Risk of Electrolyte Disorders, Syncope, and Falls in Patients Taking Thiazide Diuretics: Results of a Cross-Sectional Study
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CLINICAL RESEARCH STUDY
Risk of Electrolyte Disorders, Syncope, and Falls in
Patients Taking Thiazide Diuretics: Results of a
Cross-Sectional Study
Svenja Ravioli, MD,a Shawki Bahmad,a Georg-Christian Funk, MD,b Christoph Schwarz, MD,c
Aristomenis Exadaktylos, MD,d Gregor Lindner, MDa
a
Department of Internal and Emergency Medicine, Buergerspital Solothurn, Solothurn, Switzerland; bKarl-Landsteiner Institute for Lung
Research and Pulmonary Oncology Medical Department with Pneumology, Klinik Ottakring, Vienna, Austria; cDepartment of Internal
Medicine I, Pyhrn-Eisenwurzen Klinikum, Steyr, Austria; dDepartment of Emergency Medicine, University Hospital Inselspital, Bern,
Switzerland.
ABSTRACT
BACKGROUND: Thiazide diuretics are a mainstay in the management of hypertension and often associated
with dyselectrolytemias. We investigated the prevalence of and risk factors for hyponatremia and hypoka-
lemia in thiazide users, substance-specific differences, and the association of thiazides with syncope and
falls.
METHODS: In this cross-sectional analysis all patients admitted to an interdisciplinary emergency depart-
ment in Switzerland between January 1, 2017, and December 31, 2018, with measurements of serum
sodium and potassium were included. Data regarding serum electrolytes and creatinine were analyzed to
classify for dysnatremias, dyskalemias, and acute kidney injury. Chart reviews were performed to screen
for syncope or falls.
RESULTS: A total of 1604 patients (7.9%) took thiazides. Acute kidney injury was significantly more com-
mon in thiazide users (22.1 vs 7%, P < .0001). Hyponatremia (22.1 vs 9.8%, P < .0001) and hypokalemia
(19 vs 11%, P < .0001) were more frequent with thiazides. Thiazide use together with higher age and
female sex were independent predictors of hyponatremia and hypokalemia. A dose-dependent effect was
found for electrolyte disorders, and there was a variance in risk between the investigated substances with
chlorthalidone bearing the highest and hydrochlorothiazide the lowest risk. Patients taking thiazide diu-
retics had significantly more episodes of syncope and falls.
CONCLUSIONS: Thiazide use is a clear risk factor for hyponatremia and hypokalemia. The effect appears to
be dose-dependent and highly variable depending on the substance. Syncope and falls seem to be causally
related to thiazide use. Especially in patients who are elderly, female, and prone to falls, the use of thiazide
diuretics should be thoroughly questioned.
Ó 2021 Elsevier Inc. All rights reserved. The American Journal of Medicine (2021) 134:1148−1154
KEYWORDS: Electrolyte disorders; Falls; Hypokalemia; Hyponatremia; Syncope; Thiazide diuretics
Funding: None. Requests for reprints should be addressed to Gregor Lindner, MD,
Conflicts of Interest: GL reports personal fees from Bayer, Daiichi- Head of Department of Internal and Emergency Medicine, Buergerspital
Sankyo, Otsuka and non-financial support from Otsuka, GSK, and Pierre Solothurn, Schoengruenstrasse 42, 4500 Solothurn, Switzerland.
Fabre. SR, SB, G-CF, CS, AE report none. E-mail address: lindner.gregor@gmail.com
Authorship: All authors had access to the data and a role in writing
this manuscript.
0002-9343/© 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.amjmed.2021.04.007
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BACKGROUND association with syncope and falls, a cross-sectional analy-
Thiazide diuretics are commonly prescribed drugs and are sis of all patients admitted to the emergency department
considered a mainstay in the treatment of arterial hyperten- (ED) of the Buergerspital Solothurn between January 1,
sion.1,2 Thiazides or thiazide-like diuretics such as hydrochlo- 2017, and December 31, 2018, with on-admission measure-
rothiazide, indapamide, chlorthalidone, and metolazone were ments of sodium and potassium was conducted. The
found to be associated with hyponatremia and hypokale- Department of Emergency Medicine is an interdisciplinary
mia.1,3 Moreover, thiazides were ED with approximately 35,000 consultations per year
described to be independently associ- including medical, surgical, and
ated with hypomagnesemia.4 The CLINICAL SIGNIFICANCE trauma patients.
occurrence of thiazide-associated All patients age 18 years and
hyponatremia especially has been in Hyponatremia (22%) and hypokalemia older admitted to the ED during the
the focus of research in recent (19%) were common in patients taking study period with measurements of
years.1,5,6 Nevertheless, the mecha- thiazide diuretics. sodium and potassium on admis-
nisms leading to hyponatremia A thiazide diuretic was an independent sion, who did not withdraw consent
through thiazide diuretics appear to predictor of hyponatremia and hypoka- to scientific use of their data ver-
be complex and are incompletely lemia with specific substance and bally or written, were included.
understood so far:1 First, increased dose-dependent effects, with chlortha- Data on age, sex, length of hospi-
intake of free water was shown to be tal stay, in-hospital mortality, medi-
lidone showing the highest and hydro-
present in patients with a history of cal history, and regular medication
chlorothiazide the lowest risk. was collected. Furthermore, labora-
thiazide-associated hyponatremia
Thiazides and increasing age were tory results such as serum sodium,
compared with controls taking thia-
zides that did not develop hyponatre- independent risk factors for syncope potassium, and serum creatinine
mia. 7,8
Second, the ability of the and falls. were gathered. Electrolyte disorders
kidney to adequately excrete electro- A more careful approach to prescribing were classified as hyponatremia
lyte-free water is impaired by thiazide diuretics in elderly patients is (serum sodium 145 mmol/
direct inhibition of the sodium-chlo- L), hypokalemia (serum potassium
ride cotransporter in the distal tubule 5.0 mmol/L). Detailed chart reviews were
tion in the maximum capacity to excrete free water.1 Third, performed for all patients with thiazide diuretics on admis-
sodium and potassium loss is apparent through the natriuretic sion by the same 2 persons (SR, SB). In addition, all
effect of thiazide diuretics.9,10 patients were screened for presence of syncope and falls
Given the mentioned mechanisms of action, it is not sur- on ED admission. The list of diagnoses as well as the his-
prising that thiazide use is associated with electrolyte disor- tory of the emergency medical report were screened for
ders. In a large systematic review, it was described that presence of falls or syncope on admission. Daily thiazide
thiazide use was independently associated with the occur- medication and type of thiazide diuretic as well as daily
rence of hyponatremia and that female gender and advanced doses were extracted from the patients’ electronic charts.
age are independent predictors of its occurrence.6 Hypoka- In patients taking thiazide diuretics irregularly, the mean
lemia and its association with thiazide use on the other daily dose was calculated, whereas thiazide diuretics taken
hand is less well-studied. Furthermore, evidence concerning on an as-needed basis were not included in the analysis.
comedications, which may influence occurrence of electro- Equivalent doses of thiazides were assumed on basis of
lyte disorders during thiazide therapy, is scarce. Because the available literature:11 Hydrochlorothiazide 25 mg
thiazide diuretic use is commonly associated with discrete equivalent to chlorthalidone 12.5 mg, metolazone 5 mg, or
volume depletion as well as hyponatremia, an association indapamide 2.5 mg. Acute kidney injury was defined
with orthostatic syncope and falls may be assumed. Hence, according to the Acute Kidney Injury Network (AKIN)
we aimed to investigate 1) the prevalence of and risk factors definition.12
for hyponatremia and hypokalemia in patients taking thia-
zide diuretics; 2) substance-specific risks for the electrolyte
disorders; and 3) whether thiazide use is associated with an Statistical Methods
increased risk for syncope and falls. After completion of data collection, data were cleaned and
outliers (>95% confidence interval) were reconfirmed or
corrected. Data were exported to a statistical software pack-
METHODS age (SPSS for Windows, version 23; SPSS Inc or STATA
IC 15.1, STATA CORP, LCC) for analysis. Continuous
Study Design and Setting data are presented as median and first to third quartiles or as
To investigate the prevalence and risk factors of electrolyte mean and standard deviation (§ SD). Distribution of con-
disorders in patients taking thiazide diuretics as well as their tinuous variables was assessed using normal plots and
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logarithm transformation was performed when appropriate. Table 2 Baseline Characteristics
Categorical data are presented as absolute counts and per- No Thiazides Thiazide P Value
centages. Between-group comparisons of continuous varia-
Age (years) 57 (SD 22) 74 (SD 13)Ravioli et al Drug-Associated Adverse Effects of Thiazide Diuretics 1151
Table 3 Electrolytes in Patients with and without Thiazide univariable mulvariable
Diuretics. 15
P Value
O d d s R a t i o a n d 95% C I
No Thiazides Thiazide
Serum Sodium 138 (SD 3) 137 (SD 5)1152 The American Journal of Medicine, Vol 134, No 9, September 2021
Falls and Syncope in Patients on Thiazide angiotensin-aldosterone system.10 Also genetic predispos-
Diuretics ing factors were identified for hypokalemia.16
Overall, 8.1% of all patients admitted to the ED presented Previous studies support our current findings that hypo-
with a recent fall and 3.3% with a syncope, respectively. natremia and hypokalemia in patients with thiazide diu-
Patients with thiazide diuretic medication presented to the retics are significantly more likely in elderly as well as in
ED more frequently with a recent fall (20.5%) compared female patients.6,17 This stronger predisposition for women
with patients without thiazide diuretic (7.0%; P < .0001). to develop dyselectrolytemias with thiazide diuretics might
Additionally, episodes of syncope were significantly more originate from biological gender differences: In 1994, Chen
common in patients on thiazide diuretics (6.2%) compared et al18 found a significantly higher density of renal thiazide
with patients without thiazides (3.1%; P < .0001. Use of receptors in female compared to male rats. Furthermore,
thiazide diuretics was the strongest independent predictor they detected a decrease in thiazide receptors of >20% after
for the presence of falls or syncope at presentation to the ovariectomy, attributing a pivotal role to female sex hor-
ED even after correction for concomitant hyponatremia or mones. Only recently, female mice exposed to hydrochloro-
hypokalemia (OR 1.78, 95% CI: 1.55-2.05, P < .0001). thiazide displayed an increased sodium excretion in
Moreover, increasing age was an independent risk factor comparison with male mice, while hydrochlorothiazide-
for presence of syncope and falls (OR 1.03, 95% CI: 1.03- induced potassium excretion showed little sex differences.
1.03, P < .0001), and there was a trend for male sex being Interestingly, on a high-potassium diet, male mice proved
protective (OR 0.91, 95% CI: 0.82-1.0, P = .051). increased potassium secretion and greater distal sodium
delivery, indicating an association of more efficient adapta-
tion to potassium intake with male sex.19 However, specific
DISCUSSION causes for the higher prevalence of the discussed electrolyte
In the present analysis of a large collective of interdisciplin- disorders remain unclear but may be linked to hormonal
ary emergency patients, thiazide diuretics were found to be mechanisms and, thus, warrant further investigation. A sim-
commonly prescribed with an overall prevalence of roughly ple tool for the prediction of the occurrence of hyponatre-
8%. Patients taking thiazides were significantly and rele- mia in patients taking thiazide diuretics for arterial
vantly older than patients without thiazides and had more hypertension was suggested integrating 6 clinical factors
antihypertensive comedications, mostly inhibitors of the including age >65 years as well as female sex.20 Based on
renin-angiotensin-aldosterone system. The prevalence of these findings, a “silent epidemic of thiazide-induced hypo-
hyponatremia was high in patients taking thiazides, with natremia” was discussed.21 Especially in elderly women, it
more than 1 in 5 patients presenting with it. With a preva- is justified to avoid thiazide medication if feasible, and if
lence of 19%, hypokalemia was almost as frequent as hypo- prescribed newly, narrow monitoring of electrolytes is indi-
natremia. Moreover, it was shown, that the likelihood of cated.
hyponatremia and hypokalemia rose with increasing doses In the present analysis, a thiazide dose-dependent effect
of thiazides. Additionally, there was a vast difference in the was shown for both hyponatremia and hypokalemia. This
likelihood for hyponatremia and hypokalemia between the finding is supported by previous studies; however, the liter-
various thiazide types, with hydrochlorothiazide showing ature remains discordant.22 Nevertheless, this finding sup-
the least likelihood and chlorthalidone the highest with ORs ports the causal role of thiazide diuretics in the genesis of
of 7.63 (95% CI: 3.46-16.84) for hyponatremia and 22.7 hyponatremia and hypokalemia.
(95% CI: 9.26-55.79) for hypokalemia. Syncope and falls The at-first glance counterintuitive finding that both
on admission to the ED were significantly more common in hypo- and hyperkalemia were more prevalent in patients
patients taking thiazide diuretics, and in the multivariable taking thiazides might be explained by the fact that chronic
regression analysis, they were independent predictors even kidney disease, the number-one risk factor for hyperkale-
after correction for presence of hyponatremia and hypokale- mia, was more prevalent in this group.23 The finding of
mia. Increasing age was an independent risk factor for pres- increased hypokalemia is well-explained by the mechanism
ence of syncope and falls (OR 1.03, 95% CI: 1.03,1.03, P < of action of thiazides where increased distal tubule sodium
.0001), and there was a trend for male sex being protective. load stimulates potassium secretion and, consequently,
The high prevalence of hyponatremia and hypokalemia excretion.24
in the present collective of patients taking thiazide diuretics The various types of thiazides showed markedly differ-
stands in line with previous studies on the issue.3,13 The ent risks for the presence of hyponatremia and hypokale-
mechanisms leading to hyponatremia in patients taking mia: Although hydrochlorothiazide appeared to have the
thiazides are complex and not completely understood as lowest likelihood, while still relevant and highly significant,
outlined and summarized in a recent review on the subject.1 chlorthalidone on the other end of the spectrum had by far
More recently, genetic predispositions for thiazide-associ- the highest ORs for presence of hyponatremia and hypoka-
ated hyponatremia were described.14,15 Hypokalemia might lemia in our collective. This finding might be explained by
in part be explained by significant potassium losses result- the shorter plasma half-life of hydrochlorothiazide and
ing from thiazide intake, although many patients had con- might guide the choice of thiazide type when newly pre-
comitant medication with an inhibitor of the renin- scribing the medication for a patient.
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One of the central findings of the present study is the sig- 2. Unger T, Borghi C, Charchar F, et al. 2020 International Society of
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