ORIGINAL RESEARCH published: 29 March 2019 doi: 10.3389/fneur.2019.00305 Frequency, Risk Factors, and Prognosis of Dehydration in Acute Stroke Elena Cortés-Vicente, Daniel Guisado-Alonso, Raquel Delgado-Mederos, Pol Camps-Renom, Luis Prats-Sánchez, Alejandro Martínez-Domeño and Joan Martí-Fàbregas* Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain Edited by: Antonio Arauz, Objective: To determine the frequency, risk factors, and impact on the outcome of Instituto Nacional de Neurología y dehydration after stroke. Neurocirugía (INNN), Mexico Reviewed by: Methods: In this cross-sectional observational study, we included prospectively and Ashfaq Shuaib, consecutively patients with ischemic and hemorrhagic stroke. The serum Urea/Creatinine University of Alberta, Canada Xabier Urra, ratio (U/C) was calculated at admission and 3 days after the stroke. Dehydration Hospital Clínic de Barcelona, Spain was defined as U/C>80. Patients were treated in accordance with the standard local *Correspondence: hydration protocol. Demographic and clinical data were collected. Neurological severity Joan Martí-Fàbregas was evaluated at admission according to the NIHSS score; functional outcome was jmarti@santpau.cat assessed with the modified Rankin scale score (mRS) at discharge and 3 months after Specialty section: the stroke. Unfavorable outcome was defined as mRS > 2. This article was submitted to Stroke, Results: We evaluated 203 patients; 78.8% presented an ischemic stroke and 21.2% a section of the journal a hemorrhagic stroke. The mean age was 73.4 years ±12.9; 51.7% were men. Frontiers in Neurology Dehydration was detected in 18 patients (8.9%), nine patients at admission (4.5%), and Received: 05 February 2019 nine patients (4.5%) at 3 days after the stroke. Female sex (OR 3.62, 95%CI 1.13–11.58, Accepted: 11 March 2019 Published: 29 March 2019 p = 0.03) and older age (OR 1.05, 95%CI 1–1.11, p = 0.048) were associated with a Citation: higher risk of dehydration. Dehydration was significantly associated with an unfavorable Cortés-Vicente E, Guisado-Alonso D, outcome at discharge (OR 5.16, 95%CI 1.45–18.25, p = 0.011), but the association was Delgado-Mederos R, Camps-Renom P, Prats-Sánchez L, not significant at 3 months (OR 2.95, 95%CI 0.83–10.48, p = 0.095). Martínez-Domeño A and Conclusion: Dehydration is a treatable risk factor of a poor functional outcome after Martí-Fàbregas J (2019) Frequency, Risk Factors, and Prognosis of stroke that is present in 9% of patients. Females and elders present a higher risk Dehydration in Acute Stroke. of dehydration. Front. Neurol. 10:305. doi: 10.3389/fneur.2019.00305 Keywords: stroke, dehydration, urea, creatinine, prognosis, risk factors Frontiers in Neurology | www.frontiersin.org 1 March 2019 | Volume 10 | Article 305 Cortés-Vicente et al. Dehydration in Acute Stroke INTRODUCTION mRS > 2. The functional evaluation of the patients was assessed during face-to-face interviews 3 months after stroke. The clinical guidelines state that dehydration after stroke results If a face-to-face interview was not possible, the data were in a poorer vital and functional prognosis (1–4). Dehydration obtained by a phone interview. Responses of patients, relatives increases hemoconcentration and blood viscosity and decreases or caregivers were recorded. Demographic data (age, sex) blood pressure, factors that may worsen the effects of brain and functional status before the stroke according to the ischemia (5), resulting in greater brain damage, and more severe mRS score were collected. The main clinical features of the symptoms. Dehydration is related also with a higher risk of disease, such as stroke type (ischemic or hemorrhagic), arterial complications, such as venous thrombosis. Among other factors, territory if ischemic stroke, stroke etiology according to TOAST stroke patients may be predisposed to dehydration because of classification (15) if ischemic stroke, time elapsed from stroke decreased oral intake of water due to dysphagia (6) or low level onset to admission, reperfusion therapies if ischemic stroke, of consciousness. Stroke occurs more frequently in the elderly, admission to the Stroke Unit, presence of dysphagia, presence and dehydration is common in these patients (7). Dehydration of aphasia, length of hospitalization in days, and cardiovascular is important also because of its economic impact, as dehydration risk factors were also recorded. History of potential risk at admission is associated with higher admission costs in acute factors of dehydration, such as heart or renal failure, treatment ischemic stroke (8). with diuretics, living alone, vomiting, diarrhea, or fever, were There is substantial variation in hydration status definition recorded also. and diagnostic approach to dehydration (9). The blood Urea/Creatinine ratio (U/C) (10, 11), the blood urea Study Protocol nitrogen/Creatinine ratio (BUN/C) (6, 8, 12) and plasma Patients were treated according to the standard local protocol: osmolality (13) have been used to detect dehydration. Multi- nil per os during the first 24 h from the onset of the stroke frequency bioelectrical impedance has also been tested, and intravenous hydration with saline serum (500 ml/6 h) but appeared ineffective to diagnose dehydration correctly with potassium supplements, adjusted in selected cases when after stroke (14). These studies suggested that dehydration needed (heart or renal failure history, presence of hypoglycaemia, after stroke is a prevalent phenomenon, with a frequency vomiting, diarrhea, or fever). Glucose levels were monitored around 60% measured with de U/C ratio (10) and around periodically. After a standardized swallowing test conducted by 53% with the BUN/C ratio (6), and that it is associated a trained nurse, patients started oral hydration, and nutrition with a poor prognosis (8, 10, 12, 13). However, these (or by nasogastric tube if severe dysphagia) from day 2 onwards. studies are retrospective and did not include a follow-up Blood samples were obtained at admission and 3 days after the evaluation. Thus, it is still unclear if dehydration significantly stroke. U/C ratio was calculated. Dehydration was defined as influences outcome. a blood U/C ratio >80 (10). The study was approved by the Our aim was to determine the frequency and risk factors of ethics committee of Hospital de la Santa Creu i Sant Pau. Verbal dehydration after acute stroke, and its effects on the outcome at informed consent was obtained from all of the patients or their discharge and 3 months after stroke, using a blood biomarker of legal representatives. A signed consent was not deemed necessary dehydration as a diagnostic tool. by the committee due to the absence of a change in the routine management of the patients and also that the data obtained MATERIALS AND METHODS were anonymous. Patients Statistical Analysis This is a cross-sectional observational study of patients A descriptive data analysis was performed. Demographic prospectively and consecutively included during a 10-month characteristics were reported as means and standard deviations period. This period of time was estimated to include 185 or percentages. NIHSS scores are reported as medians and patients, the sample size needed for an estimated proportion interquartile ranges. Differences in baseline characteristics of 62% (10), a 95% confidence level, and a desired precision between dehydrated and non-dehydrated patients were of 7%. All patients had an ischemic or hemorrhagic stroke, compared using a chi-square (χ2) test for categorical variables confirmed by neuroimaging techniques (CT or MRI). Patients and a t-Test analysis was used to compare quantitative under 18 years old, admitted >72 h after stroke onset and variables. A significant difference was defined as p < 0.05. with a previous modified Rankin scale score (mRS) >2 Univariate logistic regression models between the dependent were excluded. variable (presence of dehydration) and sex, age, subtype of stroke, NIHSS score at admission, time from stroke onset Clinical Evaluation to evaluation, presence of heart, and renal failure, previous Patients were evaluated by a neurologist at admission, at use of diuretics, presence of vomiting, fever and diarrhea, discharge and 3 months after stroke. Assessment included presence of dysphagia and aphasia, admission at the Stroke evaluation of stroke severity according to the National Institute Unit and living alone, were investigated. In another analysis, of Health Stroke Scale (NIHSS) score and functional evaluation univariate logistic regression models were used also between the according to the mRS score. Investigators were blinded to dependent variable (unfavorable prognosis) and dehydration, the U/C ratio results. Unfavorable outcome was defined as NIHSS score at admission, sex, age, subtype of stroke and Frontiers in Neurology | www.frontiersin.org 2 March 2019 | Volume 10 | Article 305 Cortés-Vicente et al. Dehydration in Acute Stroke TABLE 1 | Comparison of clinical features in patients classified as either TABLE 2 | Comparison of clinical features in patients with good prognosis (mRS dehydrated or non-dehydrated during hospital admission and p-values from ≤ 2) and poor prognosis (mRS > 2) at discharge and p-values from statistical statistical analysis. analysis. Dehydrated Hydrated p value mRSa ≤ 2 mRS > 2 p-value patients patients (n = 109) (n = 94) (n = 18) (n = 185) Age, years. Mean (SD) 71.0 (12.9) 75.1 (12.6) 0.024 Age, years. Mean (SD) 80.2 (9.5) 72.8 (13.0) 0.019 Sex (Female/Male) (% males) 46/63 (57.8%) 52/42 (44.7%) 0.062 Sex (Female/Male) (% Males) 14/4 (22.2) 84/101 (54.6) 0.009 NIHSSb at admission 3 (1–6) 13 (5–18) <0.0001 Stroke type (Ischemic/ 17/1 (94.4) 143/42 (77.3) 0.089 (median–IQR) Hemorrhagic) (% Ischemic) Dehydration n, (%) 4/105 (3.7) 14/80 (14.9) 0.005 TOAST classification (n = 17) (n = 143) 0.822 Stroke type (Ischemic/ 89/20 (81.7) 71/23 (75.5) 0.287 Large-artery atherosclerosis (%) 3 (17.6) 21(14.7) Hemorrhagic) (% Ischemic) Cardioembolism (%) 7 (41.2) 51 (35.7) Admission at Stroke Unit n, (%) 75/34 (68.8) 67/27 (71.3) 0.702 Small-vessel occlusion (%) 0 (0) 11 (7.7) a Modified Rankin scale score. Stroke of other determined 1 (5.9) 9 (6.3) b National Institute of Health Stroke Scale. etiology (%) Stroke of undetermined 6 (35.3) 51 (35.7) etiology (%) Anterior arterial territory n, (%) 13/17 (76.5) 120/143 (83.9) 0.531 9.8 (SD 14) hours after the stroke onset. All of the patients were a NIHSS at admission 10 (3–13) 5 (2–14) 0.346 hydrated initially intravenously within the first 24 h of admission. (median–IQR) From the second day on, 168 (82.8%) were hydrated orally and 35 Hours from onset. Mean (SD) 7.2 (6.4) 10.1 (14.5) 0.395 (17.2%) needed hydration by nasogastric tube because of severe Renal failure n, (%) 1/18 (5.6) 26/185 (14.1) 0.311 dysphagia or low level of consciousness. All of the included Heart failure n, (%) 4/18 (22.2) 21/185 (11.4) 0.180 patients were evaluated at 3 months, 164 during face-to-face Dysphagia n, (%) 7/18 (38.9) 32/185 (17.3) 0.026 interviews, and 39 by phone. Aphasia n, (%) 4/18 (22.2) 60/185 (32.4) 0.373 Dehydration based on the blood U/C ratio was detected in 18 Diuretic treatment n, (%) 8/18 (44.4%) 72/185 (38.9) 0.647 patients (8.9%) at some point during the hospitalization. Nine Reperfusion therapy n, (%) 3/17 (17.7%) 28/143 (19.6) 0.849 patients (4.5%) were dehydrated at admission and, after 3 days Stroke Unit admission n, (%) 10/18 (55.6) 132/185 (71.4) 0.163 follow-up, the U/C ratio was normal in eight patients and only Arterial hypertension (%) 12/18 (66.7) 126/185 (68.1) 0.900 one remained dehydrated. The other nine patients (4.5%) were Diabetes Mellitus n, (%) 4/18 (22.2) 41/185 (22.2) 0.995 not dehydrated at admission, but were dehydrated 3 days after Vomiting n, (%) 2/18 (11.1) 14/185 (7.6) 0.594 the stroke. Diarrhoea n, (%) 0/18 (0) 3/185 (1.6) 0.586 Patients who presented dehydration were older (p = 0.019), Fever n, (%) 3/18 (16.7) 14/185 (7.6) 0.183 more often women (p = 0.009) and with a higher frequency of dysphagia (p = 0.026) compared to non-dehydrated patients. No mRSb > 2 at discharge n, (%) 14/18 (77.8) 80/185 (43.2) 0.005 differences in other variables were found (Table 1). From the mRS > 2 at 3 months n, (%) 13/18 (72.2) 80/185 (43.2) 0.018 multivariable logistic regression analysis, the variables associated Length of hospitalization, days. 16.4 (9.9) 12.6 (9.4) 0.098 Mean (SD) with dehydration were female sex (OR 3.62, 95% CI 1.13–11.58, Living alone n, (%) 7/18 (38.9) 49/185 (26.5) 0.261 p = 0.03) and older age (OR 1.05, 95% IC 1–1.11, p = 0.048). Patients who presented an unfavorable outcome at discharge a National Institute of Health Stroke Scale. b Modified were older (p = 0.024), had a higher NIHSS score at admission Rankin scale score. (p < 0.0001), had a higher frequency of dehydration (p = 0.005), and a non-significant trend to be females (p = 0.062) (Table 2). admission at the Stroke Unit, at discharge and 3 months after From the multivariable logistic regression analysis, the variables the stroke. A multivariate logistic regression method was used associated with an unfavorable outcome were NIHSS score (OR to ascertain independent associations between those factors 1.2, 95% CI 1.14–1.27, p < 0.0001) and dehydration (OR 5.16, with p < 0.10 from the univariate analysis. Data analysis was 95% CI 1.45–18.25, p = 0.011) (Figure 1A). carried out using Stata 13.0 (StataCorp, College Station, TX) Similarly, patients who presented an unfavorable outcome 3 for Windows. months after the stroke were significantly older (p = 0.001), had a higher NIHSS score at admission (p < 0.001), were more often females (p = 0.045), and were more often dehydrated (p = 0.018) RESULTS (Table 3). From the logistic regression analysis, the variables associated with an unfavorable outcome were high NIHSS score We studied 203 patients; 160 (78.8%) with ischemic stroke and (OR 1.24, 95% CI 1.16–1.32, p < 0.0001) and older age (OR 1.04, 43 (21.2%) with hemorrhagic stroke. Their mean age was 73.4 95% IC 1.01–1.07, p = 0.012). Dehydration was not significantly years (SD 12.9); 51.7% of them were men. The median NIHSS at associated with the outcome at 3 months (OR 2.95, 95% CI admission was five (IQR 2–14). Patients were admitted a mean of 0.83–10.48, p = 0.095) (Figure 1B). Frontiers in Neurology | www.frontiersin.org 3 March 2019 | Volume 10 | Article 305 Cortés-Vicente et al. Dehydration in Acute Stroke TABLE 3 | Comparison of clinical features in patients with good prognosis (mRS ≤ 2) and poor prognosis (mRS > 2) 3 months after the stroke and p-values from statistical analysis. mRSa ≤ 2 mRS > 2 p-value (n = 110) (n = 93) Age, years. Mean (SD) 70.1 (SD 13.4) 76.3 (SD 11.5) 0.001 Sex (Female/Male) (% males) 46/64 (58.2) 52/41 (44.1) 0.045 NIHSSb at admission 3 (1–5) 13 (6–18) <0.0001 (median–IQR) Dehydration n, (%) 5/105 (4.5) 13/80 (14.0) 0.018 Stroke type (Ischemic/ 91/19 (82.7) 69/24 (74.2) 0.138 Hemorrhagic) (% Ischemic) Admission at Stroke Unit n, (%) 75/35 (68.2) 67/26 (72.0) 0.550 a Modified Rankin scale score. b National Institute of Health Stroke Scale. detecting dehydration. The reference study included a large number of patients, but its design was retrospective, the only functional evaluation that was reported was at discharge, and a detailed description of the hydration protocol they used was not provided. Previous studies have associated elder age and female sex to dehydration (10, 16, 17). Older adults have less body water, reduced thirst signals that may lead to less water intake, and also the function of the kidneys is reduced with age and they may have problems with urine concentration. Women also have lesser body water than men. In our series, patients who were dehydrated were more likely to be elders and females. We found that dysphagia was more frequent in patients presenting dehydration, but our data did not proved it as an independent risk factor of FIGURE 1 | Comparison of mRS scores in dehydrated patients (n = 18) and dehydration by the logistic regression analysis. In the literature, non-dehydrated patients (n = 185) at discharge (A) and after 3 months (B). we found discrepant results regarding dysphagia as a dehydration risk factor (6, 18). Urea and Creatinine assays are rapid, cheap, and easily available to diagnose and follow up dehydration and are included DISCUSSION in the routine assessment of every patient with stroke. However, we acknowledge that the U/C ratio may be inaccurate in In our study, 8.9% of the patients presented dehydration based certain medical conditions such as renal or cardiac disease, on the U/C ratio at any point during the 3 first days of gastrointestinal bleeding, diarrhoea, vomiting, infections, and use hospitalization. Our data revealed that dehydration is associated of diuretics (10, 11). In our sample, we found no significant with a 5-fold higher risk of poor outcome at hospital discharge differences in these conditions between dehydrated and non- and is related to female sex and older age. dehydrated patients. Thus, the main limitation of our study is Our data regarding dehydration frequency (8.9%) showed a the absence of a “gold standard” for measuring dehydration. notable difference when compared with the only other study However, other blood biomarkers that have been proposed, that used the U/C ratio, in which 62% of patients presented such as BUN/C ratio (6, 8, 12) or plasma osmolality (13), dehydration (10). Other studies using other parameters detected have also similar limitations and are more difficult to obtain also a higher frequency (53%) of dehydration (6). Differences in the Emergency Department. Multi/frequency bioelectrical in prevalence of dehydration risk factors between both impedance is ineffective and additionally it is not easily available populations may explain these discrepancies. Also differences (14). Although of help, clinical data such as dry mouth, dry skin, in the hydration protocol used in different hospitals may be thirst or dark, and scarce urine are subjective parameters. Taking the cause, with a lower frequency in our patients because of these facts into consideration, we think that the U/C ratio is the standardized protocol we use. The higher number of blood the easiest, most cost-effective, and most reliable biomarker of tests that were used in the reference study (10) (a median hydration to use in stroke patients. Therefore, we recommend of four tests per patient compared to two systematic blood these assays at the Stroke Unit (19) to improve the maintenance controls in our study), may have increased the possibility of of homeostasis of patients with stroke. Frontiers in Neurology | www.frontiersin.org 4 March 2019 | Volume 10 | Article 305 Cortés-Vicente et al. Dehydration in Acute Stroke Another limitation of the study is that although we included In conclusion, dehydration is a common risk factor associated the statistically necessary number of patients, the group of with a poor functional outcome after stroke. Dehydration should patients with dehydration is relatively small. We expected a be systematically studied using serum biomarkers, especially in higher frequency of dehydration, based in previous studies. With elders and females. a larger sample of patients it is likely that we would have found a significant association between outcome at 3 months DATA AVAILABILITY and dehydration and we also would have been able to analyse separately risk factors associated with dehydration at admission All datasets generated for this study are included in and dehydration during hospitalization. the manuscript. However, the strength of our study is that we included consecutive evaluation of a large number of patients at discharge AUTHOR CONTRIBUTIONS and 3 months after the stroke. This provides consistency and EC-V and JM-F contributed conception and design of the reliability to our study. The findings of our study are important study. EC-V and DG-A contributed acquisition of data. EC-V because dehydration is a potentially preventable and easily organized the database and performed the statistical analysis, treatable complication in stroke. According to our results, elders wrote the first draft of the manuscript. All authors contributed and women should be carefully evaluated because they are at a interpretation of data, manuscript revision, read, and approved higher risk of dehydration after stroke. the submitted version. Although dehydration is an important prognostic risk factor in stroke patients, we are not certain that treating dehydration significantly improves outcome. A study showed that BUN/C FUNDING ratio-based saline hydration therapy in patients with acute This work was supported by Instituto de Salud Carlos III, ischemic lacunar stroke significantly increased the rate of RETICS (Redes Temáticas de Investigación Cooperativa en favorable clinical outcome with functional independence at 3 Salud) INVICTUS PLUS RD06/0019/0010 and FEDER. months after stroke. However, this was a non-blinded study that used historical controls (20). So, further studies are ACKNOWLEDGMENTS required to determine whether reversing dehydration after stroke significantly improves the functional outcome. The authors thank W. Stone for English language assistance. REFERENCES acute ischaemic stroke. Eur J Neurol. (2014) 21:1184–91. doi: 10.1111/ ene.12452 1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker 9. Bahouth MN, Gottesman RF, Szanton SL. 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Favorable provided the original author(s) and the copyright owner(s) are credited and that the outcome of blood urea nitrogen/creatinine-based hydration therapy 3 original publication in this journal is cited, in accordance with accepted academic months after acute ischemic stroke. Am J Emerg Med. (2016) 34:2414–8. practice. No use, distribution or reproduction is permitted which does not comply doi: 10.1016/j.ajem.2016.09.033 with these terms. Frontiers in Neurology | www.frontiersin.org 6 March 2019 | Volume 10 | Article 305