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Acetate, Bicarbonate and Hypotension During Hemodialysis
Acetate, Bicarbonate and Hypotension During Hemodialysis William F. Heneghan, M.D.
I
N the early 1960s hemodialysis was performed with bicarbonate in the dialysate. Although this was quite effective in restoring the serum bicarbonate to normal , it posed a practical problem. Solutions containing bicarbonate and calcium are unstable, making the use of a single concentrate impossible. The ptoblem was solved by substituting acetate for bicarbonate. 1 Acetate is readily metabolized in the body and results in bicarbonate production. No adverse effects of acetate were noted, and its alkalinizing effects were considered adequate. Although there was no direct advantage for the patient in using acetate, it did simplify dialysate preparation , and this appears to be the major reason it has become the standard dialysate buffer. Hemodialysis has changed dramatically in the last two decades, and what was true about acetate dialysis in the 1%Os may not be true today. Conclusions about the safety of acetate were drawn at a time when dialysis was much less efficient and the rate of acetate transfer into the patient was relatively low. Over the years there has been a general trend towards more effective dialysis. Improved dialyzer design, large membrane surface area, and higher blood flow rates have been utilized to achieve more rapid removal of uremic toxins: the same conditions result in a much greater acetate delivery to the patient. Since the side effects of many substances are dose dependent, the question of possible acetate toxicity can not be answered using the studies of the 1960s. Despite the widespread use of acetate for many years, the first critical comparison of acetate and bicarbonate dialysis was not published until 1978. 2 In that study Graefe et aI . found that symptoms occurred during 89% of dialyses with large surface area dialyzers when acetate was used . When bicarbonate was used, however, only 21% of the patients were symptomatic during dialysis. He also noted that during bicarbonate dialysis fluid could
From Brooklyn Hospital , Brooklyn, N .Y. R eprint requests sh ould be addressed to William F. Heneghan , MD ., Director of Hemodialysis, Brooklyn Hospital, 121 DeKalb Ave., BrookLyn, N. Y. 11201 . © 1982 by Th e National Kidney Foundation, Inc. 0272-63861821020302 ·03$01 .0010
302
be removed more rapidly (1.2 liter/hr vs. 0.7 liter/ hr) while the systolic blood pressure remained significantly higher post dialysis (117 mmHg vs. 109 mmHg). Several similar studies 3-6 have also found that acetate dialysis is associated with more frequent hypotension and patient symptoms . One recent study failed to demonstrate a difference in blood pressure control between acetate and bicarbonate dialysis. 7 In that study , however, side effects were minimized by infusing mannitol into the patient during dialysis. In addition, the first few dialyses for each patient were performed using a low urea clearance, and this would result in a reduced acetate delivery to the patient. Why is acetate associated with greater morbidity during dialysis? One explanation is that acetate itself has a direct toxic effect. With high efficiency dialysis the rate of acetate influx exceeds the metabolic clearance, 8 resulting in high serum levels of acetate. 9 Unfortunately there is no good study demonstrating a correlation between acetate blood levels and symptoms during dialysis. Hypoxemia, a well known consequence of acetate dialysis, could also be the cause of acetate associated morbidity . In order to test this hypothesis, we studied the effect of oxygen administration during dialysis. Five chronic hemodialysis patients who experienced frequent and severe hypotension were studied during a total of 30 dialyses. During half the dialyses they received nasal oxygen, and during the other half they received compressed air via an identical nasal cannula. The average fall in blood pressure, computed from all blood pressure recordings during dialysis was 17 .33 mmHg when the patient received compressed air but only 7.22 mmHg when the patient received nasal oxygen. Eight of the 15 dialyses with compressed air were terminated early because of severe hypotension, while only one of the 15 dialyses with supplemental oxygen was similarly terminated. Four of the five patients experienced fewer symptoms during dialysis when they received oxygen. This study, along with a similar study by Ahmad , 11 suggests that hypoxemia during acetate dialysis may be a significant factor causing symptoms.
American Journal of Kidney Diseases, Vol. II , No. 2, September 1982
303
ACETATE, BICARBONATE AND HYPOTENSION
Several theories have been proposed to explain dialysis hypoxemia. 12-14 The observation that hypoxemia does not occur with bicarbonate dialysis 15.16 suggests that acetate may be at fault. Oh et al. 17 have postulated that acetate metabolism leads to a reduced C02 production, hypoventilation, and hypoxemia. In order for acetate to be metabolized, it must first accept a hydrogen ion. Carbonic acid donates the hydrogen ion, leaving behind bicarbonate. In this way a substantial quantity of C02 (as carbonic acid) has been diverted into bicarbonate production. Thus the net C02 production has been reduced, resulting in hypoventilation and hypoxemia. In order to test this hypothesis, acetate was infused into normal volunteers at a rate of 4 mM/hr, a rate equivalent to the acetate influx rate with high efficiency dialysis. The P02 fell from 93.3 ± 1.1 mmHg to 78.3 ± 1. 7 mmHg, demonstrating that acetate metabolism alone will cause substantial hypoxemia. 18 So far the only established advantage of bicarbonate dialysis is that patients experience fewer symptoms. Even the most serious symptom, hypotension, is transient and usually responds to fluid replacement. Unfortunately no one has yet studied the long-term effects of repeated hypotension during dialysis, so it is premature to assume that it is benign. It is possible that there is a link between hypotension during dialysis and hypertension between dialysis. Volume overload is considered the most important cause of hypertension in chronic hemodialysis patients. The obvious treatment is fluid removal and studies have demonstrated that good blood pressure control can be achieved just by adequate fluid removal. 19.20 Since hypotension during dialysis is usually treated by fluid replacement and a reduction in the ultrafiltration rate, the patient will remain fluid overloaded. In this paradoxical way hypotension during dialysis may contribute to hypertension when the patient is off dialysis. Since bicarbonate dialysis is associated with less hypotension, higher ultrafiltration rates, and achievement of target fluid· removal in a higher percentage of patients, it may lead to better control of hypertension. Recent studies 21.22 have shown that control of hypertension is a major factor determining long-term survival in dialysis. If bicarbonate dialysis can lead to better control of hypertension, the argument for its use becomes more convincing. Hypotension during dialysis may have another
deleterious long-term effect. One way to cope with hypotension during dialysis is to avoid large area dialyzers since they are more likely to cause hypotension. This is probably one reason why only a small minority of patients are dialyzed using the most efficient dialyzers. Although side effects would be reduced with a less efficient dialyzer, urea clearance would also be reduced. Unless the duration of dialysis is increased to compensate for the reduced urea clearance, the patient will be maintained with a higher BUN. The results of the national cooperative dialysis study demonstrated that patients had a higher complication rate and more frequent hospitalization when they were maintained with a higher BUN. 23 Bicarbonate dialysis, by allowing the patient to tolerate more efficient dialysis, could result in lower BUN's and a better clinical course for the patient. Acetate was introduced when chronic dialysis was in its infancy. It became widely accepted as the standard dialysate buffer after a single paper demonstrated that six patients dialyzed with it were able to maintain acid base balance without evident side effects. 1 Only recently have several studies compared the acute effects of acetate and bicarbonate dialysis, and they clearly show that acetate is responsible for many of the symptoms seen during dialysis. Long-term comparisons of acetate and bicarbonate dialysis have not been done, but there are theoretical reasons to believe that bicarbonate may be superior. There is still a significant morbidity and mortality rate associated with chronic hemodialysis. It is not clear whether these complications are inherent to the procedure, or whether they are a toxic effect of an exogenous substance administered during dialysis. Until more data are available, acetate must be considered suspect.
REFERENCES 1. Mion CM, Hegstrom RM, Beon ST, et al: Substitution of sodium acetate for sodium bicarbonate in the bath fluid for hemodialysis. Trans Amer Soc Artif Int Organs 10:110, 1964 2. Graefe U, Milutinovitch J, Follette WC, et al: Less dialysis-induced morbidity and vascular instability with bicarbonate in dialysate. Ann Int Med 88:332, 1978 3. Iseki K, Onoyama K, Meada T, et al: Comparison of hemodynamics induced by conventional acetate hemodialysis, bicarbonate hemodialysis and ultrafiltration. Clin Neph 14:294, 1980 4. Wehle B, Asaba H, Castenfors J, et al: The influence of dialysis fluid composition on the blood pressure response during dialysis. Clin Neph 10:62, 1978
304 5. Posen GA, Mikhael R: Dialysis related hypotension: Etiology and prevention. Kidney Int (Abstr) 19:394, 1981 6. Van Stone lC: A critical comparison of bicarbonate and acetate dialyses. Cont Dial, Sept, 1980 p 25 7. Borges HR, Fryd DS, Rosa AA, et al: Hypotension during acetate and bicarbonate dialysis in patients with acute renal failure. Am 1 Nephrol 1:24-30, 1981 8. Tolchin N, Roberts lL, Hayashi 1, et al: Metabolic consequences of high mass transfer hemodialysis. Kidney Int 11:366, 1977 9. Novello A, Kelsch RC, Easterling RE: Acetate intolerance during hemodialysis. Clin Nephr 5:29, 1976 10. Heneghan WF, Brunswick lW, Oh MS, et al: Dialysis hypoxemia causes hypertension. Kidney Int 21:1, 169A, 1982 11. Ahmad S, Pabel M, Shen F, et al: The role of hypoxemia in the expression of acetate intolerance. Am Soc Nephrol (Abstr) p 33, 1980 12. Sherlock lE, Yoon Y, Ledwith lW, et al: Respiratory gas exchange during hemodialysis. Proc Clin Transpl Forum 2:171, 1972 13. Sargent lA, Gotcg FA: Bicarbonate and carbon dioxide transport during hemodialysis. Clin Nephrol 3:54, 1975 14. Craddock PR, Fehr 1, Brigham KL, et al: Complement and leukocyte mediated pulmonary dysfunction in hemodialysis. N Engl 1 Med 296:769-774, 1977 15. Nissenson AR: Prevention of dialysis induced
WILLIAM F. HENEGHAN
hypoxemia by bicarbonate dialysis. Trans Am Soc Artif Intern Organs 26:339, 1980 16. Raja R, Kramer M, Rosenbaum lL, et al: Dialysis hypoxemia with varing dialyzers and dialysate - role of acetate in etiology. Am Soc Artif Intern Organs (Abstr) 9:60, 1980 17. Oh MS, Uribarri lV, DelMonte ML, et al: Consumption of C02 in metabolism of acetate as an explanation for hypoventilation and hypoxemia during hemodialysis. Proc Clin Dial Transpl Forum 9:226, 1976 18. Oh MS, Heneghan WF, Kee CS, et al: Glucose ameliorates hypoxemia and reduction in respiratory quotient (R.Q.) induced by infusion of sodium acetate. Kidney Int 21: 175A, 1982 19. Lazarus 1M, Hampers CL, Merrill lP: Hypertension and chronic renal failure treatments with hemodialysis and nephrectomy. Arch Intern Med 133:1059, 1974 20. Vertes V, Cangiano lL, Berman LB, et al: Hypertension and end-stage renal disease. N Engl 1 Med 280:978, 1969 21. Eliahou HE, Iaina A, Reisin E, et al: Probability of survival in hypertensive and non-hypertensive patients on maintenance hemodialysis. Isr 1 Med Sci 13:33-38, 1977 22. Chester AC, Schreiner GE: Hypertension and hemodialysis. Trans Am Soc Artif Intern Organs 24:36-41, 1978 23. Lowrie EG, Laird NM, Parker TF, et al: Effect of the hemodialysis prescription on patient morbidity: Report from the National Cooperative Dialysis Study. N Engl 1 Med 305:1176~1l81, 1981
I
N the early 1960s hemodialysis was performed with bicarbonate in the dialysate. Although this was quite effective in restoring the serum bicarbonate to normal , it posed a practical problem. Solutions containing bicarbonate and calcium are unstable, making the use of a single concentrate impossible. The ptoblem was solved by substituting acetate for bicarbonate. 1 Acetate is readily metabolized in the body and results in bicarbonate production. No adverse effects of acetate were noted, and its alkalinizing effects were considered adequate. Although there was no direct advantage for the patient in using acetate, it did simplify dialysate preparation , and this appears to be the major reason it has become the standard dialysate buffer. Hemodialysis has changed dramatically in the last two decades, and what was true about acetate dialysis in the 1%Os may not be true today. Conclusions about the safety of acetate were drawn at a time when dialysis was much less efficient and the rate of acetate transfer into the patient was relatively low. Over the years there has been a general trend towards more effective dialysis. Improved dialyzer design, large membrane surface area, and higher blood flow rates have been utilized to achieve more rapid removal of uremic toxins: the same conditions result in a much greater acetate delivery to the patient. Since the side effects of many substances are dose dependent, the question of possible acetate toxicity can not be answered using the studies of the 1960s. Despite the widespread use of acetate for many years, the first critical comparison of acetate and bicarbonate dialysis was not published until 1978. 2 In that study Graefe et aI . found that symptoms occurred during 89% of dialyses with large surface area dialyzers when acetate was used . When bicarbonate was used, however, only 21% of the patients were symptomatic during dialysis. He also noted that during bicarbonate dialysis fluid could
From Brooklyn Hospital , Brooklyn, N .Y. R eprint requests sh ould be addressed to William F. Heneghan , MD ., Director of Hemodialysis, Brooklyn Hospital, 121 DeKalb Ave., BrookLyn, N. Y. 11201 . © 1982 by Th e National Kidney Foundation, Inc. 0272-63861821020302 ·03$01 .0010
302
be removed more rapidly (1.2 liter/hr vs. 0.7 liter/ hr) while the systolic blood pressure remained significantly higher post dialysis (117 mmHg vs. 109 mmHg). Several similar studies 3-6 have also found that acetate dialysis is associated with more frequent hypotension and patient symptoms . One recent study failed to demonstrate a difference in blood pressure control between acetate and bicarbonate dialysis. 7 In that study , however, side effects were minimized by infusing mannitol into the patient during dialysis. In addition, the first few dialyses for each patient were performed using a low urea clearance, and this would result in a reduced acetate delivery to the patient. Why is acetate associated with greater morbidity during dialysis? One explanation is that acetate itself has a direct toxic effect. With high efficiency dialysis the rate of acetate influx exceeds the metabolic clearance, 8 resulting in high serum levels of acetate. 9 Unfortunately there is no good study demonstrating a correlation between acetate blood levels and symptoms during dialysis. Hypoxemia, a well known consequence of acetate dialysis, could also be the cause of acetate associated morbidity . In order to test this hypothesis, we studied the effect of oxygen administration during dialysis. Five chronic hemodialysis patients who experienced frequent and severe hypotension were studied during a total of 30 dialyses. During half the dialyses they received nasal oxygen, and during the other half they received compressed air via an identical nasal cannula. The average fall in blood pressure, computed from all blood pressure recordings during dialysis was 17 .33 mmHg when the patient received compressed air but only 7.22 mmHg when the patient received nasal oxygen. Eight of the 15 dialyses with compressed air were terminated early because of severe hypotension, while only one of the 15 dialyses with supplemental oxygen was similarly terminated. Four of the five patients experienced fewer symptoms during dialysis when they received oxygen. This study, along with a similar study by Ahmad , 11 suggests that hypoxemia during acetate dialysis may be a significant factor causing symptoms.
American Journal of Kidney Diseases, Vol. II , No. 2, September 1982
303
ACETATE, BICARBONATE AND HYPOTENSION
Several theories have been proposed to explain dialysis hypoxemia. 12-14 The observation that hypoxemia does not occur with bicarbonate dialysis 15.16 suggests that acetate may be at fault. Oh et al. 17 have postulated that acetate metabolism leads to a reduced C02 production, hypoventilation, and hypoxemia. In order for acetate to be metabolized, it must first accept a hydrogen ion. Carbonic acid donates the hydrogen ion, leaving behind bicarbonate. In this way a substantial quantity of C02 (as carbonic acid) has been diverted into bicarbonate production. Thus the net C02 production has been reduced, resulting in hypoventilation and hypoxemia. In order to test this hypothesis, acetate was infused into normal volunteers at a rate of 4 mM/hr, a rate equivalent to the acetate influx rate with high efficiency dialysis. The P02 fell from 93.3 ± 1.1 mmHg to 78.3 ± 1. 7 mmHg, demonstrating that acetate metabolism alone will cause substantial hypoxemia. 18 So far the only established advantage of bicarbonate dialysis is that patients experience fewer symptoms. Even the most serious symptom, hypotension, is transient and usually responds to fluid replacement. Unfortunately no one has yet studied the long-term effects of repeated hypotension during dialysis, so it is premature to assume that it is benign. It is possible that there is a link between hypotension during dialysis and hypertension between dialysis. Volume overload is considered the most important cause of hypertension in chronic hemodialysis patients. The obvious treatment is fluid removal and studies have demonstrated that good blood pressure control can be achieved just by adequate fluid removal. 19.20 Since hypotension during dialysis is usually treated by fluid replacement and a reduction in the ultrafiltration rate, the patient will remain fluid overloaded. In this paradoxical way hypotension during dialysis may contribute to hypertension when the patient is off dialysis. Since bicarbonate dialysis is associated with less hypotension, higher ultrafiltration rates, and achievement of target fluid· removal in a higher percentage of patients, it may lead to better control of hypertension. Recent studies 21.22 have shown that control of hypertension is a major factor determining long-term survival in dialysis. If bicarbonate dialysis can lead to better control of hypertension, the argument for its use becomes more convincing. Hypotension during dialysis may have another
deleterious long-term effect. One way to cope with hypotension during dialysis is to avoid large area dialyzers since they are more likely to cause hypotension. This is probably one reason why only a small minority of patients are dialyzed using the most efficient dialyzers. Although side effects would be reduced with a less efficient dialyzer, urea clearance would also be reduced. Unless the duration of dialysis is increased to compensate for the reduced urea clearance, the patient will be maintained with a higher BUN. The results of the national cooperative dialysis study demonstrated that patients had a higher complication rate and more frequent hospitalization when they were maintained with a higher BUN. 23 Bicarbonate dialysis, by allowing the patient to tolerate more efficient dialysis, could result in lower BUN's and a better clinical course for the patient. Acetate was introduced when chronic dialysis was in its infancy. It became widely accepted as the standard dialysate buffer after a single paper demonstrated that six patients dialyzed with it were able to maintain acid base balance without evident side effects. 1 Only recently have several studies compared the acute effects of acetate and bicarbonate dialysis, and they clearly show that acetate is responsible for many of the symptoms seen during dialysis. Long-term comparisons of acetate and bicarbonate dialysis have not been done, but there are theoretical reasons to believe that bicarbonate may be superior. There is still a significant morbidity and mortality rate associated with chronic hemodialysis. It is not clear whether these complications are inherent to the procedure, or whether they are a toxic effect of an exogenous substance administered during dialysis. Until more data are available, acetate must be considered suspect.
REFERENCES 1. Mion CM, Hegstrom RM, Beon ST, et al: Substitution of sodium acetate for sodium bicarbonate in the bath fluid for hemodialysis. Trans Amer Soc Artif Int Organs 10:110, 1964 2. Graefe U, Milutinovitch J, Follette WC, et al: Less dialysis-induced morbidity and vascular instability with bicarbonate in dialysate. Ann Int Med 88:332, 1978 3. Iseki K, Onoyama K, Meada T, et al: Comparison of hemodynamics induced by conventional acetate hemodialysis, bicarbonate hemodialysis and ultrafiltration. Clin Neph 14:294, 1980 4. Wehle B, Asaba H, Castenfors J, et al: The influence of dialysis fluid composition on the blood pressure response during dialysis. Clin Neph 10:62, 1978
304 5. Posen GA, Mikhael R: Dialysis related hypotension: Etiology and prevention. Kidney Int (Abstr) 19:394, 1981 6. Van Stone lC: A critical comparison of bicarbonate and acetate dialyses. Cont Dial, Sept, 1980 p 25 7. Borges HR, Fryd DS, Rosa AA, et al: Hypotension during acetate and bicarbonate dialysis in patients with acute renal failure. Am 1 Nephrol 1:24-30, 1981 8. Tolchin N, Roberts lL, Hayashi 1, et al: Metabolic consequences of high mass transfer hemodialysis. Kidney Int 11:366, 1977 9. Novello A, Kelsch RC, Easterling RE: Acetate intolerance during hemodialysis. Clin Nephr 5:29, 1976 10. Heneghan WF, Brunswick lW, Oh MS, et al: Dialysis hypoxemia causes hypertension. Kidney Int 21:1, 169A, 1982 11. Ahmad S, Pabel M, Shen F, et al: The role of hypoxemia in the expression of acetate intolerance. Am Soc Nephrol (Abstr) p 33, 1980 12. Sherlock lE, Yoon Y, Ledwith lW, et al: Respiratory gas exchange during hemodialysis. Proc Clin Transpl Forum 2:171, 1972 13. Sargent lA, Gotcg FA: Bicarbonate and carbon dioxide transport during hemodialysis. Clin Nephrol 3:54, 1975 14. Craddock PR, Fehr 1, Brigham KL, et al: Complement and leukocyte mediated pulmonary dysfunction in hemodialysis. N Engl 1 Med 296:769-774, 1977 15. Nissenson AR: Prevention of dialysis induced
WILLIAM F. HENEGHAN
hypoxemia by bicarbonate dialysis. Trans Am Soc Artif Intern Organs 26:339, 1980 16. Raja R, Kramer M, Rosenbaum lL, et al: Dialysis hypoxemia with varing dialyzers and dialysate - role of acetate in etiology. Am Soc Artif Intern Organs (Abstr) 9:60, 1980 17. Oh MS, Uribarri lV, DelMonte ML, et al: Consumption of C02 in metabolism of acetate as an explanation for hypoventilation and hypoxemia during hemodialysis. Proc Clin Dial Transpl Forum 9:226, 1976 18. Oh MS, Heneghan WF, Kee CS, et al: Glucose ameliorates hypoxemia and reduction in respiratory quotient (R.Q.) induced by infusion of sodium acetate. Kidney Int 21: 175A, 1982 19. Lazarus 1M, Hampers CL, Merrill lP: Hypertension and chronic renal failure treatments with hemodialysis and nephrectomy. Arch Intern Med 133:1059, 1974 20. Vertes V, Cangiano lL, Berman LB, et al: Hypertension and end-stage renal disease. N Engl 1 Med 280:978, 1969 21. Eliahou HE, Iaina A, Reisin E, et al: Probability of survival in hypertensive and non-hypertensive patients on maintenance hemodialysis. Isr 1 Med Sci 13:33-38, 1977 22. Chester AC, Schreiner GE: Hypertension and hemodialysis. Trans Am Soc Artif Intern Organs 24:36-41, 1978 23. Lowrie EG, Laird NM, Parker TF, et al: Effect of the hemodialysis prescription on patient morbidity: Report from the National Cooperative Dialysis Study. N Engl 1 Med 305:1176~1l81, 1981