- Email: [email protected]
or Cool Dialysate
Treatment of Severe Intradialytic Hypotension With the Addition of High Dialysate Calcium Concentration to Midodrine and/or Cool Dialysate Raj Alappan, MD, Dinna Cruz, MD, Ali K. Abu-Alfa, MD, Rex Mahnensmith, MD, and Mark A. Perazella, MD ● Treatment of intradialytic hypotension (IDH) in the end-stage renal disease population has been a difficult task for nephrologists caring for these patients. The presence of multiple pathogenic factors contributes to hemodynamic instability and explains why therapies that modulate only a specific aspect of the problem are only partially effective. Cool dialysate (34.5°C to 35.5°C) and midodrine may provide hemodynamic stability through an increase in peripheral vascular resistance, whereas high dialysate calcium concentration (HDCa; 3.5 mEq/L) improves intradialytic blood pressure through preservation of cardiac output. Theoretically, the combination of these two types of therapies might further reduce the frequency and severity of hypotension during hemodialysis (HD). We undertook a study to evaluate the effect of HDCa added to midodrine and/or cool dialysate in the treatment of patients with severe IDH. Twenty-eight patients met the entry criteria, and 23 patients completed the prospective crossover study. Five patients dropped out of the study secondary to hypercalcemia. The addition of HDCa significantly improved post-HD mean arterial pressure (MAP; 95.6 ⴞ 12.7 versus 90.8 ⴞ 12.5 mm Hg; P ⴝ 0.002). The decreases in MAP from pre-HD to lowest intradialytic (16.3 ⴞ 8.2 versus 20.6 ⴞ 10.0 mm Hg; P ⴝ 0.009) and pre-HD to post-HD (2.0 ⴞ 8.5 versus 8.15 ⴞ 10.8 mm Hg; P ⴝ 0.002) were significantly reduced with HDCa compared with low dialysate calcium. However, there were no significant improvements in symptoms of or interventions for IDH. Thus, it appears that the addition of HDCa to midodrine and/or cool dialysate further improves blood pressure in patients with IDH. However, this therapy did not reduce symptoms or interventions required for IDH. In addition, hypercalcemia complicated this therapy in 22% of the patients. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Intradialytic hypotension (IDH); midodrine; cool dialysate; high dialysate calcium (HDCa).
S
YMPTOMATIC intradialytic hypotension (IDH) frequently complicates chronic maintenance hemodialysis (HD) sessions despite recent advances in this therapy.1 To combat this problem, a variety of therapeutic interventions have been used. The more successful measures include high dialysate sodium, cool dialysate, and midodrine.2-11 In addition, a greater concentration of calcium (3.5 versus 2.5 mEq/L) in the dialysate bath has been noted to improve intradialytic hemodynamic stability in a selected group of patients with class 3 or 4 heart failure and a left ventricular ejection fraction (LVEF) less than 40%.12 However, high calcium dialysate (HDCa; 3.5 mEq/L) has not been evaluated in a selected From the Section of Nephrology, Yale University School of Medicine, New Haven, CT. Received June 5, 2000; accepted in revised form August 25, 2000. Address reprint requests to Mark A. Perazella, MD, Associate Professor of Medicine, Yale University School of Medicine, Section of Nephrology, Department of Medicine, LMP 2071, 333 Cedar St, New Haven, CT 06520-8029. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3702-0006$35.00/0 doi:10.1053/ajkd.2001.21292 294
group of patients with severe resistant IDH requiring therapy with either midodrine or cool dialysate. It is currently unknown whether these patients would benefit from the addition of a higher dialysate calcium concentration. Thus, we conducted a prospective crossover study to determine the effect of HDCa concentration (3.5 mEq/L) compared with low dialysate calcium (LDCa) concentration (2.5 mEq/L) on hemodynamic stability during HD in patients with known IDH administered therapy with midodrine, cool dialysate, or a combination of these two therapies. MATERIALS AND METHODS The study was performed at the Gambro Healthcare Dialysis Center at Yale University (New Haven, CT) from November 29, 1999, to January 12, 2000. The protocol was approved by the institutional human investigation committee. Patients were eligible for the study if they had resistant IDH and, as a result, were under treatment with cool dialysate (35.5°C), oral midodrine administered before initiation of HD, or both interventions. The primary nephrologist determined treatment with cool dialysate and/or midodrine when the criteria for IDH were met. IDH was defined as at least three episodes of a decrease in systolic blood pressure (by at least 20 mm Hg to a level ⬍100 mm Hg) accompanied by symptoms (dizziness, blurred vision, nausea, vomiting, cramps, or fatigue) in 50% of HD treatments over 1 month. Patients who met these criteria were eligible to participate in
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the study and were then screened further for study entry. Patients were excluded from the study if the following laboratory criteria were present over the month preceding the study: mean serum calcium level (corrected for albumin level) greater than 10.5 mg/dL, mean serum phosphate level greater than 8.0 mg/dL, or mean calcium x phosphate product (Ca ⫻ PO4) greater than 80. In addition, patients currently on an LDCa bath for hypercalcemia, patients with calciphylaxis, and patients with frequent noncompliance with HD treatments were excluded. Each patient signed informed consent before enrollment. The 6-week study period consisted of two phases. Each phase was composed of nine consecutive HD treatments (3 weeks). During phase 1 (LDCa), patients were administered their usual therapy (cool dialysate, midodrine, or both) for IDH and a 2.5 mEq/L calcium concentration in the dialysate. During phase 2 (HDCa), patients were administered their usual therapy for IDH and a 3.5 mEq/L calcium concentration in the dialysate. This was the only parameter changed during HD. Drop-out criteria during the study included the development of the same parameters used for exclusion from entry onto the study, death, transplantation, or switch to peritoneal dialysis. All patients underwent dialysis on Cobe Centry System 3 volumetric dialysis machines (Cobe, Lakewood, CO), using the Baxter CAHP 170 or 210 dialysis cartridge (for nonreuse patients) and CT 190G dialysis cartridge (for reuse patients) during both phases of the study (Baxter, Deerfield, IL). The electrolyte concentration of the dialysis bath consisted of potassium, 2.0 mEq/L; magnesium, 2.5 mEq/L; and bicarbonate, 40 mEq/L, during both phases of the study. Ramped sodium modeling was tailored to each individual patient and was kept constant for both phases of the study. The temperature of the dialysis bath was maintained constant (35.5°C for patients on cool dialysate, 37°C for patients not on cool dialysate) during both phases of the study. Dialysis flow was set at 600 mL/min. Patients were not allowed to eat during dialysis, and antihypertensive medications were not administered before dialysis. All patients were maintained on their usual medications (including phosphate binders), with no changes during the study period. For the entire study, blood pressure (oscillometric measurement) and pulse were measured by arm cuff (with the patient in the standing position) before each dialysis session, then at 30-minute intervals during dialysis (with the patient seated in an upright position) and at the end of the dialysis session (with the patient standing). Pre-HD blood pressure, lowest intradialytic blood pressure, post-HD blood pressure, pre-HD and post-HD weights, and ultrafiltration volumes were recorded for each dialysis session. Mean arterial pressures (MAPs) were calculated from the systolic and diastolic blood pressures. The differences between the pre-HD MAP and lowest intradialytic MAP were calculated for each session, as well as the difference between pre-HD and post-HD MAPs. For each HD treatment, the number of interventions required for treatment of IDH, defined as Trendelenberg’s position, number and volume of saline infusions, and reduction in ultrafiltration volume, were recorded. According to center protocol, all these interventions were used to treat hypotension (systolic blood pressure ⬍ 100 mm Hg), IDH
295
symptoms, or both. An ordinal scale questionnaire, used in a previous study,11 was administered during each dialysis session to evaluate symptoms associated with IDH. Patients were asked to grade symptoms of cramps, dizziness, fatigue, or nausea on a scale of 0 (no symptoms) to 4 (severe), which were added to produce a total score. Hematocrit and serum calcium levels were determined weekly, and serum albumin, sodium, and Kt/V values were measured once during each phase. Blood urea nitrogen measurements for kinetic analysis were determined predialysis at the time of initial cannulation of the access and at the immediate end of dialysis from the arterial port 30 seconds after the blood flow was reduced to 50 mL/min. A variablevolume single-pool urea kinetic model was used to calculate Kt/V, using the best logarithmic formula of Daugirdas.
Statistics All numerical values are expressed as a mean ⫾ SD unless stated otherwise. Paired Student’s t-test was used, with P less than 0.05 considered statistically significant.
RESULTS
Fifty-seven of 145 chronic maintenance hemodialysis patients (39%) met the criteria for resistant IDH, undergoing treatment with midodrine, cool dialysate, or both therapies. Twenty-nine patients (51%) were excluded from study entry based on the following criteria: calcium level greater than10.5 mg/dL (n ⫽ 5), phosphate level greater than 8 mg/dL (n ⫽ 4), Ca ⫻ PO4 greater than 80 (n ⫽ 2), already on a 3.5-mEq/L calcium concentration bath (n ⫽ 3), calciphylaxis (n ⫽ 1), declined to participate (n ⫽ 4), unable to give consent (n ⫽ 2), a history of noncompliance with dialysis treatments (n ⫽ 3), died before the study period (n ⫽ 4), and relocation (n ⫽ 1). Twenty-eight patients (49%) were eligible to participate in the study. Six patients were on midodrine pre-HD (mean dose, 8.3 mg), nine patients were dialyzed with a 35.5°C bath, and nine patients were dialyzed using both midodrine (mean dose, 13.3 mg) and cool dialysate. Five patients (22%) were withdrawn from the study because of the development of a calcium concentration greater than 10.5 mg/dL. Twenty-three patients completed the study without complications, and their baseline characteristics are listed in Table 1. Five patients (22%) had an LVEF less than 40%. Laboratory values during the two phases of study, including Kt/V, are listed in Table 2. There were no significant differences in these values between the two phases of study. Pre-HD, lowest intradialytic, and post-HD MAPs and the differences between the pre-HD
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ALAPPAN ET AL Table 1.
Patient Baseline Characteristics
Age (y) Women (%) Black (%) Diabetes (%) Hypertension (%) CAD/CHF (%) PVD (%) Use of antihypertensive medications (%) ESRD from diabetes (%) ESRD from hypertension (%) ESRD from other causes (%)
Table 3.
63.9 ⫾ 12.7 57 48 57 91 78 61 83 43 30 27
NOTE. N ⫽ 23. Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; PVD, peripheral vascular disease.
and the lowest and post-HD MAPs for the entire group (n ⫽ 23) are listed in Table 3. Compared with the control phase, there was an improvement in the lowest intradialytic MAP during the HDCa phase, but this did not reach statistical significance (P ⫽ 0.12). There was a statistically significant improvement in the post-HD MAP during the HDCa phase (P ⫽ 0.002). HDCa also significantly reduced the decrease in pre-HD to lowest intradialytic MAP (P ⫽ 0.009), as well as the decrease in pre-HD to post-HD MAP (P ⫽ 0.002) compared with LDCa (Fig 1). MAPs in the subgroup of patients (n ⫽ 5) with an LVEF less than 40% compared with patients (n ⫽ 18) with an LVEF greater than 40% were also analyzed. In the five patients with a low LVEF, the changes in blood pressures were not statistically different and there was no significant difference in blood pressure between the two groups (data not shown). As listed in Table 2, there were no differences Table 2.
Laboratory Parameters LDCa (2.5 mEq/L)
HDCa (3.5 mEq/L)
Albumin (g/dL) 3.7 ⫾ 0.36 3.7 ⫾ 0.34 Calcium (mg/dL) 9.24 ⫾ 0.64 9.38 ⫾ 0.76 Phosphorus (mg/dL) 6.16 ⫾ 1.64 5.66 ⫾ 1.70 Calcium ⫻ phosphorus 56.4 ⫾ 13.5 52.5 ⫾ 13.9 Hematocrit (%) 37.3 ⫾ 3.69 37.1 ⫾ 3.31 Kt/V 1.50 ⫾ 0.33 1.64 ⫾ 0.33 Potassium (mmol/L) 5.1 ⫾ 0.7 5.0 ⫾ 0.7 Sodium (mmol/L) 139.8 ⫾ 2.88 139.7 ⫾ 3.59
P
⬎0.5 ⬎0.3 ⬎0.1 ⬎0.1 ⬎0.5 ⬎0.5 ⬎0.5 ⬎0.1
MAP (mm Hg)
Predialysis (PRE) Lowest (LOW) Postdialysis (POST) ⌬ PRE–LOW ⌬ PRE–POST
MAP
LDCa (2.5 mEq/L)
HDCa (3.5 mEq/L)
P
99.5 ⫾ 14.2 78.8 ⫾ 10.5 90.8 ⫾ 12.5 20.6 ⫾ 10.0 8.15 ⫾ 10.8
97.6 ⫾ 12.8 81.2 ⫾ 11.2 95.6 ⫾ 12.7 16.3 ⫾ 8.2 2.0 ⫾ 8.5
0.18 0.12 0.002 0.009 0.002
Abbreviations: ⌬ PRE–LOW, difference between predialysis MAP and lowest intradialytic MAP; ⌬ PRE–POST, difference between predialysis MAP and postdialysis MAP.
in mean serum calcium concentrations, mean serum phosphate concentrations, and mean Ca ⫻ PO4 in the LDCa and HDCa phases. Ultrafiltration volumes (HDCa, 2.8 ⫾ 3.62 L/treatment; LDCa, 2.4 ⫾ 1.37 L/treatment; P ⬎ 1.0), as well as the pre-HD (HDCa, 72.5 ⫾ 16.5 kg; LDCa, 72.9 ⫾ 16.3 kg; P ⬎ 0.5) and post-HD (HDCa, 69.5 ⫾ 15.1 kg; LDCa, 70.2 ⫾15.7 kg; P ⬎ 0.5) weights were not significantly different between the two phases of the study. Total symptom scores were recorded for the entire group during the study. In the LDCa phase, the total score for cramps was 28 (in 17 patients), fatigue was 28 (in 14 patients), nausea was 17 (in 13 patients), and dizziness was 24 (in 13 patients). In the HDCa phase, the total score for cramps was 18 (in 11 patients), fatigue was 16 (in 9 patients), nausea was 28 (in 10 patients), and dizziness was 32 (in 16 patients). None of the total symptom scores were statistically different (P ⬎ 0.10) except for dizziness (24 versus 32; P ⬍0.05), which was more common during the HDCa phase, and fatigue (28 versus 16; P ⬍ 0.05), which occurred more often in the LDCa phase. Analysis of interventions showed a need for Trendelenberg’s position in 11 patients, saline infusion in 30 patients (265 ⫾ 141.5 mL), and reduction in ultrafiltration in 32 patients in the LDCa phase. During the HDCa phase, 11 patients required Trendelenberg’s position, 30 patients were administered saline infusion (404 ⫾ 274.6 mL), and 29 patients required a reduction in ultrafiltration. All P were greater than 1.0. DISCUSSION
The treatment of symptomatic hypotension during HD remains a challenge to the nephrolo-
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Fig 1. Individual data points showing the change in MAP on LDCa and HDCa for each patient. (Left) Change in MAP from pre-HD to lowest intradialytic (⌬ [Pre MAP-Low MAP]) and (right) decline in MAP from pre-HD to post-HD (⌬ [Pre MAP-Post MAP]).
gist. Multiple pathogenic factors, including both patient- and dialysis modality–specific causes, contribute to IDH and underlie the refractory nature of this disorder.13-15 A number of varied therapeutic interventions have been used, but unfortunately, only a few of these modalities provide some benefit in the most severely affected patients.13-15 These include high dialysate sodium concentration and cool temperature dialysate.2-5 More recently, we and others reported hemodynamic benefit with pre-HD midodrine in patients with known resistant IDH.6-11 Infusion of dobutamine reduced IDH in patients with low cardiac ejection fractions,12 whereas HDCa concentration (3.5 mEq/L) also significantly improved hemodynamics during HD in patients with IDH and compromised cardiac function (class 3 or 4 heart failure with an LVEF ⬍ 40%). In that study, HDCa maintained blood pressure stability in these patients (compared with LDCa) through the prevention of a decline in cardiac output without a change in peripheral vascular resistance.13 It therefore appears that dobutamine and HDCa reduce IDH by maintaining cardiac output during the HD session. Conversely, midodrine and cool dialysate are believed to blunt IDH through improved peripheral vascular resistance and decreased blood pooling.4,5,14-16 Because both reduced cardiac function and impaired vascular response to ultrafiltration can
cause dialysis-associated hypotension, therapies directed at both these processes are intuitive. Theoretically, the combination of HDCa with midodrine and/or cool dialysate should further benefit intradialytic hemodynamics by improving both cardiac output and peripheral vascular resistance. In view of this theoretical possibility, we evaluated the clinical utility of adding HDCa to the regimen of cool dialysate, midodrine, or combined cool dialysate/midodrine in patients with known severe IDH. The addition of HDCa significantly increased post-HD MAP compared with LDCa. HDCa improved the lowest intradialytic MAP, but this did not reach statistical significance. HDCa also significantly reduced the decline in MAP from pre-HD to lowest intradialytic and pre-HD to post-HD compared with LDCa. Although there was a hemodynamic benefit associated with HDCa, the improvements in blood pressure were not associated with similar reductions in symptoms or interventions for IDH. In the subgroup of patients with an LVEF less than 40%, there was not a greater improvement in dialysis hemodynamics compared with the group with an LVEF greater than 40%. However, the small number of patients in the low-LVEF group does not allow one to draw firm conclusions. A larger number of patients with an LVEF less than 40%, as noted in
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a previous study, would likely have shown benefit from HDCa.13 Serum calcium concentration did not increase significantly in the HDCa group compared with the LDCa group. However, the exclusion criteria used for study entry selected a group at lower risk to develop hypercalcemia. Despite these criteria, five patients (22%) dropped out of the study because of the development of hypercalcemia. Furthermore, one needs to consider that more prolonged therapy with HDCa may further increase the percentage of patients who develop hypercalcemia. This suggests that HDCa may not be appropriate for some patients with IDH, especially in view of the potential risks for endorgan calcium-phosphate deposition and calciphylaxis.17 It is also important to note that we used a liberal Ca ⫻ PO4 product cutoff (⬎80) for study exclusion. Recent data suggest that a product greater than 60 increases the risk for coronary disease.18 Use of this cutoff would exclude more patients from HDCa therapy. However, more rigorous administration of non–calcium-containing phosphate binders might reduce the development of hypercalcemia and a high Ca ⫻ PO4 product and facilitate HDCa therapy in patients with IDH. In view of our results, as well as other data reported on the hemodynamic effects of HDCa in the treatment of IDH, a few recommendations for the use of HDCa are offered. First, a trial of HDCa is reasonable in patients with noncompromised cardiac function and IDH that is incompletely responsive to other therapies (midodrine, cool dialysate, etc). However, this therapy did not improve symptoms or interventions for IDH. Second, although our small number of patients with an LVEF less than 40% did not show benefit, HDCa is probably a worthwhile intervention for patients who experience both IDH and compromised heart function. Third, HDCa should not be used in patients with hypercalcemia, hyperphosphatemia, or high Ca ⫻ PO4 products. Additionally, application of HDCa therapy should prompt close monitoring of serum calcium and phosphate levels in these patients. Finally, in patients with IDH responsive to HDCa but who develop hypercalcemia, aggressive substitution of non–calcium-containing phosphate binders may reduce this occurrence.
ALAPPAN ET AL
ACKNOWLEDGMENT The authors thank Susie Nicholaou, RN Nurse Manager, Gambro Healthcare Dialysis Center, for assistance with the study.
REFERENCES 1. Perazella MA: Approach to patients with intradialytic hypotension: A focus on therapeutic options. Semin Dial 12:175-181, 1999 2. Henrich WL, Woodard TD, McPhaul JJ: The chronic efficacy and safety of high sodium dialysate: Double-blind crossover study. Am J Kidney Dis 2:349-353, 1982 3. Daugirdas JT, Al-Kudsi RR, Mg TS, Norusis MJ: A double-blind evaluation of sodium gradient hemodialysis. Am J Nephrol 5:163-168, 1985 4. Sherman RA, Rubin MP, Cody RP, Eisinger RP: Amelioration of hemodialysis associated hypotension by the use of cool dialysate. Am J Kidney Dis 5:124-127, 1985 5. Jost CM, Agarwal R, Khaur-El-Din T, Graybum PA, Victor RU, Henrich WL: Effects of cooler temperature dialysate on hemodynamic stability in “problem” dialysis patients. Kidney Int 44:606-612, 1993 6. Flynn JJ, Mitchell MC, Caruso FS, McElligott MA: Midodrine treatment for patients with hemodialysis hypotension. Clin Nephrol 45:261-267, 1996 7. Fang JT, Huang CC: Midodrine hydrochloride in patients on hemodialysis with chronic hypotension. Ren Fail 18:253-260, 1996 8. Blowey DL, Balfe JW, Gupta J, Gajaria MM, Koren G: Midodrine efficacy and pharmacokinetics in a patient with recurrent intradialytic hypotension. Am I Kidney Dis 28:132136, 1996 9. Cruz DN, Mahnensmith RL, Perazella MA: Intradialytic hypotension: Is midodrine beneficial in symptomatic hemodialysis patients? Am J Kidney Dis 30:772-779, 1997 10. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA: Midodrine is effective and safe therapy for intradialytic hypotension over 8 months of follow-up. Clin Nephrol 50:101-107, 1998 11. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA: Midodrine and cool dialysate are effective therapies for symptomatic intradialytic hypotension. Am J Kidney Dis 33:920-926, 1999 12. Anand U, Bastani B, Dhanraj P, Ballal SH: Intradialytic dobutamine therapy in maintenance hemodialysis patients with persistent hypotension. Am J Nephrol 19:459463, 1999 13. van der Sande FM, Cheriex EC, van Kuijk WHM, Leunissen KML: Effect of dialysate calcium concentrations on intradialytic blood pressure course in cardiac-compromised patients. Am J Kidney Dis 32:125-131, 1998 14. Converse RL, Jacobsen TN, Jost CMT, Toto RD, Grayburn PA, Obregon TM, Foumi-Tarazi F, Victor RG: Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension. J Clin Invest 90:16571665, 1992 15. Sherman RA: The pathophysiologic basis for hemodialysis-related hypotension. Semin Dial 1:136-142, 1988 16. Daugirdas JT: Preventing and managing hypotension. Semin Dial 7:276-283, 1994
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17. Ribeiro S, Ramos A, Brandao A, Rebelo JR, Guerra A, Resina C, Lobos AV, Carvalho F, Remedio F, Ribeiro F: Cardiac valve calcification in hemodialysis patients: Role of calcium-phosphate metabolism. Nephrol Dial Transplant 13:2037-2040, 1998
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18. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478-1483, 2000
S
YMPTOMATIC intradialytic hypotension (IDH) frequently complicates chronic maintenance hemodialysis (HD) sessions despite recent advances in this therapy.1 To combat this problem, a variety of therapeutic interventions have been used. The more successful measures include high dialysate sodium, cool dialysate, and midodrine.2-11 In addition, a greater concentration of calcium (3.5 versus 2.5 mEq/L) in the dialysate bath has been noted to improve intradialytic hemodynamic stability in a selected group of patients with class 3 or 4 heart failure and a left ventricular ejection fraction (LVEF) less than 40%.12 However, high calcium dialysate (HDCa; 3.5 mEq/L) has not been evaluated in a selected From the Section of Nephrology, Yale University School of Medicine, New Haven, CT. Received June 5, 2000; accepted in revised form August 25, 2000. Address reprint requests to Mark A. Perazella, MD, Associate Professor of Medicine, Yale University School of Medicine, Section of Nephrology, Department of Medicine, LMP 2071, 333 Cedar St, New Haven, CT 06520-8029. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3702-0006$35.00/0 doi:10.1053/ajkd.2001.21292 294
group of patients with severe resistant IDH requiring therapy with either midodrine or cool dialysate. It is currently unknown whether these patients would benefit from the addition of a higher dialysate calcium concentration. Thus, we conducted a prospective crossover study to determine the effect of HDCa concentration (3.5 mEq/L) compared with low dialysate calcium (LDCa) concentration (2.5 mEq/L) on hemodynamic stability during HD in patients with known IDH administered therapy with midodrine, cool dialysate, or a combination of these two therapies. MATERIALS AND METHODS The study was performed at the Gambro Healthcare Dialysis Center at Yale University (New Haven, CT) from November 29, 1999, to January 12, 2000. The protocol was approved by the institutional human investigation committee. Patients were eligible for the study if they had resistant IDH and, as a result, were under treatment with cool dialysate (35.5°C), oral midodrine administered before initiation of HD, or both interventions. The primary nephrologist determined treatment with cool dialysate and/or midodrine when the criteria for IDH were met. IDH was defined as at least three episodes of a decrease in systolic blood pressure (by at least 20 mm Hg to a level ⬍100 mm Hg) accompanied by symptoms (dizziness, blurred vision, nausea, vomiting, cramps, or fatigue) in 50% of HD treatments over 1 month. Patients who met these criteria were eligible to participate in
American Journal of Kidney Diseases, Vol 37, No 2 (February), 2001: pp 294-299
HIGH DIALYSATE CALCIUM FOR IDH
the study and were then screened further for study entry. Patients were excluded from the study if the following laboratory criteria were present over the month preceding the study: mean serum calcium level (corrected for albumin level) greater than 10.5 mg/dL, mean serum phosphate level greater than 8.0 mg/dL, or mean calcium x phosphate product (Ca ⫻ PO4) greater than 80. In addition, patients currently on an LDCa bath for hypercalcemia, patients with calciphylaxis, and patients with frequent noncompliance with HD treatments were excluded. Each patient signed informed consent before enrollment. The 6-week study period consisted of two phases. Each phase was composed of nine consecutive HD treatments (3 weeks). During phase 1 (LDCa), patients were administered their usual therapy (cool dialysate, midodrine, or both) for IDH and a 2.5 mEq/L calcium concentration in the dialysate. During phase 2 (HDCa), patients were administered their usual therapy for IDH and a 3.5 mEq/L calcium concentration in the dialysate. This was the only parameter changed during HD. Drop-out criteria during the study included the development of the same parameters used for exclusion from entry onto the study, death, transplantation, or switch to peritoneal dialysis. All patients underwent dialysis on Cobe Centry System 3 volumetric dialysis machines (Cobe, Lakewood, CO), using the Baxter CAHP 170 or 210 dialysis cartridge (for nonreuse patients) and CT 190G dialysis cartridge (for reuse patients) during both phases of the study (Baxter, Deerfield, IL). The electrolyte concentration of the dialysis bath consisted of potassium, 2.0 mEq/L; magnesium, 2.5 mEq/L; and bicarbonate, 40 mEq/L, during both phases of the study. Ramped sodium modeling was tailored to each individual patient and was kept constant for both phases of the study. The temperature of the dialysis bath was maintained constant (35.5°C for patients on cool dialysate, 37°C for patients not on cool dialysate) during both phases of the study. Dialysis flow was set at 600 mL/min. Patients were not allowed to eat during dialysis, and antihypertensive medications were not administered before dialysis. All patients were maintained on their usual medications (including phosphate binders), with no changes during the study period. For the entire study, blood pressure (oscillometric measurement) and pulse were measured by arm cuff (with the patient in the standing position) before each dialysis session, then at 30-minute intervals during dialysis (with the patient seated in an upright position) and at the end of the dialysis session (with the patient standing). Pre-HD blood pressure, lowest intradialytic blood pressure, post-HD blood pressure, pre-HD and post-HD weights, and ultrafiltration volumes were recorded for each dialysis session. Mean arterial pressures (MAPs) were calculated from the systolic and diastolic blood pressures. The differences between the pre-HD MAP and lowest intradialytic MAP were calculated for each session, as well as the difference between pre-HD and post-HD MAPs. For each HD treatment, the number of interventions required for treatment of IDH, defined as Trendelenberg’s position, number and volume of saline infusions, and reduction in ultrafiltration volume, were recorded. According to center protocol, all these interventions were used to treat hypotension (systolic blood pressure ⬍ 100 mm Hg), IDH
295
symptoms, or both. An ordinal scale questionnaire, used in a previous study,11 was administered during each dialysis session to evaluate symptoms associated with IDH. Patients were asked to grade symptoms of cramps, dizziness, fatigue, or nausea on a scale of 0 (no symptoms) to 4 (severe), which were added to produce a total score. Hematocrit and serum calcium levels were determined weekly, and serum albumin, sodium, and Kt/V values were measured once during each phase. Blood urea nitrogen measurements for kinetic analysis were determined predialysis at the time of initial cannulation of the access and at the immediate end of dialysis from the arterial port 30 seconds after the blood flow was reduced to 50 mL/min. A variablevolume single-pool urea kinetic model was used to calculate Kt/V, using the best logarithmic formula of Daugirdas.
Statistics All numerical values are expressed as a mean ⫾ SD unless stated otherwise. Paired Student’s t-test was used, with P less than 0.05 considered statistically significant.
RESULTS
Fifty-seven of 145 chronic maintenance hemodialysis patients (39%) met the criteria for resistant IDH, undergoing treatment with midodrine, cool dialysate, or both therapies. Twenty-nine patients (51%) were excluded from study entry based on the following criteria: calcium level greater than10.5 mg/dL (n ⫽ 5), phosphate level greater than 8 mg/dL (n ⫽ 4), Ca ⫻ PO4 greater than 80 (n ⫽ 2), already on a 3.5-mEq/L calcium concentration bath (n ⫽ 3), calciphylaxis (n ⫽ 1), declined to participate (n ⫽ 4), unable to give consent (n ⫽ 2), a history of noncompliance with dialysis treatments (n ⫽ 3), died before the study period (n ⫽ 4), and relocation (n ⫽ 1). Twenty-eight patients (49%) were eligible to participate in the study. Six patients were on midodrine pre-HD (mean dose, 8.3 mg), nine patients were dialyzed with a 35.5°C bath, and nine patients were dialyzed using both midodrine (mean dose, 13.3 mg) and cool dialysate. Five patients (22%) were withdrawn from the study because of the development of a calcium concentration greater than 10.5 mg/dL. Twenty-three patients completed the study without complications, and their baseline characteristics are listed in Table 1. Five patients (22%) had an LVEF less than 40%. Laboratory values during the two phases of study, including Kt/V, are listed in Table 2. There were no significant differences in these values between the two phases of study. Pre-HD, lowest intradialytic, and post-HD MAPs and the differences between the pre-HD
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ALAPPAN ET AL Table 1.
Patient Baseline Characteristics
Age (y) Women (%) Black (%) Diabetes (%) Hypertension (%) CAD/CHF (%) PVD (%) Use of antihypertensive medications (%) ESRD from diabetes (%) ESRD from hypertension (%) ESRD from other causes (%)
Table 3.
63.9 ⫾ 12.7 57 48 57 91 78 61 83 43 30 27
NOTE. N ⫽ 23. Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; PVD, peripheral vascular disease.
and the lowest and post-HD MAPs for the entire group (n ⫽ 23) are listed in Table 3. Compared with the control phase, there was an improvement in the lowest intradialytic MAP during the HDCa phase, but this did not reach statistical significance (P ⫽ 0.12). There was a statistically significant improvement in the post-HD MAP during the HDCa phase (P ⫽ 0.002). HDCa also significantly reduced the decrease in pre-HD to lowest intradialytic MAP (P ⫽ 0.009), as well as the decrease in pre-HD to post-HD MAP (P ⫽ 0.002) compared with LDCa (Fig 1). MAPs in the subgroup of patients (n ⫽ 5) with an LVEF less than 40% compared with patients (n ⫽ 18) with an LVEF greater than 40% were also analyzed. In the five patients with a low LVEF, the changes in blood pressures were not statistically different and there was no significant difference in blood pressure between the two groups (data not shown). As listed in Table 2, there were no differences Table 2.
Laboratory Parameters LDCa (2.5 mEq/L)
HDCa (3.5 mEq/L)
Albumin (g/dL) 3.7 ⫾ 0.36 3.7 ⫾ 0.34 Calcium (mg/dL) 9.24 ⫾ 0.64 9.38 ⫾ 0.76 Phosphorus (mg/dL) 6.16 ⫾ 1.64 5.66 ⫾ 1.70 Calcium ⫻ phosphorus 56.4 ⫾ 13.5 52.5 ⫾ 13.9 Hematocrit (%) 37.3 ⫾ 3.69 37.1 ⫾ 3.31 Kt/V 1.50 ⫾ 0.33 1.64 ⫾ 0.33 Potassium (mmol/L) 5.1 ⫾ 0.7 5.0 ⫾ 0.7 Sodium (mmol/L) 139.8 ⫾ 2.88 139.7 ⫾ 3.59
P
⬎0.5 ⬎0.3 ⬎0.1 ⬎0.1 ⬎0.5 ⬎0.5 ⬎0.5 ⬎0.1
MAP (mm Hg)
Predialysis (PRE) Lowest (LOW) Postdialysis (POST) ⌬ PRE–LOW ⌬ PRE–POST
MAP
LDCa (2.5 mEq/L)
HDCa (3.5 mEq/L)
P
99.5 ⫾ 14.2 78.8 ⫾ 10.5 90.8 ⫾ 12.5 20.6 ⫾ 10.0 8.15 ⫾ 10.8
97.6 ⫾ 12.8 81.2 ⫾ 11.2 95.6 ⫾ 12.7 16.3 ⫾ 8.2 2.0 ⫾ 8.5
0.18 0.12 0.002 0.009 0.002
Abbreviations: ⌬ PRE–LOW, difference between predialysis MAP and lowest intradialytic MAP; ⌬ PRE–POST, difference between predialysis MAP and postdialysis MAP.
in mean serum calcium concentrations, mean serum phosphate concentrations, and mean Ca ⫻ PO4 in the LDCa and HDCa phases. Ultrafiltration volumes (HDCa, 2.8 ⫾ 3.62 L/treatment; LDCa, 2.4 ⫾ 1.37 L/treatment; P ⬎ 1.0), as well as the pre-HD (HDCa, 72.5 ⫾ 16.5 kg; LDCa, 72.9 ⫾ 16.3 kg; P ⬎ 0.5) and post-HD (HDCa, 69.5 ⫾ 15.1 kg; LDCa, 70.2 ⫾15.7 kg; P ⬎ 0.5) weights were not significantly different between the two phases of the study. Total symptom scores were recorded for the entire group during the study. In the LDCa phase, the total score for cramps was 28 (in 17 patients), fatigue was 28 (in 14 patients), nausea was 17 (in 13 patients), and dizziness was 24 (in 13 patients). In the HDCa phase, the total score for cramps was 18 (in 11 patients), fatigue was 16 (in 9 patients), nausea was 28 (in 10 patients), and dizziness was 32 (in 16 patients). None of the total symptom scores were statistically different (P ⬎ 0.10) except for dizziness (24 versus 32; P ⬍0.05), which was more common during the HDCa phase, and fatigue (28 versus 16; P ⬍ 0.05), which occurred more often in the LDCa phase. Analysis of interventions showed a need for Trendelenberg’s position in 11 patients, saline infusion in 30 patients (265 ⫾ 141.5 mL), and reduction in ultrafiltration in 32 patients in the LDCa phase. During the HDCa phase, 11 patients required Trendelenberg’s position, 30 patients were administered saline infusion (404 ⫾ 274.6 mL), and 29 patients required a reduction in ultrafiltration. All P were greater than 1.0. DISCUSSION
The treatment of symptomatic hypotension during HD remains a challenge to the nephrolo-
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Fig 1. Individual data points showing the change in MAP on LDCa and HDCa for each patient. (Left) Change in MAP from pre-HD to lowest intradialytic (⌬ [Pre MAP-Low MAP]) and (right) decline in MAP from pre-HD to post-HD (⌬ [Pre MAP-Post MAP]).
gist. Multiple pathogenic factors, including both patient- and dialysis modality–specific causes, contribute to IDH and underlie the refractory nature of this disorder.13-15 A number of varied therapeutic interventions have been used, but unfortunately, only a few of these modalities provide some benefit in the most severely affected patients.13-15 These include high dialysate sodium concentration and cool temperature dialysate.2-5 More recently, we and others reported hemodynamic benefit with pre-HD midodrine in patients with known resistant IDH.6-11 Infusion of dobutamine reduced IDH in patients with low cardiac ejection fractions,12 whereas HDCa concentration (3.5 mEq/L) also significantly improved hemodynamics during HD in patients with IDH and compromised cardiac function (class 3 or 4 heart failure with an LVEF ⬍ 40%). In that study, HDCa maintained blood pressure stability in these patients (compared with LDCa) through the prevention of a decline in cardiac output without a change in peripheral vascular resistance.13 It therefore appears that dobutamine and HDCa reduce IDH by maintaining cardiac output during the HD session. Conversely, midodrine and cool dialysate are believed to blunt IDH through improved peripheral vascular resistance and decreased blood pooling.4,5,14-16 Because both reduced cardiac function and impaired vascular response to ultrafiltration can
cause dialysis-associated hypotension, therapies directed at both these processes are intuitive. Theoretically, the combination of HDCa with midodrine and/or cool dialysate should further benefit intradialytic hemodynamics by improving both cardiac output and peripheral vascular resistance. In view of this theoretical possibility, we evaluated the clinical utility of adding HDCa to the regimen of cool dialysate, midodrine, or combined cool dialysate/midodrine in patients with known severe IDH. The addition of HDCa significantly increased post-HD MAP compared with LDCa. HDCa improved the lowest intradialytic MAP, but this did not reach statistical significance. HDCa also significantly reduced the decline in MAP from pre-HD to lowest intradialytic and pre-HD to post-HD compared with LDCa. Although there was a hemodynamic benefit associated with HDCa, the improvements in blood pressure were not associated with similar reductions in symptoms or interventions for IDH. In the subgroup of patients with an LVEF less than 40%, there was not a greater improvement in dialysis hemodynamics compared with the group with an LVEF greater than 40%. However, the small number of patients in the low-LVEF group does not allow one to draw firm conclusions. A larger number of patients with an LVEF less than 40%, as noted in
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a previous study, would likely have shown benefit from HDCa.13 Serum calcium concentration did not increase significantly in the HDCa group compared with the LDCa group. However, the exclusion criteria used for study entry selected a group at lower risk to develop hypercalcemia. Despite these criteria, five patients (22%) dropped out of the study because of the development of hypercalcemia. Furthermore, one needs to consider that more prolonged therapy with HDCa may further increase the percentage of patients who develop hypercalcemia. This suggests that HDCa may not be appropriate for some patients with IDH, especially in view of the potential risks for endorgan calcium-phosphate deposition and calciphylaxis.17 It is also important to note that we used a liberal Ca ⫻ PO4 product cutoff (⬎80) for study exclusion. Recent data suggest that a product greater than 60 increases the risk for coronary disease.18 Use of this cutoff would exclude more patients from HDCa therapy. However, more rigorous administration of non–calcium-containing phosphate binders might reduce the development of hypercalcemia and a high Ca ⫻ PO4 product and facilitate HDCa therapy in patients with IDH. In view of our results, as well as other data reported on the hemodynamic effects of HDCa in the treatment of IDH, a few recommendations for the use of HDCa are offered. First, a trial of HDCa is reasonable in patients with noncompromised cardiac function and IDH that is incompletely responsive to other therapies (midodrine, cool dialysate, etc). However, this therapy did not improve symptoms or interventions for IDH. Second, although our small number of patients with an LVEF less than 40% did not show benefit, HDCa is probably a worthwhile intervention for patients who experience both IDH and compromised heart function. Third, HDCa should not be used in patients with hypercalcemia, hyperphosphatemia, or high Ca ⫻ PO4 products. Additionally, application of HDCa therapy should prompt close monitoring of serum calcium and phosphate levels in these patients. Finally, in patients with IDH responsive to HDCa but who develop hypercalcemia, aggressive substitution of non–calcium-containing phosphate binders may reduce this occurrence.
ALAPPAN ET AL
ACKNOWLEDGMENT The authors thank Susie Nicholaou, RN Nurse Manager, Gambro Healthcare Dialysis Center, for assistance with the study.
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