Biff F Palmer
Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.
N Engl J Med. 2004 Aug 5;351(6):585-92. doi: 10.1056/NEJMra035279.
Abstract/Text
要伸也編：I.日常臨床に役立つ水・電解質異常の考え方3.低カリウム血症・高カリウム血症,日本内科学会雑誌,2006；95（5）：826-834. Available from: https://www.jstage.jst.go.jp/article/naika/95/5/95_5_826/_pdf/-char/ja
Kenmei Takaichi, Fumi Takemoto, Yoshifumi Ubara, Yasumichi Mori
Analysis of factors causing hyperkalemia.
Intern Med. 2007;46(12):823-9. Epub 2007 Jun 15.
Abstract/Text
OBJECTIVE: Patients with impaired renal function or diabetes are considered to be prone to hyperkalemia. Furthermore, hyperkalemia is an adverse drug reaction of inhibitors of the renin-angiotensin system (RAS) that are established to be efficacious in these patients. However, the current status of hyperkalemia in the clinical setting remains obscure.
METHODS: A total of 9,117 patients treated at Toranomon Hospital between January and October 2005, who had serum creatinine levels below 5 mg/dL were studied. Patients on dialysis and patients using cation exchange resin or diuretics that lower serum potassium were excluded.
RESULTS: Serum potassium increased significantly accompanying the increase in serum creatinine, and was significantly elevated in diabetic patients compared to non-diabetic patients. Serum potassium also increased significantly with the administration of angiotensin-II receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEI) or beta-blockers. A combination of diabetes and RAS inhibitor administration significantly increased serum potassium compared to each factor alone in patients with a serum creatinine level below 1.5 mg/dL but not in those with a higher serum creatinine level. According to step-wise multiple regression analyses, an elevated serum creatinine level had the strongest positive correlation with the serum potassium level, followed by diabetes, ACEI use, ARB use, and age.
CONCLUSION: Lowered renal function, diabetes, use of RAS inhibitors and old age are independent factors that increase the serum potassium level. Caution should be exercised when using RAS inhibitors in diabetic patients even if their renal function is relatively preserved. In selected patients with diabetes or impaired renal function, however, RAS inhibitors can be used without hyperkalemia.
Kenmei Takaichi, Fumi Takemoto, Yoshifumi Ubara, Yasumichi Mori
The clinically significant estimated glomerular filtration rate for hyperkalemia.
Intern Med. 2008;47(14):1315-23. Epub 2008 Jul 15.
Abstract/Text
OBJECTIVE: Reduced glomerular filtration rate (GFR) is a risk factor of cardiovascular diseases. Accurate assessment of GFR together with early and appropriate treatment of chronic kidney disease (CKD) is important. Although the Japanese Society of Nephrology has recently announced two equations (equation 0.741 and equation 194) to estimate GFR for Japanese, the clinically significant estimated GFR (eGFR) in Japanese has not been identified. We examined the clinical significance of eGFR with regard hyperkalemia.
METHODS: A total of 9,196 patients who were examined and treated at the Toranomon Hospital between January and October 2005 were studied. Patients with a serum potassium level of 5 mEq/L or above or who were taking potassium adsorbent were classified as hyperkalemic. The effect of eGFR on the incidence of hyperkalemia was examined. The factors causing elevated serum potassium were analyzed after excluding the patients on potassium absorbent.
RESULTS: Multivariate analysis identified reduced eGFR, diabetes, male gender, aging, and use of renin-angiotensin system inhibitors as the factors associated with an elevated serum potassium level. In an eGFR-stratified analysis, each subgroup with eGFR below 50 mL/min/1.73 m2when equation 0.741 was used, and eGFR below 60 mL/min/1.73 m2 when equation 194 was used had a significantly higher incidence of hyperkalemia compared with almost all of the subgroups with higher eGFR.
CONCLUSION: From the viewpoint of the increase in incidence of hyperkalemia, using an eGFR below 50 mL/min/1.73 m2 as the cutoff has clinical significance when equation 0.741 is used and a cutoff at 60 mL/min/1.73 m2 is appropriate when equation 194 is used.
Lawrence S Weisberg
Management of severe hyperkalemia.
Crit Care Med. 2008 Dec;36(12):3246-51. doi: 10.1097/CCM.0b013e31818f222b.
Abstract/Text
BACKGROUND AND OBJECTIVES: Hyperkalemia is one of the few potentially lethal electrolyte disturbances. Prompt recognition and expeditious treatment of severe hyperkalemia are expected to save lives. This review is intended to provide intensivists and other interested clinicians with an understanding of the pathophysiology that underlies hyperkalemia, and a rational approach to its management.
METHODS: This article reviews and analyzes literature relevant to the pathophysiology and management of severe hyperkalemia. Methods include search of MEDLINE, and bibliographic search of current textbooks and journal articles.
RESULTS AND CONCLUSIONS: A more complete understanding of potassium homeostasis in recent years has led to new approaches to the management of severe hyperkalemia. The physiologically based sequential approach still applies. The efficacy, pitfalls, and risks of the agents available for use at each step in the sequence are critically reviewed. Rational use of the available tools will allow clinicians to successfully treat severe hyperkalemia.
A Blumberg, P Weidmann, S Shaw, M Gnädinger
Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure.
Am J Med. 1988 Oct;85(4):507-12.
Abstract/Text
PURPOSE: The development of life-threatening hyperkalemia poses a risk for patients with chronic preterminal renal failure. Various therapeutic options have been suggested for hyperkalemic emergencies in these patients; to date, however, no study has evaluated the relative efficacies of these measures in the presence of renal failure. Our goal was to examine the acute effects of a variety of therapeutic approaches, as well as those of hemodialysis, on plasma potassium levels in a hemodialysis population.
PATIENTS AND METHODS: Ten patients with terminal renal failure undergoing maintenance hemodialysis were enrolled in the study. Blood gas parameters and plasma sodium, potassium, glucose, osmolality, renin, aldosterone, epinephrine, norepinephrine, dopamine, and insulin were measured before, during, and after 60-minute infusions of bicarbonate, epinephrine, and insulin in glucose, and before, during, and after performance of regular hemodialysis for one hour.
RESULTS: Hypertonic as well as isotonic intravenous bicarbonate (2 to 4 mmol/minute) induced a marked rise in plasma bicarbonate and pH, but failed to lower the plasma potassium level (5.66 versus 5.83 mmol/liter before and after). Epinephrine, 0.05 microgram/kg/minute administered intravenously, decreased plasma potassium only slightly from 5.57 to 5.25 mmol/liter, and five patients showed no decline. On the other hand, insulin in glucose, 5 mU/kg/minute intravenously, effectively lowered plasma potassium levels from 5.62 to 4.70 mmol/liter, and hemodialysis induced the most rapid decline from 5.63 to 4.29 mmol/liter. Plasma aldosterone was elevated before treatment; it correlated with plasma potassium and dropped during intravenous bicarbonate administration or hemodialysis. Pretreatment plasma renin activity, insulin, epinephrine, norepinephrine, and dopamine levels were generally normal.
CONCLUSION: We conclude that in patients with terminal renal failure undergoing maintenance hemodialysis, intravenous bicarbonate is ineffective in lowering plasma potassium rapidly, and epinephrine is effective in only half the patients, whereas insulin in glucose is a fast and reliable form of therapy for hyperkalemic emergencies. Plasma aldosterone levels are appropriate in relationship to plasma potassium levels, and levels of other potassium-influencing hormones are generally normal.
ロケルマ添付文書（2020年3月作成(第1版)）. アストラゼネカ.
B Pitt, F Zannad, W J Remme, R Cody, A Castaigne, A Perez, J Palensky, J Wittes
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.
Abstract/Text
BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.
David N Juurlink, Muhammad M Mamdani, Douglas S Lee, Alexander Kopp, Peter C Austin, Andreas Laupacis, Donald A Redelmeier
Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
N Engl J Med. 2004 Aug 5;351(6):543-51. doi: 10.1056/NEJMoa040135.
Abstract/Text
BACKGROUND: The Randomized Aldactone Evaluation Study (RALES) demonstrated that spironolactone significantly improves outcomes in patients with severe heart failure. Use of angiotensin-converting-enzyme (ACE) inhibitors is also indicated in these patients. However, life-threatening hyperkalemia can occur when these drugs are used together.
METHODS: We conducted a population-based time-series analysis to examine trends in the rate of spironolactone prescriptions and the rate of hospitalization for hyperkalemia in ambulatory patients before and after the publication of RALES. We linked prescription-claims data and hospital-admission records for more than 1.3 million adults 66 years of age or older in Ontario, Canada, for the period from 1994 through 2001.
RESULTS: Among patients treated with ACE inhibitors who had recently been hospitalized for heart failure, the spironolactone-prescription rate was 34 per 1000 patients in 1994, and it increased immediately after the publication of RALES, to 149 per 1000 patients by late 2001 (P<0.001). The rate of hospitalization for hyperkalemia rose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P<0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P<0.001). As compared with expected numbers of events, there were 560 (95 percent confidence interval, 285 to 754) additional hyperkalemia-related hospitalizations and 73 (95 percent confidence interval, 27 to 120) additional hospital deaths during 2001 among older patients with heart failure who were treated with ACE inhibitors in Ontario. Publication of RALES was not associated with significant decreases in the rates of readmission for heart failure or death from all causes.
CONCLUSIONS: The publication of RALES was associated with abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality. Closer laboratory monitoring and more judicious use of spironolactone may reduce the occurrence of this complication.
Copyright 2004 Massachusetts Medical Society
ラジレス添付文書（2022年7月改訂（第2版）. オーファンパシフィック.
日本腎臓学会編：CKD診療ガイド2012, 東京医学社, 2012.
