ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE ESC Heart Failure 2021; 8: 2492–2501 Published online 3 May 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13395 Thirst distress in outpatients with heart failure in a Mediterranean zone of Spain Sanna Hagelberg Eng1†, Nana Waldréus2,3†, Beatriz González4, Jenny Ehrlin1, Violeta Díaz4, Carmen Rivas4, Patricia Velayos4, María Puertas4, Alba Ros4, Paula Martín4, Josep Lupón4,5,6, Antoni Bayes-Genis4,5,6 and Tiny Jaarsma1* 1 Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; 2Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; 3Theme Aging, Karolinska University Hospital, Stockholm, Sweden; 4Heart Failure Unit, Hospital Universitary Germans Trias i Pujol, Badalona, Spain; 5Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and 6CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain Abstract Aims This study aimed to evaluate psychometric properties of the Spanish version of the Thirst Distress Scale for patients with Heart Failure (TDS-HF) and to describe thirst distress-associated factors in outpatients at a heart failure (HF) clinic in Spain. Thirst is common in patients with HF, but thirst distress has rarely been addressed and may significantly decrease quality of life. Methods and results A cross-sectional study was performed assessing perceived thirst distress by patients with HF during the preceding 3 days, with the TDS-HF (scores 8 to 40). Univariable and multivariable linear regression analyses were per- formed to identify variables independently associated with thirst distress. Three-hundred two HF outpatients were included (age 67 ± 12 years, 74% male, HF duration 82 ± 75 months, left ventricular ejection fraction 42 ± 14%). Most patients were on treatment with fluid restriction (99%), sodium restriction (99%), and diuretics (70%). The psychometric evaluation of the Spanish version of the TDS-HF showed satisfactory item-total and inter-item correlations (range from 0.77 to 0.85 and 0.60 to 0.84, respectively), and internal consistency was 0.95 (Cronbach’s alpha). The majority perceived mild to moderate thirst distress, and 18% perceived it as high or severe. The mean score obtained was 16.2 ± 9.3 (median 13, Q1–Q3 8–20). Higher serum urea {beta coefficient 1.6 [95% confidence interval (CI) 0.267 to 2.92], P = 0.019} and lower potassium [beta coefficient 3.63 (85% CI 6.32 to 0.93), P = 0.009] remained significantly associated with thirst distress in the multivariable analysis, together with the dose of diuretics [beta coefficient 2.98 (95% CI 1.37 to 4.59), P < 0.001]. Treatment with angiotensin recep- tor blocker showed an independent protective effect [beta coefficient 3.62 (95% CI 6.89 to 0.345), P = 0.03]. Conclusions The psychometric evaluation of the Spanish version of the TDS-HF showed good psychometric properties. One in five patients experienced severe distress by thirst, but the majority had mild to moderate thirst distress. The dose of diuretics and angiotensin receptor blocker treatment influence thirst distress and could be clinically important targets to relieve thirst distress in patients with HF. Keywords Heart failure; Thirst; Thirst distress; Quality of life; ARB; Diuretics Received: 20 November 2020; Revised: 23 February 2021; Accepted: 21 April 2021 *Correspondence to: Dr Tiny Jaarsma, Faculty of Medicine and Health Sciences, Linköping University, SE-581 83 Linköping, Sweden. Email: tiny.jaarsma@liu.se †Both authors contributed equally to this work. Introduction health-related quality of life and suffering a large number of symptoms, such as dyspnoea, peripheral oedema, exercise in- Heart failure (HF) is a major public health problem and is in- tolerance, and fatigue.1,2 Recent studies show that thirst is creasing in prevalence due to aging population and better another common symptom experienced by HF patients.3–7 treatment of cardiovascular diseases. Beyond crucial issues Thirst is a physiological homeostatic response that makes as high morbidity, with frequent hospital readmissions, and one drinking water to restore the body’s fluid balance.8 It is still high mortality, living with HF often means reduced a subjective sensation associated with a craving for water © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Thirst distress in outpatients with heart failure 2493 and a feeling of dryness in the mouth3 and without possibility visit to an HF nurse every 3 months and one visit to a physi- to drink it causes the individual a lot of suffering. Thirst has cian every 6 months. Patients were included on follow-up been described as a distressing symptom in HF patients that visits to one of the two HF nurses participating in the study. is recognized but rarely addressed.5,9,10 About half of the pa- Exclusion criteria were diagnosis of dementia or language tients in a Mediterranean population with HF experienced barriers. frequent thirst, with 33% of them experiencing thirst every day.11 Moreover, the study showed that patients with fre- quent thirst experienced thirst more intensively and for a lon- Data collection ger duration. This indicated that thirst can be very difficult for some patients and motivates further studies in this field.11 Data were collected by a research assistant and an HF nurse. Patients with severe HF described thirst as a source for suffer- Patients scheduled to see the HF nurse were asked to fill in ing and underlined the difficulty to control and find relieve the questionnaire on thirst distress during their visit. Patients for their thirst.12 Several factors have been suggested to pro- in need of help to read the questions or to fill in the question- mote thirst in these patients, including increased activation naire were assisted by the HF nurse. of neurohormonal systems, medications, and self-care practices.5 The treatments with the greatest association are Thirst Distress Scale those prescribed to control volume status, which is a core principle in HF management.13 The non-pharmacological The Spanish version of TDS-HF (Supporting Information, treatment of fluid restriction has also been associated with Annex S1) was used to quantify the thirst distress perceived increased thirst in several studies,7,14,15 and how to manage by the patients during the preceding 3 days. TDS-HF17 is a it could be controversial.16 5-point Likert scale that consists of eight statements about Thirst as a symptom has been described by these dimen- thirst. Patients were asked to rate these from 1 (strongly dis- sions: frequency and duration, intensity, distress, and agree) to 5 (strongly agree). The total TDS-HF score ranges quality.3 Thirst frequency describes how often and duration from 8 to 40. Higher scores indicate higher thirst distress. describes for how long thirst occurs. It also describes if there The Spanish version of the scale was recently developed from is a pattern of symptom occurrence. Thirst intensity can be the TDS-HF in English. This study is the first to use the trans- described as the strength of the thirst, and studies examining lated Spanish TDS-HF in a Spanish cohort. The translation of thirst intensity in HF patients have measured it using a visual the scale was done according to international rules.19 The En- analogue scale (VAS).7,9 Thirst distress is a measure of to glish version of the scale was translated into two Spanish ver- what degree a patient is bothered by thirst. Studies have ex- sions (by a professional translator with no health care amined thirst distress by quantitative measures by using education and by a Spanish cardiologist). The two translated scales.7 Finally, the quality of a symptom is what the symp- Spanish versions were later back translated into English tom feels like and associated discomforts, as described with (US) by two professional translators. Three health care the patient’s own words. professionals compiled the final version from the two In 2011, the Thirst Distress Scale for patients with HF (TDS- back-translated English versions (authors N. W., J. L., and HF) was developed. The scale has been used in Sweden, the T. J.; N. W. and T. J. were involved in the development of Netherlands, and Japan and has proven to be successful to the original TDS-HF). To assess face validity and comprehen- assess thirst distress in HF patients.17 The aim of the present siveness, a clinician checked if the scale was easy to under- study was to (i) evaluate psychometric properties of the stand with regard to the clarity of the language. Patients Spanish version of the TDS-HF and (ii) describe thirst distress with HF (n = 3–5) were asked to describe the relevance of and identify factors associated with thirst distress in outpa- the questions in the Spanish version of the TDS-HF and the tients at an HF clinic in Spain. usability of the scale (if the scale was clear and easy to use).20 Arbitrarily, the mean total thirst distress score was divided into five categories: no distress (0–8 points), mild distress (9–16 points), moderate distress (17–24 points), high distress Methods (25–32 points), and severe distress (33–40 points). The study used a cross-sectional design. The study population consists of outpatients with a scheduled visit to the HF clinic Demographic and clinical variables at a University Hospital in Badalona, Spain, between mid-September 2018 and early November 2018. The criteria Socio-demographic clinical characteristics, co-morbidities for clinical practice referral to the HF unit have been reported (including depression), and treatments were collected from elsewhere.18 The patients have routine follow-up visits at the interviews during the visit or from patient’s medical records. clinic according to clinical status, consisting at least in one To compare doses of diuretics per day, 10 mg of torasemide ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 2494 S.H. Eng et al. were considered equivalent to 40 mg of furosemide. Patients Variables previously reported to be related to thirst dis- who had changed their dose of diuretics in the last 24 h were tress or clinically considered eventually susceptible to be as- excluded from the analysis of diuretics association with thirst sociated with thirst distress were included as independent distress. Medications that have been associated with an ef- co-variables in the univariable linear regression analyses in fect on fluid balance were also documented and classified which the TDS-HF score, as continuous variable, was the de- (opioids, antidepressants, anti-histamines, proton pump in- pendent variable. Variables with a significant result in the hibitors, and vasopressin V2 receptor blockers). Patients were univariable analyses were included in a multivariable regres- also asked on amount of fluid and sodium restriction. Only sion analysis (backward stepwise method) in order to identify blood test taken within 30 days from the visit and left ventric- factors independently related with thirst distress. Despite no ular ejection fraction (LVEF) measured within 1 year from the significant result in the initial univariable analyses, body mass visit were included in the analyses. In addition to thirst dis- index and age were included in the multivariable regression tress by the TDS-HF, thirst intensity was measured by a VAS analysis because previous studies have shown that they can with rating on a line from no thirst (0 mm) to worst possible affect thirst in HF patients.4 A multicollinearity analysis was thirst (100) to be used in concurrent validity evaluation. made to rule out collinearity between variables in the The HF clinic has a general informed consent and ethical multivariable regression (using variance inflation factor approval for studies carried out at the clinic. At their baseline range). The level of statistical significance was set at visit, patients are provided with and sign a written informed P < 0.05. Data analyses were performed using IBM SPSS consent for obtaining clinical data, analytic samples, and clin- Version 25 (Chicago, Illinois, USA). ical scales (such as the TDS-HF) and use them for research purposes. The study was performed in compliance with the law regarding the protection of personal data and in accor- dance with the international guidelines on clinical investiga- Results tion of the World Medical Association’s Declaration of Helsinki. Study population Three-hundred two patients with HF participated in the study. Another 258 patients were scheduled, but not included in the Data analysis study due to a visit with one of the nurses not participating in the study. One patient was excluded due to dementia. Table 1 Continuous data showing a normal distribution are presented shows demographics, clinical characteristics, and treatments. as the mean ± standard deviation, and data with skewed dis- In summary, mean age was 67 ± 12 years, and 224 (74%) were tribution are presented as the median and interquartile range men. Mean LVEF was 42 ± 14%, with 108 patients (49%) hav- (Q1–Q3). Normal vs. skewed distribution was assessed by ing an LVEF under 40%. Most patients (79%) were in New York normal Q–Q plots. Categorical data are presented by absolute Heart Association (NYHA) class II. Median duration of HF was numbers and percentages. The mean value and distribution 4.9 (1.6–11) years. The most frequent aetiology for HF was of responses for each item of TDS-HF were calculated, as well ischaemic heart disease (42%). Nearly all patients were pre- as the mean total thirst distress score. scribed fluid restriction and sodium restriction (99%). Most Psychometric evaluation was conducted to assess con- patients (70%) were prescribed diuretics [mean dose of furo- struct validity, concurrent validity, and internal consistency. semide 61 ± 32 mg/day and median dose of torasemide 10 The TDS-HF has not previously been used by patients with (5–10) mg/day]. Some of the patients were prescribed other HF who speak Spanish. It has been found that the factor medical therapy associated with increased thirst, such as pro- structure of a scale can be inconsistent in different language ton pump inhibitors (47%), benzodiazepines (24%), antide- versions, and therefore, an exploratory factor analysis with pressants (19%), and opioids (2%) (Table 1). maximum likelihood extraction was performed.21 Construct validity was assessed by performing an exploratory factor analysis with maximum likelihood extraction. The Kaiser– Psychometric properties of the Spanish version of Meyer–Olkin measure of sampling adequacy and the Bartlett the Thirst Distress Scale for patients with Heart test of sphericity were used to test the appropriateness of Failure factor analysis. The concurrent validity was evaluated be- tween the total score of TDS-HF and thirst intensity (VAS, Face validity of the TDS-HF was acceptable, as assessed by 0–100 mm) by using the Spearman rank correlation. Internal a convenient number of patients with regard to the ques- consistency of the TDS-HF was evaluated by calculating the tion’s relevance, clarity, and easy to use. The sampling ad- Cronbach’s alpha. Item-total and inter-item correlations were equacy was good, as evaluated with Kaiser–Meyer–Olkin calculated by using the Spearman correlation analysis. (0.92) and Bartlett’s test of sphericity (P < 0.001). ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 Thirst distress in outpatients with heart failure 2495 Table 1 Demographics and clinical characteristics Demographics N Age, years 67 ± 12 302 Gender, male 224 (74%) 302 Current smoking 53 (18%) 302 Living situation Alone 45 (15%) 302 With partner 200 (66%) 302 With others 57 (19%) 302 Educational level None 23 (8%) 301 Primary school 177 (59%) 301 Secondary school 74 (25%) 301 Higher education 27 (9%) 301 Clinical data HF duration, years 4.9 (1.6–11) 302 HF deterioration in the last 3 days 7 (2%) 302 LVEF, % 42 ± 14 220 LVEF < 40% 108 (49%) 220 2 BMI, kg/m 27 (24–30) 300 Systolic blood pressure, mmHg 126 ± 19 302 Diastolic blood pressure, mmHg 75 ± 11 302 Pulse, b.p.m. 68 (60–78) 302 HF aetiology Ischaemic heart disease 127 (42%) 302 Dilated cardiomyopathy 58 (19%) 302 Other 38 (13%) 302 Alcoholic cardiomyopathy 27 (9%) 302 Valve disease 27 (9%) 302 Hypertensive cardiomyopathy 16 (5%) 302 Toxic cardiomyopathy 9 (3%) 302 NYHA functional class NYHA class I 36 (12%) 302 NYHA class II 237 (79%) 302 NYHA class III 29 (10%) 302 NYHA class IV 0 (0%) 302 Co-morbidities Hypertension 201 (67%) 302 Hypercholesterolaemia 166 (55%) 302 Diabetes 119 (39%) 302 Renal failure 76 (42%) 183 Atrial fibrillation 56 (19%) 302 COPD 51 (17%) 302 Anaemia 41 (31%) 132 Peripheral vascular disease 38 (13%) 302 Depression 29 (10%) 302 Malignancy 20 (7%) 302 Stroke 11 (3%) 302 a Blood tests Urea, mmol/L 8.0 (6.0–12.5) 183 Sodium, mmol/L 138.9 ± 3.0 182 Potassium, mmol/L 4.51 ± 0.48 182 Creatinine, μmol/L 95.0 (76.0–129) 183 Hb, g/L 135 ± 19 132 NT-proBNP, pg/mL 704 (190–2894) 90 eGFR, mL/min 66.1 ± 28.1 183 Non-pharmaceutical treatments Fluid restriction (any) 300 (99%) 302 Fluid restriction, 1500 mL/day 277 (92%) 302 Sodium restriction (any) 300 (99%) 302 Sodium restriction, 3500 mg/day 281 (93%) 302 Cardiac resynchronization therapy 28 (9%) 302 Implantable cardioverter defibrillator 47 (16%) 302 Pharmaceutical treatment Diuretics 212 (70%) 302 Diuretics dose changes in the last 24 h 7 (2%) 302 Furosemide dose, mg/day 61 ± 32 92 Torasemide dose, mg/day 10 (5–10) 115 (Continues) ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 2496 S.H. Eng et al. Table 1 (continued) Demographics N ACE inhibitors 137 (45%) 302 Angiotensin receptor blockers 49 (16%) 302 Beta-blockers 285 (94%) 302 Mineralocorticoid receptor antagonists 193 (64%) 302 ARNI 59 (20%) 302 Ivabradine 47 (16%) 302 Vasopressin V2 receptor blocker 1 (0.3%) 302 Proton pump inhibitors 141 (47%) 302 Opioids 5 (2%) 302 Antidepressants 57 (19%) 302 Benzodiazepines 71 (24%) 302 Anti-histamines 0 (0%) 302 TDS-HF total score 16.2 ± 9.3 302 ACE, angiotensin-converting enzyme; ARNI, angiotensin receptor–neprilysin inhibitors; BMI, body mass index; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; Hb, haemoglobin; HF, heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; TDS-HF, Thirst Distress Scale for patients with Heart Failure. Data are presented as n (%), mean ± standard deviation, or median (Q1–Q3). a Within previous 30 days. Exploratory factor analysis showed that one single factor Thirst distress explained 73% of the variance of the Spanish version of the TDS-HF. Concurrent validity analysis showed that the All patients completed the TDS-HF. Items 1, 2, 7, and 8 had the TDS-HF was significantly correlated with thirst intensity lowest mean value as many patients responded with 1 (r = 0.59; P < 0.001). (Table 2). The lowest mean value was 1.58 ± 1.16 for Item 8 The internal consistency of the TDS-HF was 0.95 (‘My thirst feels difficult to overcome’). The highest mean (Cronbach’s alpha). Homogeneity of the items was accept- value occurred in Item 3 and Item 4, the highest being able (r > 0.4). The lowest item-total correlation was in Item 2.56 ± 1.44 for Item 4 (‘My mouth feels dry when I am thirsty’). 6 (‘When I drink less water, my thirst gets worse’, r = 0.77), The mean thirst distress score was 16.2 ± 9.3 (range 8–40). and the highest was in Item 1 (‘My thirst bothers me a lot’, Twenty-six per cent of patients suffered no thirst distress r = 0.85). Inter-item correlations showed the strongest corre- (scores 0–8), 40% mild (9–16), 17% moderate (17–24), 9% high lations for Items 1 (‘My thirst bothers me a lot’) and 2 (‘I am (25–32), and 9% severe thirst distress (33–40; Figure 1). very uncomfortable when I am thirsty’, r = 0.84), and 7 (‘I am so thirsty I could drink water uncontrollably’) and 8 (‘My thirst feels difficult to overcome’, r = 0.83). The lowest Factors associated with thirst distress correlations were found for Items 4 (‘My mouth feels dry when I am thirsty’) and 8 (‘My thirst feels difficult to over- Table 3 shows univariable and multivariable regression anal- come’, r = 0.60). yses taking the thirst distress score as the dependent Table 2 Scores of the items and item distribution Agreement for each item, n (%) Strongly disagree Strongly agree Item Mean ± SD 1 2 3 4 5 1. My thirst bothers me a lot 1.87 ± 1.30 181 (60%) 45 (15%) 35 (12%) 15 (5%) 26 (8.6%) 2. I am very uncomfortable when I am thirsty 2.06 ± 1.39 161 (53%) 52 (17%) 32 (11%) 24 (7.9%) 33 (11%) 3. My mouth feels like sandpaper when I am thirsty 2.27 ± 1.40 126 (42%) 69 (23%) 46 (15%) 22 (7.3%) 39 (13%) 4. My mouth feels dry when I am thirsty 2.56 ± 1.44 92 (31%) 81 (27%) 49 (16%) 29 (9.6%) 51 (17%) 5. My saliva is very thick when I am thirsty 2.26 ± 1.43 129 (43%) 76 (25%) 26 (8.6%) 31 (10.3%) 40 (13%) 6. When I drink less water, my thirst gets worse 1.91 ± 1.36 184 (61%) 40 (13%) 31 (10%) 16 (5.3%) 31 (10%) 7. I am so thirsty I could drink water uncontrollably 1.75 ± 1.36 212 (70%) 33 (11%) 15 (5%) 6 (2%) 36 (12%) 8. My thirst feels difficult to overcome 1.58 ± 1.16 220 (73%) 38 (13%) 15 (5%) 8 (2.6%) 21 (7%) SD, standard deviation. ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 Thirst distress in outpatients with heart failure 2497 Figure 1 Prevalence of the predefined categories of thirst distress. No (standardized β = 0.17; P = 0.019), lower potassium (stan- distress (0–8 points); mild distress (9–16 points); moderate distress dardized β = 0.188; P = 0.009), lack of angiotensin receptor (17–24 points); high distress (25–32 points); and severe distress (33–40 points). blocker (ARB) treatment (standardized β = 0.156; P = 0.03), and higher dose of loop diuretics (standardized β = 0.259; P = 0.001) remained independently associated with thirst dis- tress. As both depression and antidepressants can influence thirst and thirst distress and only one third of patients taking antidepressants had a diagnosis of true depression, both var- iables were included in the multivariable analysis. Figure 2 shows thirst distress score (boxplots) among different doses of diuretics. Discussion Two main results can be derived from the present study, in which the newly developed TDS-HF in Spanish was used to measure thirst distress in a Spanish cohort of HF outpatients. First, although the majority of Spanish HF outpatients suffer mild to moderate thirst distress, almost one in five suffered variable. No multicollinearity was found for the variables in moderate–severe thirst-related distress, which is not a negli- the multivariable logistic regression (variance inflation factor gible number of patients. And second, several drugs com- range, 1.012–1.038). In the multivariable regression model monly used in HF patients might facilitate lower levels of that included also age, gender, body mass index, NYHA class, thirst distress, such as ARB, in contrast to depression, and antidepressant treatment, only higher urea angiotensin-converting enzyme (ACE) inhibitors. A third Table 3 Linear regression with variables associated with thirst distress Univariable Multivariable B coefficient 95% CI P-value B coefficient 95% CI P-value Not Not standardized Standardized Lower Upper standardized Standardized Lower Upper Age 0.016 0.022 0.068 0.101 0.71 -- -- -- -- -- -- -- -- -- -- Gender 3.29 0.156 0.923 5.66 0.007 -- -- -- -- -- -- -- -- -- -- Current smoking 0.637 0.026 0.397 2.123 0.65 a BMI 0.001 0.001 0.195 0.197 0.99 -- -- -- -- -- -- -- -- -- -- NYHA class 4.31 0.216 2.1 6.52 <0.001 -- -- -- -- -- -- -- -- -- -- Diabetes mellitus 0.209 0.011 2.358 1.940 0.85 Hypertension 1.32 0.067 0.901 3.541 0.24 a,b Renal failure 2.367 0.091 0.569 5.304 0.11 a,c Anaemia 1.119 0.038 2.245 4.482 0.51 Depression 4.87 0.155 1.35 8.39 0.007 -- -- -- -- -- -- -- -- -- -- Stroke 4.44 0.09 10 1.15 0.12 a,d Urea 1.77 0.193 0.449 3.1 0.009 1.6 0.17 0.267 2.92 0.019 a Potassium 2.99 0.156 5.76 0.21 0.04 3.63 0.188 6.32 0.93 0.009 a,d Creatinine 0.57 0.061 0.78 1.91 0.41 a Dose of diuretics 3,04 0.272 1.8 4.28 <0.001 2.98 0.259 1.37 4.59 <0.001 ACEI 0.31 0.02 2.42 1.80 0.77 ARB 2.93 0.117 5.75 0.096 0.04 3.62 0.156 6.89 0.345 0.03 Antidepressants 3.53 0.15 0.881 6.19 0.009 -- -- -- -- -- -- -- -- -- -- ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; NYHA, New York Heart Association. In the multivariable analyses, striped cells represent those variables included in the back-stepwise model but that did not remain into it (non-significant variables) while blank cells correspond to those variables not included in the analysis. Dose of diuretics: 0 = no diuretics; 1 = 1–40 mg/day; 2 = 41–80 mg/day; 3 = >80 mg/day. Less than 302 (Table 1). N = 173 in the multivariable analysis. a 2 Estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation) < 60 mL/min/1.73 m . b According to the World Health Organization criteria (<13 g/dL in men and <12 g/dL in women). c d Log-transformed and per 1 SD. ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 2498 S.H. Eng et al. Figure 2 Boxplots of thirst distress score among different doses of di- Spain, causing about 3–5% of all hospital admissions.22 In the uretics. The central box represents the values from the lower to the up- present study, increased thirst distress was associated in the per quartile; the middle lines represent the median; the whiskers extend to the minimum and maximum values, excluding far out values that are univariable analysis with female gender, depression, worse not displayed; and the blue dash represents mean values (N = 205). NYHA class, lower serum potassium, increased levels of serum urea and creatinine, and treatments such as antidepressants and diuretics. In contrast, patients with a history of stroke and, remarkably, patients receiving ARB experienced less thirst distress. The fact that medications can induce thirst has been previ- ously shown.13,23 In our study, we found that diuretics and antidepressants increase thirst distress in HF patients while ARB seemed to decrease it. Diuretics have already been asso- ciated with thirst in HF patients.13 This effect has been explained by the dehydration that can be caused by the excretion of fluids from the kidneys. Inter- estingly, but not surprisingly, we found a clear association be- tween the degree of thirst distress and the doses of loop diuretics, not only with loop diuretic prescription. The higher the dose, the stronger the thirst distress. The increased sympathetic activity and the high levels of circulating angiotensin II present in HF patients can be asso- ciated with an increased activity of the thirst centre in the circumventricular organ of the hypothalamus.24 Sympathetic interesting and novel finding was the association found be- stress causes vasoconstriction of the salivary glands with de- tween thirst distress and low blood levels of potassium. creased salivary secretion. The decrease in saliva is detected The Spanish-language version of the TDS-HF captured the by specific receptors in the mouth that are sensitive to content of the original scale with relevant adaption to the changes in friction and osmosis in the mouth mucosa. These cultural context. Thirst distress as measured with the receptors will activate the thirst centre. Angiotensin II binds TDS-HF was moderately associated with thirst intensity directly to receptors in the thirst centre and thereby causes (r = 0.59), which was also seen for the original scale thirst.24,25 In the present study, ARBs were associated with (r = 0.56).17 These results confirm that the intensity and dis- less thirst distress. ARBs are recommended to patients tress of thirst are different dimensions of the same symptom who experience negative side effects of ACE inhibitors,1 in and should therefore be assessed with different our cohort mainly due to persistent cough. ACE inhibitors measurements. and ARBs are common medications for HF patients. The The mean obtained score in this study was quite similar to mechanism for these drugs is to inhibit the effect of angio- the mean thirst distress score in the study by Waldréus et al. tensin II to control the neurohormonal activity in HF. In ad- with data from Sweden, the Netherlands, and Japan dition to the suppression of renin–angiotensin–aldosterone (16.4 ± 7.8).17 Differences in total thirst distress score were system, both angiotensin receptor–neprilysin inhibitors quite small between that countries; the biggest difference (ARNI) and ACE inhibitors have another mechanism of action was observed between Sweden and Japan (17.3 ± 7.6 vs. by the promotion of natriuresis. ARNI prevents the degrada- 15.4 ± 8.0). It has been suggested that thirst might differ be- tion of natriuretic peptides through inhibition of neprilysin tween countries not only due to differences in demographics and ACE inhibitors by decreased degradation of the and treatments but also due to climate, culture, and dietary vasodilatory and natriuretic peptide bradykinin.26,27 This habits.17 Our study does not intend to investigate differences dual action with both renin–angiotensin–aldosterone system between countries, but maybe future research could broaden inhibition and increased natriuresis could explain both the the perspective of factors that influence thirst in HF patients. superiority of ACE inhibitors and ARNI compared with ARB An international study could also be important to get closer in modifying patient’s prognosis and the increased thirst.1 to determine prevalence of thirst in HF patients globally. Studies on rats have suggested that increased levels of bra- dykinin are also associated with polyuria and polydipsia. The dipsogenic effect of ACE inhibitors in rats is believed to exist Factors associated with thirst distress in humans too.28 We hypothesized that patients on ARB might experience This is the first study to examine thirst distress in HF patients less thirst because of the change from ACE inhibitors to ARB in a Spanish cohort. HF is one of the leading health issues in and, in a speculative way, maybe patients who experience ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 Thirst distress in outpatients with heart failure 2499 severe thirst could be advised to switch medications from but one study showed that most clinicians are unsure about ACE inhibitors to ARB. the usefulness of these interventions.9 Introducing a screen- Antidepressants were also associated with increased thirst ing of thirst is an important step towards helping patients in the univariable analysis, although lost significance in the who develop or suffer from thirst. This could be especially im- multivariable analysis. Different antidepressants have portant in groups more disposed to develop thirst. Because anti-cholinergic effect that modulates the regulation of the treatments have shown to affect thirst, individual assessment salivary glands by the autonomic nervous system. These of treatments could be helpful for patients experiencing changes include alterations in saliva composition and salivary thirst. As this study suggests, patients experiencing thirst secretion rate that can cause dry mouth.23 Another plausible might benefit from changing medication from ACE inhibitors reason for increased thirst observed in patients on antide- to ARB. However, as ARBs are inferior in modifying patient pressants is the depression itself, which was also associated prognosis in HF, our findings need to be confirmed in other with thirst in the univariable analysis. Over 20% of HF pa- studies. tients are estimated to suffer from depression.29 Stress, anx- If possible, the patients could benefit from lowering the iety, and depression have a significant effect on reducing dose of diuretics as well. Further studies are needed on strat- saliva and causing dry mouth.30 The high sympathetic activity egies for thirst relief. Factors associated with thirst are possi- seen in HF patients can be even more increased in patients ble target points to be included in these studies. experiencing psychological distress, such as depression and anxiety.31 The increased sympathetic activity could contribute to the increased thirst in depressive patients.23 Limitations Low serum potassium was another factor related to in- creased thirst distress. This is a new finding not described The strength of this study was a large study sample including previously. Beside to diet, serum potassium levels can be 302 patients. However, most study participants were men lowered by diuretic treatment. Remarkably, our results (74%), which limit the generalizability to all HF patients. showed that low serum potassium increased thirst distress in- Also, another limitation of the generalizability is the setting dependently of diuretics and no collinearity was found be- at an outpatient clinic. The study population had a relatively tween both variables in the regression analysis. The role of mild to moderate HF, according to LVEF, dominating NYHA potassium in thirst in HF patients is not well elucidated, but II, and moderate levels of N-terminal pro-B-type natriuretic possible mechanisms can be related to the vasodilator and peptide. This further limits the generalizability of the results natriuretic effects of potassium. Increased potassium causes to those taking higher doses of diuretics and in higher NYHA endothelium-dependent vasodilatation through stimulation class (NYHA III–IV). With regard to content validity, we did not of Na+/K+ ATPase pump and opening of potassium channels, do separate analysis for the Spanish version of the TDS-HF. which hyperpolarize the vascular smooth muscle cell leading And this is a recommendation for future studies.36 to vasodilatation32 and reducing the sensitivity to catechol- Given the cross-sectional design of this study, causality amine and angiotensin II-related vasoconstriction.33 We hy- cannot be determined and confounding factors cannot be ex- pothesized that potassium can disrupt the increased cluded. The blood samples and LVEF were not taken at time sympathetic processes in HF and thereby decrease thirst in of the visit but from a medical database. To ensure that these HF patients. variables were representative of the present data, only blood Our study also showed that women suffered from more samples taken within 30 days and LVEF within 1 year were in- thirst distress than men. This is in line with a recent study ex- cluded. Urine sodium, which is a marker of natriuresis and amining thirst trajectories from hospital admission to 4 weeks might potentially modify thirst, was not measured in this of follow-up.7 Other studies, in contrast, have shown that study. In a previous study, the results showed that patients men with HF are thirstier than women.4 Studies on healthy admitted to hospital for worsening of HF had significantly in- subjects have found no difference in thirst between genders, creased thirst compared with patients without HF.37 The uri- but xerostomia (feeling of dry mouth) is more common in nary sodium was significantly lower in patients with HF, women.34 Other explanations for the increased thirst distress which is consistent with the neurohumoral activation associ- in women with HF might be that they experience a greater ated with this syndrome (70 vs. 107 mmol/L; P < 0.006), but degree of anxiety and depression.35 there was no correlation with thirst.37 Moreover, the differ- Despite the negative impact thirst has on daily life of these ence in serum sodium that was measured (1.4 mmol/L) is patients, in current practice, there is no structural clinical hardly sufficient to explain the greatly increased thirst among evaluation of thirst in HF patients or current guidelines on the HF patients. A very low urinary sodium excretion how to help these patients manage their thirst. Though the (<30 mmol/L) has been associated with poor short-term absence of guidelines, there are some common strategies prognosis, but not with thirst, in older patients with recommended by health care professionals. Common strate- multimorbidity.38 As only a few studies have investigated gies include the use of ice chips or taking small sips of water, the relation between natriuresis and thirst in HF, it can be ESC Heart Failure 2021; 8: 2492–2501 DOI: 10.1002/ehf2.13395 2500 S.H. Eng et al. advised to include such data in future studies to strengthen patients can receive the care needed that might contribute to our knowledge of thirst in HF. improved quality of life. Cut-off scores used to categorize the total thirst distress score into categories were chosen arbitrarily. However, they were based on a logical reasoning based on what the mean Conflict of interest score of each item would be if the mean total score was di- vided by the number of items. For this study, only data on None declared. prescribed fluid restriction were collected and no data on ac- tual fluid intake. Funding Conclusions None. The Spanish-language version of the TDS-HF was shown to be reliable and valid. One in five experienced severe distress by thirst, although on average the total population seemed Supporting information mildly to moderately stressed. Several factors, such as de- pression, diuretic dose, and ARB treatment, can influence Additional supporting information may be found online in the thirst distress in HF patients, and they are important targets Supporting Information section at the end of the article. when screening for thirst and also for thirst relief. Based on our results, treatment with ARB might have an independent Data S1. 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