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The association between serum potassium levels -- even at "normal" concentrations -- and increased risk of short-term, all-cause mortality signal the critical need for more research, closer monitoring of patients, and increased vigilance for achieving and maintaining normokalemia, experts warn.

"Based on our results, clinicians should definitely monitor 'grey zone' patients closely," Maria Lukács Krogager, MD, of Aalborg University in Denmark, co-author of a study published in the , told 番茄社区app.

Added the authors of an , Bertram Pitt, MD, of the University of Michigan School of Medicine in Ann Arbor, and Patrick Rossignol, MD, PhD, of Centre Hospitalier Universitaire de Nancy in France: the short-term mortality risks associated with serum potassium in patients with hypertension should be regarded as a "wake-up call."

For the study, which involved a cohort of 44,799 patients on drug therapy for hypertension, even minor deviations within the normal range (3.5–5.0 mmol/L) were associated with a significantly increased risk of 90-day all-cause mortality. These levels fell at the high end of the normal range (>4.7 mmol/L hazard ratio [HR] 1.48), and at the low end of normal (3.5-3.7 mmol/L; HR 1.70; and 3.8 to 4.0 mmol/L; HR 1.21).

"Despite the widespread use of diuretics and other drugs that influence potassium levels in patients with hypertension, a search for optimal values of serum potassium has not been performed," Krogager said. "The normal potassium interval is defined based on apparently healthy individuals. The current results suggest this approach is problematic when assessing short-term mortality risk."

The analysis showed that mortality in relation to seven pre-defined potassium levels was U-shaped, with the lowest mortality in the interval 4.1 to 4.4 mmol/L. Whether serum potassium is a risk factor or a risk marker remains unknown, Krogager said. However, monitoring serum potassium concentrations in patients with hypertension immediately following initiation of antihypertensive medication could improve survival.

"The potential number of deaths is staggering given the growing incidence of hypertension in our aging population and the recent evidence suggesting the need for more intensive blood pressure lowering," Pitt and Rossignol wrote. "While future prospective studies will be required to verify the exact level of potassium associated with death in a broader population of patients with hypertension, the fact remains that potassium levels considered within the normal range by many clinicians, and often ignored, are associated with an increased risk of death."

The researchers suggested that future studies should focus on the frequency of potassium measurement, potassium fluctuations over time, and the effect of potassium regulation on mortality. Preliminary results from their new study of patients with both hypertension and hyperkalemia indicate that potassium normalization is associated with improved 90-day survival, said Krogager.

Results from a Spanish study appear to support this finding. In 2,164 consecutive patients with acute heart failure followed for a median of 2.8 years after hospital discharge, analysis of long-term monitoring data showed that potassium normalization was independently associated with lower mortality risk (P=0.001).

Conversely, persistent abnormal serum potassium concentrations were linked to a higher risk of death compared with serum potassium levels that were maintained in the normal range or that returned to normal, Julio Núñez, MD, PhD, of Hospital Clinico Universitario de Valencia, Spain, and colleagues reported online in .

"These findings support the need for close monitoring of serum potassium after an episode of acute decompensated heart failure," the researchers wrote. "In addition, they suggest that maintaining serum potassium levels within normal range may be considered a therapeutic target."

In an that accompanied that study, Nancy K. Sweitzer, MD, PhD, and Sophia Airhart, MD, both of the University of Arizona Sarver Heart Center in Tucson, noted that although hyperkalemia was associated with sudden death, overall mortality was driven by all-cause cardiovascular and heart failure-related deaths (71.7% and 31.7%, respectively). "This evidence suggests a more nuanced association that warrants further evaluation," they cautioned.

No correction of hyperkalemia was made on 60.2% of measurement occasions, the editorialists pointed out. "This strong and significant observation, in association with the mortality risk elucidated in the manuscript, is a call toward increased vigilance in the clinical community to achieve and maintain normokalemia."

Studies of patients living in the community also demonstrate an association between serum potassium levels and all-cause mortality, cardiovascular disease (CVD) and non-CVD death, particularly in patients on diuretics.

Results from an analysis of pooled data from the Multi-Ethnic Study of Atherosclerosis and the Cardiovascular Health Study showed that non-hospitalized patients with a serum potassium of 5.0 mmol/L or greater had a 41% higher risk for all-cause mortality independent of kidney function or other CVD risk factors. Such patients also had a 50% higher risk for CVD death and a 40% higher risk for non-CVD death compared with patients with a serum potassium level in the range of 4.0–4.4 mmol/L, reported Jan M. Hughes-Austin, MD, of the University of California San Diego, and colleagues, writing in the study published in the .

These associations were consistently stronger in patients on diuretics, the team noted. "Although our data are observational, it may be reasonable to address other factors that influence serum potassium if found to be elevated in diuretic users."

In an , Robert D. Toto, MD, of the University of Texas Southwestern Medical Center in Dallas, said clinicians "should pay close attention to patients with a serum potassium level above 5.0 mmol/L, because it may be a risk marker for both CVD and non-CVD mortality."

Many questions remain unanswered, Toto added. "These include how often we should measure potassium as well as what, when, and how best to treat deviations in serum potassium," he said. "Given the aging population and the high rates of diabetes, [chronic kidney disease], and heart disease, future research designed to provide answers to these questions is critical."