Q J Med 2003; 96: 911-917
© Association of Physicians 2003; all rights reserved.
Risk factors for thiazide-induced hyponatraemia
From the Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Received 20 February 2003 and in revised form 17 September 2003
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Background: Thiazide-induced hyponatraemia is common and potentially life threatening. In the absence of well-defined risk factors for this complication, guidelines for prescribing cannot be established.
Aim: To examine whether a subgroup of patients is particularly susceptible to this complication.
Design: Retrospective case-control study.
Methods: We defined and recruited cases of symptomatic hyponatraemia that necessitated hospitalization from January 1996 to April 2002. Controls were selected from 8420 patients being prescribed thiazides and seen at the same institution during that period of time.
Results: There were 223 cases and 216 controls, with a median 115 days thiazide use. Cases were older than controls (76 ± 9 vs. 66 ± 13 years, p < 0.001) and lighter (52.3 ± 10.3 vs. 63.4 ± 3 kg, p < 0.001). By univariate analysis, serum potassium level, use of indapamide, elderly home institutionalization and physical immobility were risk factors for thiazide-induced hyponatraemia, but gender, duration of thiazide use, concomitant therapy with loop diuretics, angiotensin-converting enzyme inhibitors or non-steroidal anti-inflammatory drugs, and renal function were not. By stepwise logistic regression analysis, patient age, body weight and serum potassium were the only independent predictive factors. Each 10-year increment of age was associated with a two-fold increase in risk (hazards ratio 2.14, 95%CI 1.59–2.88). For a 5 kg increment in mass, there was a 27% decrease in odds ratio (odds ratio 0.77, 95%CI 0.68–0.87). One SD increase in serum potassium (0.84 mmol/l) was associated with a 63% decrease in risk (odds ratio 0.37, 95%CI 0.27–0.50; p < 0.0001).
Discussion: Hyponatraemia is a common problem after thiazide therapy. Extra caution and close monitoring are warranted when prescribing thiazides for elderly patients with low body mass.
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Introduction |
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Hyponatraemia is the most frequent electrolyte disorder in clinical practice.1 Electrolyte disturbance is common after administration of thiazide diuretics, and hyponatraemia is a typical complication, with an estimated incidence of 11% in one series of 114 geriatric patients.2 The disorder is a potential cause of morbidity and mortality,3 and 12 attributable deaths were reported in a group of 129 cases of severe diuretic-related hyponatraemia found by searching the medical literature.4 The impact of diuretic-induced hyponatraemia has recently been reviewed,5 but little attention has been given to the use of well-defined factors to identify susceptible patients before prescription of this time-honoured medication. Despite its consistent recommendation as one of the first-choice anti-hypertensive medications by committees from the US,6 the WHO,7 the UK8and a recent major trial (ALLHAT),9,10 little is known about practical guidelines on the use of thiazide, and our understanding of the causes of thiazide-induced hyponatraemia is even more meagre.
Since the detailed description of thiazide-induced hyponatraemia over four decades ago,11 large-scale prospective studies have not demonstrated a uniform reduction of serum sodium concentration secondary to long-term thiazide use.12–15 The question arises as to whether a subgroup of patients is susceptible to adverse effects of this class of diuretics. The purpose of this study was to assess the characteristics of patients with thiazide-induced hyponatraemia, and determine the clinical risk factors that were predictive of this complication.
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Subjects
All hospital admissions for thiazide diuretic induced hyponatraemia (case group) at the Prince of Wales Hospital, Hong Kong, were identified by computerized hospital registries from January 1996 to April 2002. We defined and included clinically significant hyponatraemia episodes which were symptomatic, necessitating hospitalization, with a plasma sodium < 130 mmol/l.16–18 The diagnosis of thiazide-induced hyponatraemia was based on a history of diuretic use and the finding that hyponatraemia resolved after discontinuing the offending agent, in the absence of other specific therapies for hyponatraemia,19 and a general absence of other factors known to impair water excretion. Patients with thyroid and adrenocortical insufficiency were excluded. We included thiazide diuretics of different half-lives, ranging from short-acting diuretics (bendrofluazide/bendroflumethiazide, hydrochlorothiazide) to medium-acting ones (chlorothiazide, indapamide) as well as thiazide-containing combination diuretics.20,21
The control group was selected from patients being prescribed thiazides on an out-patient basis at our hospital throughout the ascertainment period, and with no thiazide-induced hyponatraemia. Briefly, after compiling a name list of patients receiving thiazides in alphabetical order (including those from the case group) a control was selected by taking the patient immediately following each case of thiazide-induced hyponatraemia on the list. To adjust for the time at risk (of developing hyponatraemia after thiazide), we assessed each subject in the control group on the day closest to the episode of hyponatraemia in the matched subject from the case group.
Health status and covariates were ascertained by case-record review, supplemented by telephone interviews where necessary. Validation of thiazide formulary and concurrent medication prescription was studied using the computer system shared by all government hospitals under Hong Kong Hospital Authority. Data collection procedures were identical for cases and controls.
Statistical analysis
Data were analyse using the Statistical Package for the Social Sciences (SPSS) for Windows, v. 11.0. Data were expressed as means ± SD unless otherwise specified. Univariate comparisons between cases and controls used Student's t test for continuous variables and the 
2 test or Fisher's exact test for discrete variables. Multiple logistic regression was used to examine predictors for thiazide-induced hyponatraemia, with a model constructed from variables encompassing covariates identified by our investigation and previous studies. Odds ratios and 95%CIs were calculated. A p value < 0.05 was considered significant. All probabilities were two-tailed.
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Patient characteristics
A total of 223 patients with thiazide-induced hyponatraemia (case group), with mean serum concentration of 116 mmol/l (range 98 to 128 mmol/l), were identified. Hyponatraemia resolved in all these patients after withdrawal of thiazide diuretics. Computed tomography brain imaging was performed in 47 confused patients to exclude cerebral causes of hyponatraemia.
The control group, comprising 216 subjects, was randomly selected from a total of 8420 patients who were prescribed thiazide diuretics during the same period without hyponatraemia.
Indapamide accounted for approximately half of the thiazide diuretics being prescribed in our cohort. The diuretics included, in descending order of prescription frequency from our population: indapamide (42.8%); fixed combination of hydrochlorothiazide plus amiloride (17.3%); hydrochlorothiazide alone (16.1%); hydrochlorothiazide plus triamterene combination (15.4%); and bendrofluazide (8.4%). The major indication for thiazides was treatment of hypertension. Incidence of congestive heart failure comorbidity (which affects water metabolism) did not differ between cases and controls (9.4% vs. 13.4%, p = 0.229).
Twenty patients in the case group and eight controls died during the study period; none of the mortality in the case group was directly accountable to hyponatraemia.
Tables 1 and 2 summarize the pertinent characteristics of cases and controls.
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Univariate analysis
There was an excess of females in the patients being given thiazide diuretics. Hyponatraemia appeared to occur in a larger proportion of female patients (F:M ratio 2.3 in cases vs. 1.6 in controls), but the observed difference fell just short of statistical significance (p = 0.051).
Cases were older than controls (76 ± 9 vs. 66 ± 13 years, p < 0.001), and had lower body mass (52.3 ± 10.3 vs. 63.4 ± 3 kg, p < 0.001). Institutionalization and physical disability (defined by independence of walking), were also risk factors for thiazide-induced hyponatraemia. Compared to controls, cases were more likely to receive indapamide then bendrofluazide and hydrochlorothiazide/triamterene, although the number of cases given the latter two thiazide diuretics was small. Mean serum potassium was lower in cases (3.4 ± 0.9 mmol/l) than in controls (4.0 ± 0.6 mmol/l, p < 0.001). There was a weak correlation between serum potassium and duration of thiazide use (r = -0.2, p = 0.001), but the latter did not predict the risk of hyponatraemia. Median duration of thiazide use in cases was 105 days (range 1–4479 days). Further analysis showed that the use of three medications was associated with serum potassium concentration: concurrent use of a potassium-sparing diuretic and an angiotensin-converting enzyme inhibitor was associated with significantly higher serum potassium, whereas prescription of indapamide led to lower potassium level (details not shown). For instance, serum potassium was significantly higher in the presence of concurrent angiotensin-converting enzyme inhibitor use (3.9 ± 0.8 mmol/l vs. 3.6 ± 0.8 mmol/l, p = 0.02).
Of the variables that were considered, no significant correlations were detected between the risk of hyponatraemia and diabetes mellitus, cigarette smoking status, concurrent use of angiotensin-converting enzyme inhibitor, non-steroidal anti-inflammatory drugs or loop diuretics. In addition, the dosage of thiazide per kg of body weight did not differ significantly between cases and controls in either gender.
Multivariate analysis
Multivariate analysis used a logistic regression model, with stepwise selection for relevant variables and those associated with thiazide-induced hyponatraemia at an 
-level < 0.1 in our univariate analysis. Under multivariate analysis (Table 3), only patient age, body weight and serum potassium concentration remained strong risk factors. Each 10 years of age conferred a two-fold increased risk (hazard ratio 2.14, 95%CI 1.59–2.88; p < 0.0001). There was a 27% decreased risk for each additional 5 kg body weight (odds ratio 0.73, 95%CI 0.65–0.83; p = 0.0001). Serum potassium levels were inversely associated with the occurrence of thiazide-induced hyponatraemia. One SD increase in potassium level (0.84 mmol/l) was associated with a 63% decreased risk (odds ratio 0.37, 95%CI 0.27–0.50; p < 0.0001).
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Despite the proposed mechanism of water retention and cation depletion in hyponatraemia secondary to thiazide,3,5,11,22–25 this electrolyte disorder is often thought to be rapid in onset, unpredictable and idiosyncratic.24 The literature documentation of this disease entity has been limited to isolated case reports,16,26–34 and given this major limitation,35 a properly designed and interpreted case-control study is crucial to define a high-risk subgroup exposed to thiazide therapy in which the risk of hyponatraemia is attenuated. This is the largest report to date of patients in whom anthropometric and clinical data have been examined and evaluated in a standardized manner. For the sake of clinical relevance and practical purpose, we choose to focus only on hyponatraemia episodes that were symptomatic and thus required hospitalization. A plasma sodium < 130 mmol/l would lower plasma osmolality by approximately 20 mOsm/kg: approximately the threshold at which clinical symptoms have occurred in experimental studies of hyponatraemia.18 We found three major risk factors of severe thiazide-induced hyponatraemia: age, lower body weight and hypokalaemia.
The predominance of the elderly in diuretic-induced hyponatraemia, as observed from our study and others,30,36–40 emphasizes the caution warranted in treating this group with thiazides. Risks might include that of developing hyponatraemia after thiazide diuretics and/or propensity to develop symptoms with hyponatraemia. In the few published series, as well as in this study, the mean age of thiazide-induced hyponatraemic patients consistently exceeded 70 years.16,36,37,39–41 A number of hypotheses have been suggested to account for this. Of note, a contemporary experiment by Clark et al.42 shows that healthy elderly subjects do not excrete free water as efficiently as younger ones do. In particular, elderly subjects with a previous history of thiazide-induced hyponatraemia have impaired urinary dilution capacity, and hence increased susceptibility to thiazide.43 Among the explanations, blunted prostaglandin synthesis is an attractive possibility,44 and could result from aging or propensity among the elderly for polypharmacy, including non-steroidal anti-inflammatory agents. A putative role for the latter, however, was not borne out in this study, in which similar proportion of cases (16%) and controls (17%) reported the simultaneous use of non-steroidal anti-inflammatory drugs.
In keeping with previous case reports and case series,37 we found a greatly increased risk of thiazide-related hyponatraemia from lower body mass. The reason why such patients are more prone to complications from diuretics remains puzzling. As the relationship still holds true after adjustment for age and gender difference in our multivariate model, as well as dosage by body weight, we propose the following possibility. Plasma sodium level is determined by the ratio between the total quantity of solutes and the total body water.44 It is thus conceivable that sodium concentration might change to a greater degree in a subject with smaller body size, and hence less total body water. Secondly, small body mass or muscle wasting, as observed in another case series,36 might also signify underlying illness.
The common occurrence of hypokalaemia in the case group underlines the intertwined relationship between kaliuretic effects and hyponatraemic effects of thiazides. The finding of low serum potassium level as an independent predictor of thiazide-induced hyponatraemia in our final model is a testimony to the concept of sodium-potassium movement proposed almost half a century ago.45 In the presence of a large potassium deficit, transcellular ion exchange (potassium exits and sodium enters cells) might contribute to hyponatraemia. Our attempts to relate the prescription of relevant medication and subsequent development of hypokalaemia should be considered carefully before recommendation of any prescription guidelines. It seems logical to propose that thiazide-induced hyponatraemia could be prevented by appropriate potassium supplementation and medication with less serum-potassium-lowering effect (such as combination with a potassium-sparing diuretic), but this question cannot be answered by the present observational study, and at present it is conjecture only.
We did not find a statistical significant gender difference, despite previous suggestions by others.4,17,36,37,40 None of these studies, except one,40 adjusted for preferential prescription of thiazide diuretics for female patients, and thus their validity is unclear. In fact, reports of the proportion of females with thiazide-induced hyponatraemia in literature (76%39 to 79%4) resemble our finding of 70%. Careful scrutiny of prescription rates of thiazide diuretics among three large series, all involving 1000 patients or above, revealed female proportions of 66%46 and 68%,2 with female gender being an independent predictor of thiazide use.47 The correlation between diuretic use and female gender was confirmed in another local survey48 and our study. In other words, we argue that the apparent female preponderance of thiazide-induced hyponatraemic adverse events is related to over-representation of females in thiazide-treated cohorts rather than intrinsic susceptibility to the electrolyte disturbance. The non-predictive value of gender on thiazide-induced hyponatraemia is further supported by our carefully matched case-control study.
Notwithstanding the reproducibility of thiazide-induced hyponatraemia from literature documentation49 and experimental study,16 there is a word of caution concerning the unpredictability in the timing of its occurrence. This electrolyte disorder was once thought to occur soon after or within two weeks of commencing thiazide diuretics.5,24,49 The available evidence from our large case series suggests otherwise. Duration of thiazide use ranged from 1 day up to 12 years before the development of symptomatic hyponatraemia, and did not differ between cases and controls. Delayed manifestation of hyponatraemia after diuretic prescription was reaffirmed in another recent case series of thiazide-induced hyponatraemia involving 180 patients.40 Potassium depletion, whose risk correlates with the duration of chronic thiazide therapy,48 might have been responsible for the late manifestation of thiazide-induced hyponatraemia. Our observation underscores the need for regular vigilance of hyponatraemic complication for all patients as long as they remain on thiazide, although the impact of regular potassium replacement on subsequent risk of developing hyponatraemia is difficult to ascertain.
Several limitations need to be acknowledged, given the retrospective study design. First, we did not address the role of excessive water intake and salt restriction, both of which can certainly cause positive water balance and negative electrolyte balance,4,5,42,50 and could be the initiating event of thiazide-induced hyponatraemia. Of note, dietary patterns could have been confounded by the level of patient self-care capability and institutionalization, both of which were associated with the development of sodium disorder after thiazide in our univariate analysis. Inadequate sodium and potassium intake might have been important in the frail elderly, who are more susceptible to this disorder. These dietary factors would be difficult to obtain reliably in a retrospective study. The generalizability of our analysis needs further validation, although it is considered plausible in light of close proximity of our dietary sodium intake51,52 as compared to other populations. The risk of hyponatraemia after loop diuretics prescription cannot be precisely evaluated in the current study, because of the small number of patients taking concurrent loop diuretic medication in our cohort.
One strength worth mentioning is our recruitment of controls from the out-patient clinics, instead of a purely hospital-based setting, thereby avoiding referral bias by selecting for subjects who were the most ill, and thus prescribed thiazides. Although the absolute risk of complications in patients receiving thiazide in the community is not known, it seems likely that the risk factors implicated would apply for most cases outside the hospital setting.
In conclusion, our case-control study highlights the potential risk factors of symptomatic thiazide-induced hyponatraemia disorders, which in conjunction with an increased understanding of the pathophysiology and awareness of such complication, will hopefully allow more rational use of this therapeutic agent.
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Acknowledgments |
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This study was supported in part by the CUHK research account 6901031. We are indebted to Mr Benjamin Lee from pharmacy for providing the valuable data and Ms Leung Wai Yin for clerical support. An abstract of this work was presented at the American Society of Nephrology 2002 Renal Week in Philadelphia, USA.
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Footnotes |
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Address correspondence to Dr C.C. Szeto, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China. e-mail: ccszeto{at}cuhk.edu.hk
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