Abstract
Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD), but there is no consensus on its definition. In 2015, Flythe proposed a definition of IDH (Definition 1 in this study): nadir systolic blood pressure (SBP) <90 mmHg during hemodialysis for patients with pre-dialysis SBP <159 mmHg, and nadir SBP <100 mmHg during hemodialysis for patients with pre-dialysis SBP ≥160 mmHg. This prospective observational cohort study investigated the association of frequent IDH based on Definition 1 with clinical outcomes and compared Definition 1 with a commonly used definition (nadir SBP <90 mmHg during hemodialysis, Definition 2). The incidence of IDH was observed over a 3-month exposure assessment period. Patients with IDH events ≥30% were classified as ‘frequent IDH’; the others were ‘infrequent IDH’. All-cause mortality, cardiovascular mortality, and all-cause hospitalization events were followed up for 36 months. This study enrolled 163 HD patients. The incidence of IDH was 11.1% according to Definition 1 and 10.5% according to Definition 2. The Kaplan-Meier curves showed that frequent IDH patients had higher risks of all-cause mortality (p = 0.009, Definition 1; p = 0.002, Definition 2) and cardiovascular mortality (p = 0.021, Definition 1). Multivariable Cox regression analysis indicated that frequent IDH was independently associated with a higher risk of all-cause mortality (Model 1: HR = 2.553, 95%CI 1.334–4.886, p = 0.005; Model 2: HR = 2.406, 95%CI 1.253–4.621, p = 0.008). In conclusion, HD patients classified as frequent IDH are at a greater risk of all-cause mortality. This highlights the significance of acknowledging and proactively managing frequent IDH within the HD patients.
Background
Hemodialysis is a widely used treatment for patients with end-stage renal disease (ESRD) and involves the removal of waste products and excess fluids from the blood through an artificial kidney machine [Citation1]. In addition to vascular access events (e.g., thrombosis, stenosis, and infection) [Citation2], intradialytic hypotension (IDH) is a common complication during hemodialysis and mainly occurs when plasma fluid removal through ultrafiltration outpaces the rate of refilling [Citation3–5]. IDH is associated with adverse outcomes, including increased mortality [Citation6], cardiovascular events [Citation7], vascular access thrombosis [Citation8], organ/limb ischemia [Citation9, Citation10], and decreased quality of life [Citation11–13]. Several factors contribute to the development of IDH, such as changes in blood volume [Citation14], low pre-dialysis systolic blood pressure (SBP), diabetes [Citation15], interdialytic weight gain (IDWG) [Citation7], first dialysis day of a week [Citation16], dialysate composition [Citation17], and dialysate temperature [Citation18]. Despite numerous attempts to reduce the incidence of IDH [Citation19–22], it remains a major concern in managing patients with ESRD undergoing hemodialysis.
Currently, there is no consensus on the definition of IDH, which has led to variability in its reported incidence, which ranges from 4% to 68.9% [Citation23, Citation24]. Different definitions of IDH have been reported, which include one or more of the following components: decrease in SBP by a given value/percentage, SBP decreases below a given threshold, patient self-reported symptoms, and intervention during treatment. The Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines define IDH as a decrease in SBP by ≥20 mmHg or mean arterial pressure (MAP) by ≥10 mmHg, accompanied by symptoms such as abdominal discomfort, yawning, nausea, and dizziness [Citation25]. The European best practice guidelines have a similar definition to K/DOQI [Citation26]. According to some authors, the selection of an appropriate IDH definition should be based on the specific objectives of the study [Citation23, Citation27]. For example, studies that emphasize patients’ quality of life may prefer to adopt IDH definitions encompassing symptoms or interventions [Citation13].
Flythe et al. [Citation24] proposed a definition of IDH based on retrospective study results: patients with pre-dialysis SBP <159 mmHg presenting with nadir SBP <90 mmHg during hemodialysis or patients with pre-dialysis SBP ≥160 mmHg presenting with nadir SBP <100 mmHg during hemodialysis. Although frequent IDH (≥30%) based on this definition was found associated with all-cause mortality [Citation24], its relationship with other clinical endpoints such as cardiovascular death, all-cause hospitalization events, vascular access, and arteriovenous fistula (AVF) events remained under-investigated. Prospective studies are needed to verify the value of this definition in predicting patient outcomes.
The previous study by Flythe et al. [Citation24] only examined the impact of IDH on all-cause death but did not examine other patient outcomes. Therefore, this prospective observational cohort study investigated the association of frequent IDH based on Definition 1 (Flythe’s definition Citation24] with clinical outcomes and compared Definition 1 with Definition 2 (nadir SBP <90 mmHg during hemodialysis), which was also investigated in Flythe’s study.
Methods
Study design and patients
This single-center prospective cohort study was conducted at the Blood Purification Center of North Huashan Hospital, Fudan University. All eligible patients were enrolled on September 1, 2018, and underwent a 30-day adaptation period. Subsequently, the patients were followed up for 3 months (the exposure assessment period). The observation period started on January 1, 2019, and was the start of the at-risk period. The patients still receiving hemodialysis treatment at the study center on December 31, 2021, had a total at-risk period of at least 36 months (). The patients were considered at risk from the start of the observation period until death, leaving the study center (due to transfer to another center or transplantation), or at the end of the study period (December 31, 2021).
Figure 1. CONSORT diagram.
The inclusion criteria were age >18 years and undergoing routine maintenance hemodialysis. The exclusion criteria were a short life expectancy, the possibility of short-term recovery of renal function or a short-term change to another renal replacement therapy judged by at least two nephrologists according to the patient’s condition, organ failure (other than renal dysfunction), untreated solid or hematological tumors diagnosed within the last 5 years, active gastrointestinal bleeding within the past month, uncorrected or uncorrectable congestive heart failure, myocardial infarction, cerebral infarction, or history of cerebral hemorrhage within the last 3 months, dementia, inability or refusal to measure blood pressure with the upper arm, inability to cooperate with the study or sign an informed consent form, or refusal to participate in this study. Polysulfone membrane dialyzers were used for all patients, with bicarbonate as the buffer base. All patients underwent hemodialysis at a standard temperature of 36.5 °C as the starting temperature.
The study followed the guidelines of the Declaration of Helsinki. The study protocol was approved by the Institutional Ethics Review Board of Huashan Hospital, Fudan University (approval # KY2016-394). Written informed consent was obtained from each participant before enrollment.
IDH definition and grouping
In this study, two definitions of IDH were used. In Definition 1, IDH was defined as patients with pre-dialysis SBP <159 mmHg who presented with nadir SBP <90 mmHg during hemodialysis session or patients with pre-dialysis SBP ≥160 mmHg who presented with nadir SBP <100 mmHg during hemodialysis session. In Definition 2, IDH was defined as nadir SBP <90 mmHg during dialysis. Blood pressure was measured using an automatic upper arm sphygmomanometer every 30 min during hemodialysis. An IDH event was identified when a patient’s SBP in a particular hemodialysis session met the criteria mentioned above.
The incidence of IDH was determined by calculating the percentage of hemodialysis sessions in which IDH occurred during the 3-month exposure assessment period. Based on the frequency of IDH during the exposure assessment period, the patients were divided into two groups. The patients who experienced IDH in ≥30% of their hemodialysis sessions were classified as the frequent IDH group, while those who had IDH in <30% of their hemodialysis sessions were classified as the IDH infrequent group [Citation24].
Clinical outcomes
The primary outcome was all-cause mortality. The secondary outcomes included cardiovascular mortality, primary all-cause hospitalization event, and vascular access/AVF event (for AVF population only). Cardiovascular mortality was defined as death resulting from heart attack, coronary artery disease, arrhythmia, congestive heart failure, cardiomyopathy, cardiac arrest, cardiac valve disease, pulmonary edema, cerebral hemorrhage, ischemic encephalopathy, or hypoxic encephalopathy [Citation7]. A vascular access/arteriovenous fistula (AVF) event was defined as stenosis that exceeded 50% of the internal diameter of the fistula, with a natural blood flow <600 mL/min for grafts or <500 mL/min for fistulas, pressure ratio >0.5 at the venous end of the graft or fistula or >0.75 at the arterial end of the graft, acute thrombosis, when catheter blood flow was <200 mL/min or blood pump blood flow was <200 mL/min to meet the required blood flow for dialysis prescription, elevated dialysis venous pressure, difficulty in puncture, decreased dialysis adequacy, or abnormal signs of the fistula [Citation28].
The patients were hospitalized if any of the following occurred: vascular access-related infections, vascular access events, infections unrelated to vascular access, congestive heart failure, outpatient on intensive dialysis unable to tolerate intensive dialysis, and any diseases that required hospitalization (e.g., myocardial infarction, cerebral hemorrhage, cerebral infarction, gallstones, tumors, trauma, fractures, etc.).
Data collection
Demographic and hemodialysis-related information was collected, including sex, age, dialysis vintage, type of vascular access (including AVF, arteriovenous graft, and tunneled cuff catheter [TCC]), body mass index, etiology of ESRD (including glomerular disease, diabetes mellitus, hypertension, and other diseases), average pre-dialysis SBP and diastolic blood pressure (DBP), average net ultrafiltration volume (UFV), IDWG, and percent intradialytic weight gain (IDWG%). Blood samples were collected in the final week of December 2018 and served as the baseline values. The biochemical parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T (TnT), C-reactive protein (CRP), intact parathyroid hormone (iPTH), calcium (Ca), phosphorus (P), calcium-phosphorus product (Ca*P), hemoglobin, albumin, ferritin, serum creatinine, total cholesterol, and low-density lipoprotein cholesterol (LDL). Dialysis adequacy was determined using the urea clearance index Kt/V=–ln (R-0.008t) + (4-3.5 R) × UF/W [Citation29]. The geriatric nutritional risk index (GNRI) was calculated as GNRI = [1.489 × albumin (g/L)] + [41.7 × (weight/WLo)], where WLo means ideal weight and was calculated from the Lorentz equations: for men: H-100-[(H-150)/4]; for women: H-100-[(H-150)/2.5] (H: height) [Citation30]. The simplified creatinine index (SCI) was calculated as SCI (mg/kg/day) = 16.21 + 1.12 × (1 if male; 0 if female) − 0.06 × age (years) − 0.08 × spKt/Vurea + 0.009 × pre-dialysis serum creatinine concentration (μmol/L) [Citation31].
Statistical analysis
The continuous variables were presented as means ± standard deviations or medians with 25th and 75th percentiles, whereas the categorical variables were shown as counts and percentages. Student’s t-test (for normally distributed variables) or the Mann-Whitney U test (for non-normally distributed variables) was used to analyze the continuous variables, while the categorical variables were analyzed using the chi-square test or Fisher’s exact test. The κ statistics was used to evaluate the consistency between the two definitions. Kaplan-Meier survival curves and log-rank tests were used to compare endpoint event incidences between the frequent and infrequent IDH groups. Univariable analysis was conducted using Cox proportional hazards models, with all clinically relevant factors being included. Variables with two-sided P-values <0.1 in the univariable analyses were included in the multivariable analysis, and the variables were filtered through the stepwise regression/enter method. Statistical significance was considered at P-values <0.05 (two-sided). All statistical analyses were performed using StataCorp version 14.2 (Texas, USA).
For all-cause mortality, the variables included in Model 1 were Frequent IDH (Definition 1), DM, Nt-proBNP, GNRI, and SCI. After stepwise regression screening, the remaining variables in Model 1 were Frequent IDH (Definition 1), DM, and Nt-proBNP. The variables included in Model 2 were Frequent IDH (Definition 2), DM, Nt-proBNP, GNRI, and SCI. After stepwise regression screening, the remaining variables in Model 2 were Frequent IDH (Definition 2), DM, and Nt-proBNP. For cardiovascular death, the variables included in Model 1 were Frequent IDH (Definition 1), DM, NT-proBNP, and SCI. After stepwise regression, only DM was retained in the model. The variables included in Model 2 were Frequent IDH (Definition 2), DM, NT-proBNP, and SCI. After stepwise regression, only DM was retained in the model. For all-cause hospitalization, the variables included in Model 1 were Frequent IDH (Definition 1), DM, CVD history, history of statin use, NT-proBNP, CRP, iPTH, albumin, and SCI, which were entered into the model in an enter manner. Finally, the variables included in Model 1 were Frequent IDH (Definition 1), DM, CVD history, history of statin use, NT-proBNP, CRP, iPTH, albumin, and SCI. The variables included in Model 2 were Frequency IDH (Definition 2), DM, CVD history, history of statin use, NTproBNP, CRP, iPTH, albumin, and SCI, which were entered in an enter manner. Finally, the variables in the model were Frequent IDH (Definition 2), DM, CVD history, history of statin use, NT-proBNP, CRP, iPTH, albumin, and SCI.
Results
Baseline characteristics of the patients
A total of 165 patients were initially enrolled in the study. Two patients died during the adaptation and exposure assessment periods, leaving 163 patients who entered the at-risk period and were included in the final analysis (). Of the 163 patients, 103 (63.19%) were male and 60 (36.81%) were female. The mean age was 62.1 ± 11.4 years, and the mean dialysis vintage was 53 months. The etiologies of ESRD included glomerular disease (47 [28.83%]), diabetes mellitus (38 [23.31%]), hypertension (33 [20.25%]), and other causes (45 [27.61%]) ().
Table 1. Baseline characteristics of hemodialysis patients in IDH frequent/infrequent groups by Definition 1 and Definition 2.
The incidence of IDH was 11.1% (Definition 1) or 10.5% (Definition 2). The two definitions were consistent (κ = 0.98). According to Definitions 1 and 2, 48 (29.45%) and 45 (27.61%) patients were identified as frequent IDH. The demographic, hemodialysis-related, and biochemical parameters of the frequent and infrequent IDH groups are presented in . The infrequent IDH group had more male patients and higher pre-dialysis SBP and DBP but lower iPTH, total cholesterol, and LDL than the frequent IDH group (all p < 0.05).
Clinical outcomes
During the at-risk period, 37 deaths (22.70%) occurred, including 17 cardiovascular deaths (10.43%). There were 105 primary all-cause hospitalizations (64.42%), 48 primary vascular access events (29.45%), and 42 primary AVF events (25.77% in the AVF population). Based on Definition 1, frequent IDH patients had a higher incidence of all-cause mortality (37.50% vs. 16.52%, p = 0.004) and cardiovascular mortality (18.75% vs. 6.96%, p = 0.025). Based on Definition 2, frequent IDH patients had a higher incidence of all-cause mortality (35.56% vs. 17.80%, p = 0.016) (). Kaplan-Meier survival analysis revealed that all-cause mortality was significantly higher in the frequent IDH group compared with the infrequent IDH group for both definitions (Definition 1: p = 0.002, Definition 2: p = 0.009, ). According to Definition 1, cardiovascular mortality was significantly higher in the frequent IDH group than in the infrequent IDH group (p = 0.021, ), while this difference was not significant according to Definition 2 (p = 0.163, ). The primary all-cause hospitalization event was similar in the two groups according to both definitions (Definition 1: p = 0.082, Definition 2: p = 0.132, ).
Figure 2. Kaplan-Meier curves of all-cause mortality between IDH frequent and IDH infrequent group according to (A) Definition 1, (B) Definition 2; cardiovascular mortality between the frequent and infrequent IDH groups according to (C) Definition 1, (D) Definition 2; and primary all-cause hospitalization event between IDH frequent and IDH infrequent group according to (E) Definition 1, (F) Definition 2.
Table 2. Outcomes of hemodialysis patients in IDH frequent/infrequent groups by Definition 1 and Definition 2.
Univariable and multivariable analysis
The multivariable Cox regression analysis revealed that frequent IDH was independently associated with a higher risk of all-cause mortality (Model 1: HR = 2.553, 95%CI 1.334–4.886, p = 0.005; Model 2: HR = 2.406, 95%CI 1.253–4.621, p = 0.008). Diabetes and NT-proBNP were also independently associated with all-cause mortality in both models ().
Table 3. Univariable and multivariable Cox regression analyses of all-cause mortality.
Only diabetes was independently associated with cardiovascular mortality (Model: HR = 5.278, 95%CI 2.008–13.875, p = 0.001; Model 2: HR = 5.278, 95%CI 2.008–13.875, p = 0.001) (). In addition, higher CRP (Model 1: HR = 1.010, 95%CI 1.003–1.018, p = 0.006; Model 2: HR = 1.011, 95%CI 1.003–1.018, p = 0.006) and statin use (Model 1: HR = 1.688, 95%CI 1.031–2.763, p = 0.037; Model 2: HR = 1.676, 95%CI 1.023–2.745, p = 0.040) were found to be independently associated with all-cause hospitalization. Frequent IDH was not significantly associated with this outcome (). Supplementary Tables S1 and S2 present the univariable analyses for cardiovascular mortality and vascular access/AVF events.
Table 4. Univariable and multivariable Cox regression analyses of cardiovascular mortality.
Table 5. Univariable and multivariable Cox regression analyses of all-cause hospitalization.
Discussion
The present study showed that IDH was a common complication of hemodialysis, with an incidence of 11.1% (Definition 1) or 10.5% (Definition 2). In addition, HD patients classified as frequent IDH are at a greater risk of all-cause mortality. This highlights the significance of acknowledging and proactively managing frequent IDH within the HD patients.
The lack of a consensus definition for IDH is a significant obstacle in effectively preventing and treating this condition. Previous studies have used various definitions of IDH, but the rationale for selecting a particular definition has not been well-documented [Citation23]. One of the most commonly used criteria for IDH was nadir SBP <90 mmHg during hemodialysis (Definition 2), but it does not consider the baseline SBP, while Definition 1 added pre-dialysis SBP as a stratification factor to reflect the extent of blood pressure decrease. The current study underscores the need for an evidence-based, consensus definition that applies to a broad range of hemodialysis patients, much like the definition of hypertension in the general population [Citation23, Citation29, Citation32]. Other previous definitions also included symptoms, but such symptoms can be subjective and vary among different patients experiencing a similar drop in SBP [Citation25, Citation26]. Furthermore, not all patients report symptoms, and the completeness and accuracy of symptom and intervention records cannot be guaranteed [Citation23]. It poses challenges for large-scale studies and database analyses [Citation27]. Furthermore, certain symptoms or interventions may not be solely attributable to IDH [Citation33], and asymptomatic IDH may also impact prognosis [Citation24]. Using objective data without symptoms or interventions as the definition for IDH may be a more practical approach to address these challenges. Therefore, Flythe et al. [Citation24] started with a simple and objective definition (nadir SBP <90 mmHg during hemodialysis) that did not include symptoms and stratified the patients according to pre-dialysis SBP to determine new SBP thresholds to determine IDH. Definition 1 was proposed by Flythe et al. [Citation24] based on a large-scale retrospective study that included 11,801 patients. Assimon et al. [Citation27] and Flythe et al. [Citation24] later suggested that frequency-based definitions were consistent with the theory of repeated episodes of pathogenicity and dose-response effects and should be widely used.
The present study used two definitions for IDH, with Definition 1 being stricter than Definition 2. The present study confirmed the independent association between frequent IDH and all-cause mortality using Definitions 1 and 2, as supported by Flythe et al. [Citation24]. According to Flythe et al. [Citation24], patients with blood pressure reduction not as extreme as nadir 90 mmHg might have clinical relevance beyond mortality, while cardiovascular injury only occurs when SBP is <90 mmHg [Citation24]. The Kaplan-Meier and multivariable Cox regression analyses in the present study suggested that frequent IDH, according to both definitions, were independently associated with all-cause mortality. Furthermore, diabetes was found to be an independent risk factor for IDH, consistent with a previous study [Citation15]. NT-proBNP, a biomarker of cardiac function, was also associated with all-cause mortality. Higher levels of NT-proBNP before hemodialysis are correlated with increased arterial stiffness, left ventricular index, and arteriosclerosis in the hemodialysis population, indicating that these patients may have poorer cardiac function and more severe arterial stiffness/sclerosis [Citation34–37].
While Flythe et al. [Citation24] only examined all-cause mortality, the present study also examined cardiovascular mortality, hospitalization, and vascular access/AVF events. The Kaplan-Meier analysis showed a correlation between frequent IDH and cardiovascular mortality according to Definition 1, consistent with the study by Stefansson et al. [Citation7] using the KDOQI definition. The mechanism of cardiovascular injury caused by IDH may be myocardial stunning, leading to coronary ischemia, which increases the risk of cardiovascular mortality over time [Citation38]. The cumulative damage caused by frequent IDH may also have an impact on cardiovascular mortality [Citation28]. It is reasonable to believe that further research with larger sample sizes, multiple centers, and longer observation periods may help clarify the correlation between frequent IDH, according to Definition 1, and cardiovascular mortality. Meanwhile, the Kaplan-Meier analysis did not demonstrate a correlation between frequent IDH according to Definition 2 and cardiovascular mortality. Diabetes was an independent risk factor for cardiovascular mortality, consistent with a previous study that reported a similar correlation between diabetes and cardiovascular mortality [Citation39]. Larger scale and better-designed studies may still find a deeper relationship between Definition 1 and cardiovascular mortality.
The Kaplan-Meier and multivariable analyses revealed that frequent IDH was not associated with primary all-cause hospitalization. Previous studies by Stefansson et al. [Citation7] and Sands et al. [Citation15] reported a positive association between IDH and heart failure/volume-load hospitalization events and earlier primary all-cause hospitalization events, respectively. The difference in the findings may be due to the complexity of all-cause hospitalization events, which are influenced by various factors such as the indication for hospitalization, outpatient/inpatient surgical classification, hospital classification, medical resources, medical system differences, and economic situation.
The incidence of primary vascular access/AVF events did not differ between the frequent and infrequent IDH groups. Although Chang et al. [Citation8] revealed a correlation between IDH and vascular access thrombosis events, the definition used in that study was different, and the authors suggested that IDH might be a co-morbid condition for other thrombosis-prone conditions, such as an inflammatory or poorer nutritional status. Only a few thrombosis events in vascular access/AVF events were observed in the present study; considering the potential effect of inflammatory status on survival [Citation40] and vascular access/AVF [Citation41–43], it is possible that the relationship between frequent IDH and vascular access/AVF events according to the two definitions used in this study is inconclusive and needs to be clarified by larger and well-designed multicenter studies.
The study has several limitations. First, it was a single-center study with a relatively small sample size, especially the endpoint events of cardiovascular mortality, limiting the generalizability and reliability of the findings. Additionally, the post hoc power analysis revealed a power of 0.837 for Definition 1 and 0.699 for Definition 2. Second, a selection bias might be present since patients with heart failure or MI were excluded. Still, patients with recent heart failure and myocardial infarction may experience more IDH and complications due to heart failure or myocardial infarction during the recovery or subsequent survival period, preventing the observation of the real impact of IDH on the outcomes [Citation3]. In addition, the life expectancy of such patients is unpredictable and may have a bias toward the endpoint events. Therefore, these patients were excluded from observing the cumulative effects of frequent IDH on the endpoints, but it might decrease generalizability. Furthermore, crucial factors such as the antihypertensive regimen and the timing of patients’ medication intake were not addressed, introducing a potential source of confounding. Finally, the definition of IDH, in the study is not standardized. Therefore, further well-designed, large-sample, multicenter studies are needed to validate the findings of this study and provide a better understanding and consensus on the relationship between IDH and clinical outcomes in hemodialysis patients.
Conclusion
In conclusion, the study highlights that patients identified as experiencing frequent IDH face a significantly heightened risk of all-cause mortality. This underscores the critical importance of acknowledging and proactively addressing the issue of frequent IDH within the HD patients. The findings emphasize the imperative for healthcare practitioners to be vigilant about monitoring and managing IDH to enhance patient outcomes.
Authors’ contributions
YW, JL, and LY conceived and designed the study. YW, TW, XZ, and JX provided data interpretation. LY and JL conducted the data analysis. YW and JL drafted and revised the manuscript. YW and JL were responsible for data collection. YW performed patient recruitment. YW and JL contributed equally to this work. All authors have reviewed and approved the manuscript for submission.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki guidelines. The Institutional Ethics Review Board of Huashan Hospital, Fudan University, approved the study protocol (IRB No. KY2016-394). Written informed consent was obtained from all participants.
Supplemental Material
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The authors express their gratitude to the participants for their cooperation in the study.
Disclosure statement
The authors declare no conflicts of interest.
Data availability statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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References
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