | Placebo 40 mmol/d KCl 40 mmol/d K3Cit |
| Parallel Randomized Controlled Trials | |||
| Barcelo et al., 1993 | 144 | 57 Spanish adults,g 27–64 years of age, with moderately severe active lithiasis and low/low-normal urinary citrate | Placebo 30–60 mmol/d K3Cit |
| Mean Achieved Urinary Potassium Excretion, mmol/d | Description of Adverse Events | Blood Potassium Concentrations | |
|---|---|---|---|
| Lowb | Highc | ||
| 60 | 82 | 3 placebo and 4 K supplement participants reported abdomen pain and nausea; resolved and did not require withdrawal of treatment | Serum K, by period (mmol/L) Baseline: 3.6 ± 0.42 Placebo: 3.6 ± 8.4 Potassium: 3.7 ± 8.5 |
| 87 | 104 | 4 KCl participants reported gastrointestinal irritation; resolved with reduction in supplementation | Serum K, by period (mmol/L): Baseline: 4.2 ± 0.04 Placebo: 3.9 ± 0.04 KCl: 4.1 ± 0.05 (p = .012 compared to placebo) |
| ~50d | ~180d | Completed without incident | Plasma K, by period (mmol/L): Control: 3.84 ± 0.05 Potassium: 3.99 ± 0.12 |
| 77 | 122/125e | No significant differences in hematocrit or plasma sodium, chloride, bicarbonate, creatinine, albumin, renin activity and aldosterone, or 24-hour urinary sodium and creatinine | Plasma K, by period (mmol/L): Placebo: 4.4 ± 0.3 KCl: 4.6 ± 0.2 (p < .01 compared to placebo) KHCO3: 4.4 ± 0.3 |
| 58 | 95/84f | No report provided | Serum K, by period (mmol/L): Placebo: 4.2 ± 0.3 KCl: 4.4 ± 0.3 (p < .01 compared to placebo) K3Cit: 4.3 ± 0.3 (p < .01 compared to placebo) |
| ~61h | 105i | 1 placebo and 2 K3Cit participants dropped out due to gastrointestinal intolerance 3 K3Cit participants reported mild nausea, epigastric pain, or abdominal distention | No significant changes in serum K |
| Reference | Duration, Weeksa | Participants | Intervention |
|---|---|---|---|
| Jehle et al., 2013 | 104 | 201 healthy, Swiss adults, 65–80 years of age | Placebo 60 mmol/d K3Cit |
| Macdonald et al., 2008 | 104 | 276 postmenopausal, British women, 55–65 years of age | Placebo 55.5 mmol/d K3Cit 18.5 mmol/d K3Cit 300 grams additional fruit and vegetables/d |
| Gregory et al., 2015 | 52 | 83 U.S. women, mean of 66 years of age,l with postmenopausal osteopenia | Placebo 40 mmol/d K3Cit |
| Obel, 1989 | 16 | 48 black, Kenyan adults, 23–56 years of age, with mildly increased blood pressure | Placebo 64 mmol/d K supplement |
| Siani et al., 1987 | 15 | 37 Italian adults, 21–61 years of age, with SBP v 160 mm H and/or DBP v 90 mm Hg | Placebo 48 mmol/d K supplement |
| Chatterjee et al., 2017 | 12 | 29 African American adults, at least 30 years of age, with prediabetes | Placebo 40 mmol/d KCl |
| Bulpitt et al., 1985 | 12 | 33 British adults, mean of 55 years of age,o with hypertension, receiving a K-losing diuretic | Control 64 mmol/d K supplementp |
| Mean Achieved Urinary Potassium Excretion, mmol/d | Description of Adverse Events | Blood Potassium Concentrations | |
|---|---|---|---|
| Lowb | Highc | ||
| 75 | 109 | 3 K3Cit participants discontinued due to gastrointestinal discomfort, and 1 discontinued due to severe diarrhea Adverse events were of minor severity and balanced among groups | Plasma K, end of trial (mmol/L): Placebo group: 3.8 ± 0.3 K3Cit group: 3.9 ± 0.3 (p < .05 compared to placebo) |
| 51j | 106/75/70k | K3Cit generally well tolerated; minor side effects were reported (indigestion, bloating) | Trend for higher serum K in the 55.5 mmol/d K3Cit, compared to other groups, although still in reference range |
| NR | NR | Moderate to severe gastrointestinal symptoms were more frequently reported in K3Cit group as compared to placebo group (19.0 versus 9.8 percent, respectively) | Higher prevalence of hyperkalemia in the placebo group as compared to K3Cit group (14.6 versus 4.8 percent, respectively; p = .23) |
| 56 | 102m | No major adverse events | No significant change in serum K concentrations in K supplement group Placebo group had similar results |
| NR | 87 | No major adverse events | Plasma K, end of trial (mmol/L): Placebo group: 4.4 ± 0.1 K group: 4.3 ± 0.1 |
| (−8.69)n | (+32.12)n | K supplement was well tolerated | Serum K, end of trial (mmol/L): Placebo group: 3.81 ± 0.2 K group: 4.00 ± 0.2 (p < .05 compared to placebo) |
| 55 | 95 | Plasma creatinine, end of trial (μmol/L)q: Control group: 110 ± 9 K group: 84 ± 5 1 patient in each group reported decreased appetite at end of trial |
Plasma K, end of trial (mmol/L)r: Control group: 3.5 ± 0.09 K group: 3.8 ± 0.09 (p < .05 compared to placebo) |
| Reference | Duration, Weeksa | Participants | Intervention |
|---|---|---|---|
| Svetkey et al., 1987 | 8 | 116 U.S. adults, mean age of approximately 51 years, with DBP between 90 and 105 mm Hg, untreated during trial | Placebo 120 mmol/d K supplement |
| Braschi and Naismith, 2008 | 6 | 85 British adults, 22–65 years of age, with BP f 160/105 mm Hg | Placebo 30 mmol/d KCl 30 mmol/d K3Cit |
| Naismith and Braschi, 2003 | 6 | 59 British adults, 25–65 years of age | Placebo 24 mmol/d KCl |
| Franzoni et al., 2005 | 4 | 104 Italian adults, 35–65 years of age, with mild to moderate hypertension, untreated during trial | Control 30 mmol/d K-aspartate |
| Miller et al., 1987 | 4 | 38 pairs of identical twin, U.S. children, mean 11.6 ± 3.8 years of age | Placebo ~36–45 mmol/d liquid K supplement |
| Mean Achieved Urinary Potassium Excretion, mmol/d | Description of Adverse Events | Blood Potassium Concentrations | |
|---|---|---|---|
| Lowb | Highc | ||
| NR | NR | 1 participant discontinued K supplement due to side effects 2 participants discontinued placebo due to side effects K supplement versus placebo, percent of participants reporting: abdominal pain (18 versus 9 percent, respectively), change in bowel habits (10 versus 14 percent, respectively), gas (20 versus 10 percent, respectively) | Not reported |
| 67 | 90/98s | K capsules were well tolerated, with no clinically significant side effects | Plasma K, change from baseline (mmol/L): Placebo: −0.01 [−0.26, 0.23] KCl: 0.03 [−0.26, 0.32] K3Cit: −0.20 [−0.43, 0.02] |
| NR | NR | 1 KCl group participant reported increase in appetite 2 placebo group participants reported side effects (nausea, transitory polyuria); symptoms resolved during study |
Not reported |
| 58 | 82 | No reported adverse effects from the K supplement | Serum K, end of trial (mmol/L)t: Control: 4.18 ± 0.46 K group: 4.38 ± 0.26 (p < .001 compared to control) |
| 37 | 49 | No major adverse effects Some reports of transient nausea on initiation of supplementation, subsided after a few days | Not reported |
| Reference | Duration, Weeksa | Participants | Intervention |
|---|---|---|---|
| Sundar et al., 1985 | 4 | 50 Indian adults, mean age of approximately 46 years, with mild to moderate hypertension, untreated during trial | Placebo ~60 mmol/d K supplement |
NOTES: Mean achieved urinary potassium excretion values are presented in mmol. To convert the mmol value to milligrams, multiple the excretion level by 39.1. BP = blood pressure; DBP = diastolic blood pressure; K = potassium; K3Cit = potassium citrate; KCl = potassium chloride; KHCO3 = potassium bicarbonate; SBP = systolic blood pressure.
aFor crossover trials, duration is per period.
bRepresents usual intake, placebo, or control period or group.
cThis group represents the period or group intended to have the highest level of potassium intake in the study.
dEstimated from a bar graph in the publication.
ePresented as potassium chloride and potassium bicarbonate estimates, respectively.
fPresented as potassium chloride and potassium citrate estimates, respectively.
gOnly 38 completed all 36 months.
hNo values for the placebo group were reported in the paper, but it was noted that the values did not change for the placebo group over time. Value in the table reflects pretreatment urinary potassium excretion of the potassium citrate group.
iUrinary potassium excretion at month 36 of treatment.
jValue is the mean baseline urinary potassium excretions plus mean change at 104 weeks.
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.
| Mean Achieved Urinary Potassium Excretion, mmol/d | Description of Adverse Events | Blood Potassium Concentrations | |
|---|---|---|---|
| Lowb | Highc | ||
| 56 | 81 | No report provided | Plasma K, end of trial (mmol/L): Placebo group: 3.93 ± 0.21 K group: 4.13 ± 0.26 (p < .001 compared to control) |
kValues are the mean baseline urinary potassium excretions plus mean change at 104 weeks for the high K3Cit, the low K3Cit, and the vegetable/fruit intervention groups, respectively.
lMean age 65.1 ± 5.9 years in supplementation group (n = 42), 66.1 ± 7.1 years in placebo group (n = 41).
mThis group had higher urinary potassium excretion at baseline as compared to the control group.
nChange from baseline. Baseline urinary potassium concentrations were not provided.
oMean age 56.1 ± 1.6 years in supplementation group (n = 14), 54.2 ± 1.9 years in control group (n = 19).
pAdministered as slow-release potassium tablets.
qPlasma creatinine at baseline was 94 ± 6 μmol/L in the potassium supplement group and 104 ± 8 μmol/L in the control group.
rPlasma potassium at baseline was 3.7 ± 0.12 mmol/L in the potassium supplement group and 3.7 ± 0.08 mmol/L in the control group.
sPresented as potassium chloride supplementation group and potassium citrate supplementation group, respectively.
tSerum potassium at baseline was 4.14 ± 0.43 mmol/L in the potassium supplement group and 4.19 ± 0.50 mmol/L in the control group.
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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