Potassium is an essential dietary mineral and electrolyte. The term electrolyte refers to a substance that dissociates into ions (charged particles) in solution, making it capable of conducting electricity. Normal body function depends on tight regulation of potassium concentrations both inside and outside of cells (1).
Maintenance of membrane potential
Potassium is the principal positively charged ion (cation) in the fluid inside of cells, while sodium is the principal cation in the fluid outside of cells. Potassium concentrations are about 30 times higher inside than outside cells, while sodium concentrations are more than ten times lower inside than outside cells. The concentration differences between potassium and sodium across cell membranes create an electrochemical gradient known as the membrane potential. A cell's membrane potential is maintained by ion pumps in the cell membrane, especially the sodium, potassium-ATPase pumps. These pumps use ATP (energy) to pump sodium out of the cell in exchange for potassium (Figure 1). Their activity has been estimated to account for 20%-40% of the resting energy expenditure in a typical adult. The large proportion of energy dedicated to maintaining sodium/potassium concentration gradients emphasizes the importance of this function in sustaining life. Tight control of cell membrane potential is critical for nerve impulse transmission, muscle contraction, and heart function (2, 3).
Cofactor for enzymes
A limited number of enzymes require the presence of potassium for their activity. The activation of sodium, potassium-ATPase requires the presence of sodium and potassium. The presence of potassium is also required for the activity of pyruvate kinase, an important enzyme in carbohydrate metabolism (2).
An abnormally low plasma potassium concentration is referred to as hypokalemia. Hypokalemia is most commonly a result of excessive loss of potassium, e.g., from prolonged vomiting, the use of some diuretics, some forms of kidney disease, or metabolic disturbances. The symptoms of hypokalemia are related to alterations in membrane potential and cellular metabolism. They include fatigue, muscle weakness and cramps, and intestinal paralysis, which may lead to bloating, constipation, and abdominal pain. Severe hypokalemia may result in muscular paralysis or abnormal heart rhythms (cardiac arrhythmias) that can be fatal (2, 4).
Conditions that increase the risk of hypokalemia (5)
- The use of potassium-wasting diuretics (e.g., thiazide diuretics or furosemide)
- Severe vomiting or diarrhea
- Overuse or abuse of laxatives
- Anorexia nervosa or bulimia
- Magnesium depletion
- Congestive heart failure (CHF)
In rare cases, habitual consumption of large amounts of black licorice has resulted in hypokalemia (6, 7). Licorice contains a compound (i.e., glycyrrhizic acid) with similar physiologic effects to those of aldosterone, a hormone that increases urinary excretion of potassium. Low dietary intakes of potassium do not generally result in hypokalemia (5). However, research indicates that insufficient dietary potassium increases the risk of a number of chronic diseases (see Disease Prevention).
The Adequate Intake (AI)
In 2004, the Food and Nutrition Board of the Institute of Medicine established an adequate intake level (AI) for potassium based on intake levels that have been found to lower blood pressure, reduce salt sensitivity, and minimize the risk of kidney stones (4; Table 1).
Table 1. Adequate Intake (AI) for Potassium
||19 years and older
The diets of Western industrialized cultures are quite different from those of prehistoric cultures and the few remaining isolated primitive cultures. Among other differences, the daily intake of sodium chloride (salt) in Western industrialized cultures is about three times higher than the daily intake of potassium on a molar basis, whereas salt intake in primitive cultures is about seven times lower than potassium intake (8). The relative deficiency of dietary potassium in the modern diet may play a role in the pathology of some chronic diseases.
Several large epidemiological studies have suggested that increased potassium intake is associated with decreased risk of stroke. A prospective study of more than 43,000 men followed for eight years found that men in the top quintile (1/5) of dietary potassium intake (median intake, 4,300 mg/day) were only 62% as likely to have a stroke than those in the lowest quintile of potassium intake (median intake, 2,400 mg/day) (9). The inverse association was especially high in men with hypertension. However, a similar prospective study of more than 85,000 women followed for 14 years found a much more modest association between potassium intake and the risk of stroke (10). Another large study that followed more than 9,000 people for an average of 16 years found that potassium intake was inversely related to stroke only in black men and men with hypertension (11). However, black men and women reported significantly lower potassium intakes than white men and women (1,606 mg/day vs. 2,178 mg/day). More recent data from the same population indicate that those with potassium intakes higher than 1,352 mg/day were only 72% as likely to have a stroke as those with potassium intakes lower than 1,352 mg/day (12). A prospective study in 5,600 men and women older than 65 years found that low potassium intake was associated with a significantly increased incidence of stroke in individuals not taking diuretics (13). More recently, a prospective study in a cohort of 26,556 male smokers reported that higher intake of potassium was associated with a nonsignificant reduction in risk of cerebral infarction (14). Taken together, the epidemiological data suggest that a modest increase in fruit and vegetable intake (rich sources of dietary potassium), especially in those with hypertension and/or relatively low potassium intakes, could significantly reduce the risk of stroke.
At least four cross-sectional studies have reported significant positive associations between dietary potassium intake and bone mineral density (BMD) in populations of premenopausal, perimenopausal, and postmenopausal women as well as elderly men (15-17). The average dietary potassium intakes of the study participants ranged from about 3,000 to 3,400 mg/day, while the highest potassium intakes exceeded 6,000 mg/day and the lowest intakes ranged from 1,400 to 1,600 mg/day. In all of these studies, BMD was also positively and significantly associated with fruit and vegetable intake. One study that examined changes in BMD over time found that higher dietary potassium intakes (and fruit and vegetable intakes) were associated with significantly less decline in BMD at the hip in men, but not in women, over a four-year period (17). However, a prospective study that followed 266 elderly women found that women in the highest quartile of potassium excretion had higher BMD measures after five years compared to women in the lowest quartile of potassium excretion (18), suggesting that eating potassium-rich foods may help to prevent osteoporosis.
Potassium-rich foods, such as fruit and vegetables, are also rich in precursors to bicarbonate ions, which buffer acids in the body. The modern Western diet tends to be relatively low in sources of alkalai (fruit and vegetables) and high in sources of acid (fish, meats, and cheeses). When the quantity of bicarbonate ions is insufficient to maintain normal pH, the body is capable of mobilizing alkaline calcium salts from bone in order to neutralize acids consumed in the diet and generated by metabolism (19). Increased consumption of fruit and vegetables reduces the net acid content of the diet and may preserve calcium in bones, which might otherwise be mobilized to maintain normal pH. Support for this theory was provided by a study of 18 postmenopausal women, which found that potassium bicarbonate supplementation decreased urinary acid and calcium excretion, resulting in increased biomarkers of bone formation and decreased biomarkers of bone resorption (20). Other studies have reported that short-term (<3 months) supplementation with potassium citrate decreased urinary acid excretion and biomarkers of bone resorption in postmenopausal women (21) and also ameliorated the negative effects of a high-salt diet on bone metabolism (22). However, a recent two-year randomized controlled trial found potassium citrate supplementation did not reduce bone turnover or increase BMD in postmenopausal women (23). Overall, consumption of potassium-rich fruit and vegetables may improve BMD and help lower the risk of osteoporosis.
Abnormally high urinary calcium (hypercalciuria) increases the risk of developing kidney stones. In individuals with a history of developing calcium-containing kidney stones, increased dietary acid load was significantly associated with increased urinary calcium excretion (24). Increasing dietary potassium (and alkalai) intake by increasing fruit and vegetable intake or by taking potassium bicarbonate supplements has been found to decrease urinary calcium excretion. Additionally, potassium deprivation has been found to increase urinary calcium excretion (25, 26). A large prospective study of more than 45,000 men followed for four years found that men whose potassium intake averaged more than 4,042 mg/day were only half as likely to develop symptomatic kidney stones as men whose intake averaged less than 2,895 mg per day (27). A similar study that followed more than 90,000 women over a period of 12 years found that women in the highest quintile of potassium intake (averaging 3,458 mg/day) were only 65% as likely to develop symptomatic kidney stones as women in the lowest quintile of potassium intake (averaging 2,703 mg/day) (28). In both of these prospective studies, dietary potassium intake was derived almost entirely from potassium-rich foods, such as fruit and vegetables.
High blood pressure (hypertension)
A number of studies indicate that groups with relatively high dietary potassium intakes have lower blood pressures than comparable groups with relatively low potassium intakes (29). Data on more than 17,000 adults who participated in the Third National Health and Nutrition Examination Survey (NHANES III) indicated that higher dietary potassium intakes were associated with significantly lower blood pressures (30). The results of the Dietary Approaches to Stop Hypertension (DASH) trial provided further support for the beneficial effects of a potassium-rich diet on blood pressure (31). Compared to a control diet providing only 3.5 servings/day of fruit and vegetables and 1,700 mg/day of potassium, consumption of a diet including 8.5 servings/day of fruit and vegetables and 4,100 mg/day of potassium lowered blood pressure by an average of 2.8/1.1 mm Hg (systolic BP/diastolic BP) in all subjects and by an average of 7.2/2.8 mm Hg in those with hypertension. More information about the DASH trial is included in the article on Sodium.
In 1997, a meta-analysis of 33 randomized controlled trials including 2,609 individuals assessed the effects of increased potassium intake, mostly in the form of potassium chloride (KCl) supplements, on blood pressure (32). Increased potassium intake (2,300-3,900 mg/day) resulted in slight but significant blood pressure reductions that averaged 1.8/1.0 mm Hg in people with normal blood pressure and 4.4/2.5 mm Hg in people with hypertension. Subgroup analysis indicated that the blood pressure-lowering effect of potassium was more pronounced in individuals with higher salt intakes and in trials where black individuals were a majority of the participants. A clinical trial in 150 Chinese men and women with borderline to mild hypertension found that moderate supplementation with 500 mg/day of potassium chloride for 12 weeks resulted in a significant 5 mm Hg reduction in systolic BP compared to placebo; no changes in diastolic BP were observed in this study (32). Like many Western diets, the customary diet of this population was high in sodium and low in potassium. A cross-over trial in 14 hypertensive individuals reported that supplementation with potassium citrate was equally as effective in lowering blood pressure as potassium chloride (33). A more recent cross-over trial in 42 adults with mild, untreated high blood pressure compared the effects of supplemental potassium chloride or potassium bicarbonate with a placebo (34). Supplementation with potassium chloride slightly decreased ambulatory systolic BP but had no effect on office systolic BP, while supplementation with potassium bicarbonate did not affect blood pressure measurements. Both supplements resulted in improved endothelial function and other cardiovascular benefits (34). However, a cross-over trial in 48 adults with early hypertension (defined as a diastolic BP of greater than 80 mm Hg but less than 100 mg Hg), who were not taking anti-hypertensive medication, reported that increased potassium intake through dietary or supplemental (potassium citrate) means did not improve blood pressure or vascular function (35). Increasing potassium intake by consuming a diet rich in fruit and vegetables may help lower blood pressure and may have other health benefits (see the article on Fruit and Vegetables). Supplemental potassium might help lower blood pressure in some individuals, but potassium supplements should only be used in consultation with a medical provider (see Supplements).
The richest sources of potassium are fruit and vegetables. A dietary survey in the US indicated that the average dietary potassium intake is about 2,300 mg/day for adult women and 3,100 mg/day for adult men (30). The potassium content of some relatively potassium-rich foods is listed in milligrams (mg) in Table 2 (36). For more information on the nutrient content of foods, search the USDA food composition database.
Table 2. Some Food Sources of Potassium
|Potato, baked with skin
||6 fluid ounces
|Plums, dried (prunes)
||6 fluid ounces
||6 fluid ounces
|Raisin bran cereal
|Lima beans, cooked
|Acorn squash, cooked
||½ cup (cubes)
Multivitamin-mineral supplements in the US do not contain more than 99 mg of potassium per serving. Higher doses of supplemental potassium are generally prescribed to prevent and treat potassium depletion and hypokalemia. The use of more potent potassium supplements in potassium deficiency requires close monitoring of serum potassium concentrations. Potassium supplements are available as a number of different salts, including potassium chloride, citrate, gluconate, bicarbonate, aspartate and orotate (37). Because of the potential for serious side effects, the decision to use a potent potassium supplement should be made in collaboration with one's health care provider (see Safety).
Abnormally elevated serum potassium concentrations are referred to as hyperkalemia. Hyperkalemia occurs when potassium intake exceeds the capacity of the kidneys to eliminate it. Acute or chronic renal (kidney) failure, the use of potassium-sparing diuretics, and insufficient aldosterone secretion (hypoaldosteronism) may result in the accumulation of excess potassium due to decreased urinary potassium excretion. Oral doses greater than 18 grams taken at one time in individuals not accustomed to high intakes may lead to severe hyperkalemia, even in those with normal kidney function (4). Hyperkalemia may also result from a shift of intracellular potassium into the circulation, which may occur with the rupture of red blood cells (hemolysis) or tissue damage (e.g., trauma or severe burns). Symptoms of hyperkalemia may include tingling of the hands and feet, muscular weakness, and temporary paralysis. The most serious complication of hyperkalemia is the development of an abnormal heart rhythm (cardiac arrhythmia), which can lead to cardiac arrest (38). The Food and Nutrition Board of the Institute of Medicine did not set a tolerable upper intake level (UL) for potassium because adverse effects from high dietary intakes of potassium have not been reported in healthy individuals (4). See Drug interactions for a discussion of the medications that increase the risk of hyperkalemia.
Adverse reactions to potassium supplements
Gastrointestinal symptoms are the most common side effects of potassium supplements, including nausea, vomiting, abdominal discomfort, and diarrhea. Intestinal ulceration has been reported after the use of enteric-coated potassium chloride tablets. Taking potassium with meals or taking a microencapsulated form of potassium may reduce gastrointestinal side effects. The most serious adverse reaction to potassium supplementation is hyperkalemia (see Toxicity). Individuals with abnormal kidney function and those on potassium-sparing medications (see Drug interactions) should be monitored closely to prevent hyperkalemia (5, 37).
The classes of medication known to increase the risk of hyperkalemia (elevated serum potassium) are listed in Table 3 (38), and medications known to increase the risk of hypokalemia (low serum potassium) are listed in Table 4 (5). Individuals are encouraged to consult their physicians regarding any dietary restriction that may apply when taking such medications.
Table 3. Medications Associated with Hyperkalemia
||Spironolactone, triamterene, amiloride
|Angiotensin converting enzyme (ACE) inhibitors
||Captopril, enalapril, fosinopril
|Nonsteroidal anti-inflammatory agents (NSAID)
||Indomethacin, ibuprofen, ketorolac
|Angiotensin receptor blockers
||Losartan, valsartan, irbesartan, candesartan
Table 4. Medications Associated with Hypokalemia
||Albuterol, terbutaline, pirbuterol, isoetharine, fenoterol, ephedrine, isoproterenol, metaproterenol, theophylline
|Tocolytic (labor suppressing) agents
||Acetazolamide, thiazides, chlorthalidone, indapamide, metolazone, quinethazone, bumetanide, ethacrynic acid, furosemide, torsemide
|Substances with mineralocorticoid effects
||Licorice, carbenoxolone, gossypol
||Penicillin, nafcillin, carbenicillin
||Caffeine, phenolphthalein, sodium polystyrene sulfonate
Linus Pauling Institute Recommendation
There is considerable evidence that a diet supplying at least 4.7 grams/day of potassium is associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. Fruit and vegetables are among the richest sources of dietary potassium, and a large body of evidence supports the association of increased fruit and vegetable intakes with reduced risk of cardiovascular disease (39, 40). Consequently, the Linus Pauling Institute recommends increasing potassium intake to at least 4.7 grams/day by increasing consumption of potassium-rich foods (see Sources), especially fruit, vegetables, and nuts.
Older adults (>50 years)
A diet supplying at least 4.7 grams/day of potassium is also appropriate for healthy older adults since such diets are associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. This recommendation does not apply to individuals who have been advised to limit potassium consumption by a health care professional (see Safety).
Authors and Reviewers
Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in February 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in December 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in December 2010 by
Pao-Hwa Lin, Ph.D.
Associate Research Professor
Division of Nephrology
Duke University Medical Center
Copyright 2001-2016 Linus Pauling Institute
1. Peterson LN. Potassium in nutrition. In: O'Dell BL, Sunde RA, eds. Handbook of nutritionally essential minerals. New York: Marcel Dekker, Inc; 1997:153-183.
2. Sheng H-W. Sodium, chloride and potassium. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Company; 2000:686-710.
3. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.
4. Food and Nutrition Board, Institute of Medicine. Potassium. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, D. C.: National Academies Press; 2005:186-268. (The National Academies Press)
5. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339(7):451-458.
6. Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. 1994;23(2):359-377. (PubMed)
7. Mumoli N, Cei M. Licorice-induced hypokalemia. Int J Cardiol. 2008;124(3):e42-44. (PubMed)
8. Young DB, Lin H, McCabe RD. Potassium's cardiovascular protective mechanisms. Am J Physiol. 1995;268(4 Pt 2):R825-837. (PubMed)
9. Ascherio A, Rimm EB, Hernan MA, et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation. 1998;98(12):1198-1204. (PubMed)
10. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30(9):1772-1779. (PubMed)
11. Fang J, Madhavan S, Alderman MH. Dietary potassium intake and stroke mortality. Stroke. 2000;31(7):1532-1537. (PubMed)
12. Bazzano LA, He J, Ogden LG, et al. Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow-up study. Stroke. 2001;32(7):1473-1480. (PubMed)
13. Green DM, Ropper AH, Kronmal RA, Psaty BM, Burke GL. Serum potassium level and dietary potassium intake as risk factors for stroke. Neurology. 2002;59(3):314-320. (PubMed)
14. Larsson SC, Virtanen MJ, Mars M, et al. Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male smokers. Arch Intern Med. 2008;168(5):459-465. (PubMed)
15. New SA, Bolton-Smith C, Grubb DA, Reid DM. Nutritional influences on bone mineral density: a cross-sectional study in premenopausal women. Am J Clin Nutr. 1997;65(6):1831-1839. (PubMed)
16. New SA, Robins SP, Campbell MK, et al. Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health? Am J Clin Nutr. 2000;71(1):142-151. (PubMed)
17. Tucker KL, Hannan MT, Chen H, Cupples LA, Wilson PW, Kiel DP. Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. Am J Clin Nutr. 1999;69(4):727-736. (PubMed)
18. Zhu K, Devine A, Prince RL. The effects of high potassium consumption on bone mineral density in a prospective cohort study of elderly postmenopausal women. Osteoporos Int. 2009;20(2):335-340. (PubMed)
19. Morris RC, Frassetto LA, Schmidlin O, Forman A, Sebastian A. Expression of osteoporosis as determined by diet-disordered electrolyte and acid-base metabolism. In: Burkhardt P, Dawson-Hughes B, Heaney R, eds. Nutritional Aspects of Osteoporosis. San Diego: Academic Press; 2001:357-378.
20. Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris RC, Jr. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med. 1994;330(25):1776-1781. (PubMed)
21. Marangella M, Di Stefano M, Casalis S, Berutti S, D'Amelio P, Isaia GC. Effects of potassium citrate supplementation on bone metabolism. Calcif Tissue Int. 2004;74(4):330-335. (PubMed)
22. Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab. 2002;87(5):2008-2012. (PubMed)
23. Macdonald HM, Black AJ, Aucott L, et al. Effect of potassium citrate supplementation or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal women: a randomized controlled trial. Am J Clin Nutr. 2008;88(2):465-474. (PubMed)
24. Trinchieri A, Zanetti G, Curro A, Lizzano R. Effect of potential renal acid load of foods on calcium metabolism of renal calcium stone formers. Eur Urol. 2001;39 Suppl 2:33-36. (PubMed)
25. Lemann J, Jr., Pleuss JA, Gray RW. Potassium causes calcium retention in healthy adults. J Nutr. 1993;123(9):1623-1626. (PubMed)
26. Morris RC, Jr., Schmidlin O, Tanaka M, Forman A, Frassetto L, Sebastian A. Differing effects of supplemental KCl and KHCO3: pathophysiological and clinical implications. Semin Nephrol. 1999;19(5):487-493. (PubMed)
27. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328(12):833-838. (PubMed)
28. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497-504. (PubMed)
29. Barri YM, Wingo CS. The effects of potassium depletion and supplementation on blood pressure: a clinical review. Am J Med Sci. 1997;314(1):37-40. (PubMed)
30. Hajjar IM, Grim CE, George V, Kotchen TA. Impact of diet on blood pressure and age-related changes in blood pressure in the US population: analysis of NHANES III. Arch Intern Med. 2001;161(4):589-593. (PubMed)
31. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117-1124. (PubMed)
32. Whelton PK, He J, Cutler JA, et al. Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. JAMA. 1997;277(20):1624-1632. (PubMed)
33. He FJ, Markandu ND, Coltart R, Barron J, MacGregor GA. Effect of short-term supplementation of potassium chloride and potassium citrate on blood pressure in hypertensives. Hypertension. 2005;45(4):571-574. (PubMed)
34. He FJ, Marciniak M, Carney C, et al. Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives. Hypertension. 2010;55(3):681-688. (PubMed)
35. Berry SE, Mulla UZ, Chowienczyk PJ, Sanders TA. Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial. Br J Nutr. 2010:1-9. (PubMed)
36. US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 22. 2009. Available at: http://ndb.nal.usda.gov//. Accessed 3/15/10.
37. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.
38. Mandal AK. Hypokalemia and hyperkalemia. Med Clin North Am. 1997;81(3):611-639. (PubMed)
39. Liu S, Manson JE, Lee IM, et al. Fruit and vegetable intake and risk of cardiovascular disease: the Women's Health Study. Am J Clin Nutr. 2000;72(4):922-928. (PubMed)
40. Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282(13):1233-1239. (PubMed)