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Physiological changes during hemodialysis in patients with intradialysis hypertension

2006; Elsevier BV; Volume: 69; Issue: 10 Linguagem: Inglês

10.1038/sj.ki.5000266

1523-1755

Kang‐Ju Chou, P.-T. Lee, Chien‐Liang Chen, Chuen‐Wang Chiou, Chih‐Yang Hsu, Hsiao‐Min Chung, C.-P. Liu, H.-C. Fang,

Heart Rate Variability and Autonomic Control

Intradialysis hypertension is a frustrating complication among hemodialysis (HD) patients. This study was conducted to investigate the physiological changes during intradialytic hypertension. The beat-to-beat continuous heart rate, hematocrit (Hct) changes during HD, serum levels of nitric oxide, plasma levels of catecholamine, renin, endothelin (ET-1), cardiac output (CO), and peripheral vascular resistance (PVR) were measured before and after HD in patients prone to develop intradialysis hypertension (n=30) and from age, sex-matched control HD subjects (n=30). It was found that the baseline values of Hct, serum levels of nitric oxide, plasma levels of catecholamine, renin, and ET-1, CO, PVR, and power index (low frequency/high frequency ratios) of heart rate variability were not significantly different between the patients and control subjects. In the hypertension-prone group, the plasma levels of catecholamine, renin, and the serial measurements of power index, did not show significant changes. However, the patients showed a significant elevation of systemic vascular resistance (56.8±9.2% vs 17.7±9.5; P<0.05), ET-1 (510.9±43.3 vs 276.7±30.1 pg/ml; P<0.05) and a significant decrease of nitric oxide (NO)/ET-1 balance (0.018±0.003 vs 0.034±0.005; P<0.05) at the end of HD compared with the control patients. It was found that the physiological changes in intradialysis hypertension patients were characterized by inappropriately increased PVR through mechanisms that did not involve sympathetic stimulation or renin activation but might be related with altered NO/ET-1 balance. Intradialysis hypertension is a frustrating complication among hemodialysis (HD) patients. This study was conducted to investigate the physiological changes during intradialytic hypertension. The beat-to-beat continuous heart rate, hematocrit (Hct) changes during HD, serum levels of nitric oxide, plasma levels of catecholamine, renin, endothelin (ET-1), cardiac output (CO), and peripheral vascular resistance (PVR) were measured before and after HD in patients prone to develop intradialysis hypertension (n=30) and from age, sex-matched control HD subjects (n=30). It was found that the baseline values of Hct, serum levels of nitric oxide, plasma levels of catecholamine, renin, and ET-1, CO, PVR, and power index (low frequency/high frequency ratios) of heart rate variability were not significantly different between the patients and control subjects. In the hypertension-prone group, the plasma levels of catecholamine, renin, and the serial measurements of power index, did not show significant changes. However, the patients showed a significant elevation of systemic vascular resistance (56.8±9.2% vs 17.7±9.5; P<0.05), ET-1 (510.9±43.3 vs 276.7±30.1 pg/ml; P<0.05) and a significant decrease of nitric oxide (NO)/ET-1 balance (0.018±0.003 vs 0.034±0.005; P<0.05) at the end of HD compared with the control patients. It was found that the physiological changes in intradialysis hypertension patients were characterized by inappropriately increased PVR through mechanisms that did not involve sympathetic stimulation or renin activation but might be related with altered NO/ET-1 balance. Acute complications such as hypotension, hypertension, and muscle cramps prevent uremic patients from having a safe and comfortable hemodialysis (HD) treatment. The pathogenesis of HD-related hypotension has frequently been investigated and seems easy to understand; it includes cardiac performance, integrity of the cardiovascular reflex control, delayed plasma refilling from the extravascular space, uremic dysautonomia, activation of cytokines, changes in blood osmolality, release of neurohumoral mediators, and excessive ultrafiltration1.Daurgirdas J.T. Dialysis hypotension. A hemodynamic analysis.Kidney Int. 1991; 39: 323-346Google Scholar, 2.Kersh E.S. Kronfield S.J. Unger A. et al.Autonomic insufficiency in uremia as a cause of hemodialysis-induced hypotension.N Engl J Med. 1974; 290: 650-653Crossref PubMed Scopus (213) Google Scholar, 3.Daurgirdas J.T. Pathophysiology of dialysis hypotension: an update.Am J Kidney Dis. 2001; 38: S11-S17Abstract Full Text Full Text PDF Scopus (242) Google Scholar, 4.Pelosi G. Emdin M. Carpeggiani C. et al.Impaired sympathetic response before intradialytic hypotension: a study based on spectral analysis of heart rate and pressure variability.Clin Sci. 1999; 96: 23-31Crossref PubMed Scopus (73) Google Scholar, 5.Barnas M.G. Boer W.H. Koomans H.A. Hemodynamic patterns and spectral analysis of heart rate variability during dialysis hypotension.J Am Soc Nephrol. 1999; 10: 2577-2584PubMed Google Scholar, 6.Lee P.T. Fang H.C. Chen C.L. et al.High vibration perception threshold and autonomic dysfunction in hemodialysis patients with intradialysis hypotension.Kidney Int. 2003; 64: 1089-1094Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar and so on. However, the mechanisms of dialysis-related hypertension have not yet been well explored. Many explanations for the phenomenon of intradialytic hypertension, including augmented release of renin, activation of the sympathetic nervous system, and endothelial dysfunction have been proposed.7.Zucchelli P. Santoro A. Zuccala A. Genesis and control of hypertension in hemodialysis patients.Semin Nephrol. 1988; 8: 163-168PubMed Google Scholar, 8.Cirit M. Akcicek F. Terzioglu E. et al.'Paradoxical' rise in blood pressure during ultrafiltration in dialysis patients.Nephrol Dial Transplant. 1995; 10: 1417-1420PubMed Google Scholar, 9.Mees E.J.D. Role in blood pressure during hemodialysis – ultrafiltration: a paradoxical phenomenon?.Int J Artif Organs. 1996; 19: 569-570PubMed Google Scholar None of these possible explanations, or their inter-relationships, has been studied in a controlled experimental setting. To investigate the hemodynamic changes and responses of autonomic nervous function during intradialytic hypertension of HD patients, the changes of autonomic function of intradialytic hypertensive patients were studied by measuring the heart rate variability (HRV), which was proposed to be a sensitive and well-established tool for investigating the autonomic nervous system during HD.10.Pomeranz B. Macaulay R.J. Caudill M.A. et al.Assessment of autonomic function in humans by heart rate spectral analysis.Am J Physiol. 1985; 248: H151-H153PubMed Google Scholar, 11.Vita G. Bellinghieri G. Trusso A. et al.Uremic autonomic neuropathy studied by spectral analysis of heart rate.Kidney Int. 1999; 56: 232-237Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Plasma levels of epinephrine, norepinephrine, rennin, and endothelin (ET-1), and serum levels of nitric oxide (NO) were measured at the beginning and the end of HD. Echocardiograms were performed to evaluate the changes of cardiac output (CO) and peripheral vascular resistance (PVR) before and after HD. The general characteristics of the groups are shown in Table 1. Body height, dry weight, body mass index, ultrafiltration volume, albumin, hematocrit (Hct), duration of maintenance dialysis, and baseline heart rate were not significantly different between the groups. However, baseline mean arterial pressure of group A were significantly different from those of group B (105±3 vs 95±3 mm Hg, P<0.05). The laboratory data before and after HD are shown in Table 2. Before HD there were no significant differences among all of the variables. However, significant differences in the plasma concentrations of norepinephrine and renin between groups A and B were found at the end of HD (204±27 vs 363±62 pg/ml and 10.6±2.8 vs 24.9±7.3 pg/ml, respectively; P<0.05 for both). When before and after HD measurements were compared, there were no significant differences in the plasma concentrations of epinephrine, norepinephrine, and renin in group A, but the serum levels of norepinephrine and renin increased significantly at the end of HD in group B (253±47 vs 363±62 pg/m and 15.1±3.1 vs 24.9±7.3 pg/ml; both P<0.05).Table 1General characteristicsPatient characteristicsHypertension proneControlsP-valueNumber of patients3030—Age (years)53.2±3.954.3±4.2NSMale/female13/1713/17NSDuration of maintenance dialysis (months)49.9±7.453.1±9.1NSBody height (cm)159.8±1.6158.9±1.7NSBody weight (kg)52.2±1.653.9±2.0NSBody mass index20.4±0.421.3±0.6NSUltrafiltration volume (l)2.1±0.32.3±0.3NSSerum albumin (g/dl)4.2±0.14.2±0.1NSi-PTH (pg/ml)189.7±56.2343.7±105.7NSBaseline Hct (%)28.5±1.128.8±0.6NSBaseline mean arterial pressure (mmHg)105±395±3<0.05Baseline pulse rate (min−1)73±272±2NSBaseline LF/HF ratio2.4±0.42.1±0.3NSAbbreviations: LF/HF ratio, ratio of low- and high-frequency power of heart rate variability; NS, not significant.All data are presented as mean±s.e.m. Open table in a new tab Table 2Laboratory data before and after hemodialysisHypertension proneControlsP-valueBefore hemodialysis Plasma potassium (mEq/l)4.4±0.34.4±0.5NS Plasma free calcium (mg/dl)4.2±0.14.4±0.1NS Plasma epinephrine (pg/ml)97.1±13.599.0±8.5NS Plasma norepinephrine (pg/ml)225±43253±47NS Plasma renin concentration (pg/ml)10.8±3.415..1±3.1NSAfter hemodialysis Plasma potassium (mEq/l)3.2±0.1*3.3±0.1*NS Plasma free calcium (mg/dl)5.0±0.1*5.1±0.1*NS Plasma epinephrine (pg/ml)87.6±9.8100.4±6.8NS Plasma norepinephrine (pg/ml)204±27363±62*<0.05 Plasma renin concentration (pg/ml)10.6±2.824.9±7.3*<0.05Abbreviation: NS, not significant.All data are presented as mean±s.e.m.*P<0.05 when compared with values before hemodialysis. Open table in a new tab Abbreviations: LF/HF ratio, ratio of low- and high-frequency power of heart rate variability; NS, not significant. All data are presented as mean±s.e.m. Abbreviation: NS, not significant. All data are presented as mean±s.e.m. *P<0.05 when compared with values before hemodialysis. Figure 1a shows the changes in mean arterial blood pressure of each group. There were significant elevations of mean arterial blood pressure in group A (at 3 and 4 h after beginning HD vs baseline; P<0.05), but no significant changes were seen in group B throughout the whole dialysis session. Serial changes of percentage of blood volume (BV) during HD are depicted in Figure 1b. There were no differences between the baseline levels of the groups. However, the levels increased gradually with time. The values of changes of BV in group B patients were statistically higher than those of group A during the whole course of HD. As the ultrafiltration rates of the groups were similar, the lesser changes of percentage of BV in group A implied a faster refilling of intravascular volume. Spectral analysis data of HRV are shown in Figure 1c. The baseline values of LH/HF ratios of both groups were not significantly different. The serial measurements of low frequency/high frequency (LF/HF) ratios rose progressively and reached significantly higher levels during the 3rd and 4th hour periods of HD in group B patients (2.1±0.3 vs 3.1±0.5 and 3.7±0.5; both P<0.05). The LF/HF ratios in group A patients, however, did not change significantly throughout the whole dialysis session. The changes of COs and PVRs are displayed in Table 3. The baseline levels of both of them were not significantly different between groups. However, at the end of HD the elevations of PVR were significantly higher in group A patients than those of group B (56.8±9.2 vs 17.7±9.5%; P<0.05).Table 3Cardiac output and peripheral vascular resistance before and after hemodialysisHypertension proneControlP-valueBefore hemodialysis CO (l/min)6.4±0.95.4±0.3NS PVR (Wood units)16.7±1.518.4±1.3NSAfter hemodialysis CO (l/min)5.4±0.84.8±0.3NS PVR (Wood units)24.7±2.5**20.6±1.7*NS Change of CO in percentage (%)18.2±5.212.5±5.2NS Change of PVR in percentage (%)56.8±9.217.7±9.5<0.05Abbreviation: NS, not significant.All data are presented as mean±s.e.m.*P<0.05 when compared with values before hemodialysis, **P<0.005 when compared with values before hemodialysis. Open table in a new tab Abbreviation: NS, not significant. All data are presented as mean±s.e.m. *P<0.05 when compared with values before hemodialysis, **P<0.005 when compared with values before hemodialysis. The plasma concentrations of nitric oxide (nitrate+nitrite) and ET-1 before and after HD are shown in Table 4. The predialysis levels of both of them were comparable in the two study groups. The postdialysis NO levels displayed significantly decreased in both groups, but showed no significant differences between groups. The postdialysis ET-1 levels were significantly elevated in group A as compared with that of group B and predialysis levels. Although the NO/ET-1 balance was significantly depressed after HD in both groups, it was significantly less in group A than that of group B.Table 4Plasma concentrations of nitric oxide (nitrate+nitrite) and endothelin (ET-1) before and after hemodialysisHypertension proneControlP-valueBefore hemodialysis NO (μM)41.2±6.132.9±4.5NS ET-1 (pg/ml)345.6±34.5287.4±29.3NS NO/ET-10.869±0.5020.129±0.013NSAfter hemodialysis NO (μM)7.2±0.9**7.9±0.9**NS ET-1 (pg/ml)510.9±43.3**276.7±30.1<0.05 NO/ET-10.018±0.003**0.034±0.005**<0.05Abbreviations: NO, nitric oxide; ET-1, endothelin; NS, not significant.All data are presented as mean±s.e.m.*P<0.05 when compared with values before hemodialysis, **P<0.005 when compared with values before hemodialysis. Open table in a new tab Abbreviations: NO, nitric oxide; ET-1, endothelin; NS, not significant. All data are presented as mean±s.e.m. *P<0.05 when compared with values before hemodialysis, **P 55–60%), dry weight was lowered gradually until the disappearance of these manifestations and the occurrence of intradialytic hypotension or muscle cramps. On the contrary, dry weight was raised when intradialysis hypotension or muscle cramps developed without significant interdialysis weight gain (>5% body weight) or other precipitating factors. Patients with diabetes mellitus, congestive heart failure (more severe than NYHA Functional class II), or medications that may affect the cardiovascular or autonomic nervous system (including antihypertensive medications) were excluded from the study, or the medications were discontinued for 2 weeks prior to the study. All patients complied with the fluid restriction recommendations and restricted their weight gain to less than 1 kg per day and less than 5% of postdialysis dry weight between two consecutive HD sessions. All procedures were performed in the afternoon between 13:00 and 17:00 hours. Regular HD was performed in a quiet room. The serum potassium levels of each patient were checked before the study. If the levels were not within the range of 4–5 mEq/l the study was rescheduled. The blood urea nitrogen, plasma levels of creatinine, sodium, potassium, chloride, free calcium, and Hct were checked at the beginning and the end of HD. To measure plasma levels of epinephrine, norepinephrine, and renin, 10 ml of blood was collected from the HD access after a 10-min rest in the supine position before and at the end of HD. Blood samples were kept on ice before separation in a refrigeration centrifuge at 4°C, and then stored at -70°C until processing. Epinephrine and norepinephrine plasma concentrations were determined with a Beckmann System Gold high-performance liquid chromatograph (HPLC) and electrochemical detection (Chromsystems no. 41 000). A catecholamine-detection kit (Chromsystems Catalog no. 5000) included a probe preparation system, HPLC column, and all necessary chemicals and buffers. The lower detection limit was 10 pg/ml for both epinephrine and norepinephrine, with a coefficient of variation of 6.2% for norepinephrine and 6.8% for epinephrine, respectively. All specimens were assayed within 1 week after sampling. Active renin concentration was determined in plasma using an immunoradiometric assay (Renin IRMA, Daiichi, Tokyo, Japan). The range of assay was 5–500 pg/ml. The intra-assay variation was 1.4% and the interassay variation 1.5%. Each sample was assayed in duplicate. To measure nitric oxide (NO) and ET-1, blood samples were collected from the HD access after a 10-min rest in the supine position before and at the end of HD. Blood samples (5 ml) were centrifuged at 1000 g for 15 min. After centrifugation, serum was aliquoted and stored at -70°C until batch analysis. Measurements of serum concentrations of total nitrites and nitrates were performed by using an NO analyzer (Sievers 280, Boulder, CO, USA). Because there is no evidence that the blood should contain any significant amounts of nitrites and nitrates other than that contributed by NO, we can assume that the NO concentration deduced from the chemiluminescence experiment does represent the true NO concentration in the blood. The procedure is described briefly as follows. Serum samples were deproteinized by zinc sulfate and the supernatants after deproteinization were collected for further analysis.23.Moshage H. Kok B. Hulzenga J.R. Jansen P.L.M. Nitrite and nitrate determinations in plasma: a critical evaluation.Clin Chem. 1995; 41: 892-896PubMed Google Scholar Assay of serum nitrites and nitrates was then carried out according to the NO analyzer manufacturer's instructions. Vanadium (III) chloride was used as the reducing agent in the system. A sodium nitrate (100 mM) solution (NaNO3) was prepared and diluted to various concentrations for the calibration test. Of a standard concentration, 10 μl of NaNO3 was injected into the Radical Purger, which was linked to the NO analyzer, to obtain the calibration curve and the peak area for each standard concentration was measured. Deproteinized serum samples were then injected and the NO concentrations measured after correction for background noise. The Intra-assay and interassay coefficients of variation were 4.8 and 5.8%. Plasma samples for ET-1 measurements were collected using EDTA as an anticoagulant. Samples were immediately centrifuged at 3000 g for 10 min, and the plasma was stored at -70°C until further analysis. Endothelin was measured by immunoassay (R&D System Inc., Minneapolis, MN, USA). The detection limit was 1 pg/ml for ET-1. There was <1% crossreactivity with big ET-22 to 38. Intra-assay and interassay coefficients of variation were 4.5 and 6.6%, respectively. Results were expressed as pg/ml. Each sample was assayed in duplicate. Hematocrit was continuously and noninvasively monitored during each session using the Crit-Line instrument (In-Line Diagnostics, Riverdale, UT, USA). Continuously monitored Hct has been reported to have good correlation with Hct determined by centrifugation (R=0.89),24.Leypoldt J.K. Cheung A.K. Steuer R.R. et al.Determination of circulating blood volume by continuously monitoring hematocrit during hemodialysis.J Am Soc Nephrol. 1995; 6: 214-219PubMed Google Scholar and the differences of Hct could be used to represent the relative changes of BV during HD.25.Rodriguez H.J. Domenici R. Diroll A. Goykhman I. Assessment of dry weight by monitoring changes in blood volume during hemodialysis using Crit-Line.Kidney Int. 2005; 68: 854-861Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 26.Shulman T. Heidenheim A.P. Kianfar C. et al.Preserving central blood volume: changes in body fluid compartments during hemodialysis.ASAIO J. 2001; 47: 615-618Crossref PubMed Scopus (50) Google Scholar Before HD, a sterile, plastic, disposable blood chamber (Beta prototype; In-Line Diagnostics, Riverdale, UT, USA) was placed in the blood circuit between the arterial blood tubing and the dialyzer. The Crit-Line instrument uses a transmissive photometric technique to determine the Hct based on both the absorption properties of hemoglobin and the scattering properties of red blood cells passing through the blood chamber. The percentage of BV changes was calculated using an equation previously described.27.Steuer R.R. Leypoldt J.K. Cheung A.K. et al.Hematocrit as an indicator of blood volume and a predictor of intradialytic morbid events.ASAIO J. 1994; 40: M691-M696Crossref PubMed Scopus (89) Google Scholar%BV change=[(Hctinitial/Hctfinal)−1]×100% Blood pressure was checked 10 min before puncturing, at the beginning of dialysis, every 15 min during HD, and at the end of HD, using an automatic blood pressure device (Colin Press-Mate BP-8800; Colin, Komaki City, Japan). We prepared a Holter ECG recorder for all patients while receiving HD. The Holter ECG signal was recorded for the entire duration of HD using an Oxford solid state three-channel recorder (Medilog® Holter Recorder; Oxford Instruments, Fremont, CA, USA). Using Microsoft Excel software version 2.0 to detect the QRS complex, the signals were automatically processed on the Oxford laser Holter scanner to perform HRV analysis. Spectral analysis of HRV was performed every 5 min using the Welch method on short-lasting heart rate tracers. Heart rate variability analysis was carried out according to the recommendations of the task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.28.Malik M. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use.Circulation. 1996; 93: 1043-1065Crossref PubMed Google Scholar Power spectral analysis was performed by fast Fourier transformation for the Holter ECG signals. Low frequency (0.04–0.15 Hz) represented sympathetic activity, and HF (0.15–0.4 Hz) represented parasympathetic activity. The ratio of LF/HF represented the balance between sympathetic and parasympathetic activity.28.Malik M. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use.Circulation. 1996; 93: 1043-1065Crossref PubMed Google Scholar, 29.Akselrod S. Gordon D. Madwed J.B. et al.Hemodynamic regularion: investigation by spectral analysis.Am J Physiol. 1985; 249: H867-875PubMed Google Scholar, 30.Askelrod S. Gordon D. Ubel F.A. et al.Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control.Science. 1981; 213: 220-223Crossref PubMed Scopus (3991) Google Scholar Echocardiograms were performed before and at the end of HD using a Sonos 5500 (HP, Agilent, Palo Alto, CA, USA) echocardiographic system. M-mode measurements were obtained according to the American Society of Echocardiography standards. We measured aortic annulus dimension (Ao) and aortic Doppler velocity time integral (AoVTI). The reproducibility (s.d./mean of three successive measurements) of Ao and AoVTI measurement was 5±3 and 8±4% (mean±s.d.). The blood pressure was measured twice by an experienced nurse using arm cuff measurements of a sphygmonometer (Baumanometer® Kompak Model, Copiague, NY, USA) after at least 10 min of rest in a supine position in a quiet room immediately prior to the echocardiograms. The reproducibility of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was 6±4 and 5±3% (mean±s.d.). The SVR were determined using the following equations:MBP(mmHg)=(SBP+2DBP)3SV(ml)=AoVTI×πAo24CO(l/min)=SV×HR1000SVR=MBPCO All data are expressed as mean±s.e.m. To analyze the data, we applied unpaired t-tests to test the differences between the groups, and repeated measurements of analysis of variance (ANOVA) to examine the differences among serial measurements within the groups. The Student–Neuman–Keuls test was used for pairwise comparisons among serial measurements. Data before and after HD were analyzed using paired t-tests. All P-levels were two-tailed, and values of less than 0.05 were considered significant. Statistical analyses were conducted using SPSS 8.0.1C (SPSS Inc., Chicago, IL, USA). This work was supported by grants from the Kaohsiung Veterans General Hospital (VGHKS 95-006) to Dr Kang-Ju Chou and (VGHKS 90-26) to Dr Hua-Chang Fang.