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Continuous extracorporeal renal replacement therapies: membranes and solutions for fluid replacement
)COMMUNICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .DES . . . . . . .EXPERTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
Continuousextracorporeal renal replacementtherapies: membranesandsolutions for fluid replacement HP Kierdorf,
C Leue, S Arns
M
any efforts have been made to reduce the high mortality of patients with acute renal failure (ARF); one of these is continuous renal replacement therapies (CCRT). These treatments, first published in 1977 as “continuous arteriovenous hemofiltration (CAVH)” by Kramer et al for patients with ARF, quickly gained ground owing to its simplicity [ 11. However, bloodpressure-dependent filtration could not adequately control azotemia in hemodynamically unstable patients. A number of treatment methods aimed at combining the advantages of continuous therapy with a higher effectiveness have been developed since the beginning of the eighties [2, 31. The common feature of these new methods, for instance continuous arteriovenous hemodialysis (CAVD), and pump-assisted venovenous methods, such as continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVD), is that their greater efficacy enables them to satisfactorily maintain even hemodynamically unstable
Department of Internal Medicine II, University Clinic of the Technical University, Aachen, Germany.
hypercatabolic patients with ARF and multiple organ dysfunction syndrome (MODS) [3]. In contrast to CAVH in these forms of treatment, daily fluid exchange reaches 25 to 40 L so that the composition of the substitution fluid becomes more relevant than in early low volume CAVH. In recent years, bioincompatibility of membrane materials (eg cuprophane) has been shown to have negative influence on the survival of critically ill ARF patients [4, 51. As CRRT are used 24 hours a day, biocompatibility of the employed membranes seems to be of major importance.
Solutions for fluid replacement: importance of buffer Renal replacement therapy in ARF has three major aims [6]: detoxification, fluid elimination and compensation of acidosis. In CRRT, the physical properties of hemofiltration, hemodialysis or hemodiafiltration techniques are therefore used. In continuous treatment forms exclusively utilizing hemofiltration, the ultrafiltrate is completely replaced by a sterile substitute solution. For suffi-215
cient control of azotemia (also in hypercatabolic patients) CVVH treatment minimally requires a total of 20-30 L hemofiltrate per day [7]. In techniques utilizing hemodialysis, a defined quantity of dialysate passes on the outer side of the dialyzator, using the counterflow principle. A certain quantity of ultrafiltrate is still produced, so that the therapy represents a combination of dialysis and filtration, ie of diffusive and convective transport [8]. The dialysate flow rate is l-2 L/h (24-48 L/d). Substitution fluids and dialysate used in CRRT have been primarily developed for intermittent hemofiltration or peritoneal dialysis. In CRRT techniques, including dialysis, any ready-to-use commercial dialysis solution may be employed. In such commercially available fluids lactate (30-45 mmol/L), which is converted to bicarbonate on an equimolar basis under physiological conditions, is used as the buffer to correct acidosis. The lactate buffer has the advantage of greater stability over a physiologic bicarbonate buffer. However, lactate is thought to have negative effects on metabolic parameters, eg enhanced protein catabolism and decreased regeneration rate of ATP 191, and on hemodynamic parameters [ lo]. The theoretical disadvantages of lactatebuffered substitution fluids are listed in table I. Lactate-buffered substitution solutions or dialysate may lead to a daily lactate load of 8001,300 mmol. ARF patients, especially those with concomitant hepatic insufficiency or hemodynamic instability, present an increased plasma lactate level. Reports of a reduced lactate tolerance and a tendency to develop hyperlactataemia during treatment with lactate-buffered solutions are also extent [l 11. In patients with lactacidosis and hepatic failure. conversion of lactate into bicarbonate
R&an Urg 1998 ; 7 : 215-9 ~72Elsevier,
Pars
. . . HP . . . .Kierdorf’et . . . . . . . . . .al . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
TABLE I. Theoreticat disadvantages of lactate-buffered replacement fluids in CRRT. -_..____ ., I. ..-.- _--_ _._ .“..l_^ __--- 111_-.,-_.....”. l
l
l
l
l
Reducedhemodynamic stability Conversion from lactateto bicarbonate needsenergy Hypercatabolism - Reduced ATP-regeneration - Protein catabolism Negahve Influence on lymphocyte function Reduced control of acidosis in patients with hepatic insufficiency or strong hypoxemia ^_.
is also diminished, and hyperlactatemia due to the lactate-buffer in the substitution solution can be a negative side effect in continuous treatment of critically ill patients Il2J. As early as 19X.5 the possibility of bicarbonarebuffered substituion fluids for CAVH have been indicated out as an alternative [ I3 I. There is some evidence that metabolic and hemodynamic disadvantages of lactate buffering can be avoided by the use of hicarbonatebuffered solutions 13, IO. 14). The disadvantage of solutions with a bicarbonate-buffer is that the limited stability of the bicarbonate requires addition directly prior to application of- the substitution solution 1141. We Investigated the influence of a lactate-buffered and a bicarbonatebuffered substitution solution on acidbase status. electrolytes and metabolic changes in critically ill patients with ARF and MODS undergoing CVVII 1IS]. Patients received a bicarbonate-solution on days l-4 and a lactate-solution on days 5-8, or in the reverse order. The composition of the solutions manufactured by Schiwa, Germany is given m r&k II. All critically ill patients with ARF were effectively treated by CVVH using tither bicarbonate-buffered or lactate-buffered solutions. Within 48 hours uremia was well controlled in both groups and hyperhydration was well balanced with a daily hemofiltrate of about 29 L, in accordance with the data of other group< using
R&n
Urg 1698
; 7 :215-g
,“_
_
__ ._
-._
L-”
,,.-.,.
_.*..“.“~._-.
__
lactate-buffered substitution solutions [ 16. 171. There was no difference in mean arterial blood pressure (7.5.5 f 24.0 mm Hg for all patients) or in the need for positive inotropic substances neither between the two groups nor within each group. Primarily acetate, but also lactate buffer. have been shown to exert li lIf?giltiVe influence on mean arterial blood pressure and cardiac function 110, IX, 191. During hyperlactataemia (lactate = 354 mmol/L) a reduced myocardial performance ( IS aus B) due to an increased intra-
cellular lactate concentration, leading to reduced cellular ATP production, has been reported. A correlation of mean arterial blood pressure to the degree of lactate intolerance has also been described. As mentioned above, in our study there was no negative influence of lactate buffer, the hemodynamic status of the patients was comparable using either the bicarbonate or lactate-buffered solutions. This blood pressurestability is probably due to the fact that in our patients, despite a significantly higher lactate level during the substitution with lactate-buffer. lactate levels never left the normal limits. On days 1-4 the lactate level was increased in the group receiving the lactate-buffer (JI = 0.002). on day S-8 in group A, receiving rhe lactate-buffer in this phase (p = 0.00 18). Within both groups there was a significant difference between the phase with bicarbonate and the phase with lactate substitution (/7 = 0.0018; table II/). Comparing
TABLE II. Composition of lactate-buffered (Ski05@) and bicarbonatebuffered (SH35Hep@) replacement solutions for CRRT. Other commonly used compositions are given in parenthesis.
Sodium (mmol/L)
142 (135-l 50)
140 (138-142)
Chloride (mmoliL)
103 (100-112)
110 (108-110)
Lactate (mmol/L)
44.5 (33-45)
3.0 (O-3.0)
Bicarbonate
34.5 (33-43.5)
(lTlMO\/L)
Calcium (mmol/L)
2.0 (1.5-2.0)
1 75 (1.5-l .75)
Magnesium (mmol/L)
0.75
Potassium (mmol/L)
0.5 -
(o-4)
(O-2)
Glucose (mmoliL)
^.
216
5.6 (O-l 1.2) -. .~ “.. _^ I.- ” “l_-. .., .I.
_
(D-5.6) ..; _^--“_^ ,.“,-...-. .“. _.,_- _-__.
CCRl? membranes and solutions for fluid replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
TABLE III. Comparison of acid-base status (mean and SD) of patients with ARF and MODS during CVVH with bicarbonate-buffered or lactate-buffered replacement solutions in a cross-over study (adapted from 15).
BeforeCWH Daysl-4 Days5-8
7.38 f 0.06 7.43f 0.03 7.43f: 0.05
7.43f: 0.07 7.43f 0.07 7.42zt 0.07
Bicarbonate BeforeCWH (mmol/L) Daysl-4 Days5-8
19.9f 4.4 22.5+ 2.5 23.2f 3.0*
23.5+ 3.9 23.8 f 2.5** 22.5i: 2.3’**
PH
Lactate (mmol/L)
BeforeCWH Daysl-4 Days5-8
2.54f 2.49 0.76+ 0.86 2.05f 1.21* p < 0.05 vsgroup A; *”
* p < 0.05 vs days 1-4 within group A; ‘* ARF: acute renal failure: MODS: multibe orclan hemofiltration; SD: standard deviation: -
dvsfunction .
lactate values before CVVH treatment in both groups, there was a slight decrease in lactate, the decrease being most marked during bicarbonate substitution. Renal acidosis was sufficiently controlled with no difference in pH or base excess between the groups or within the groups (table Ill). On days 14 bicarbonate concentration was significantly higher 0, = 0.035) in the group receiving lactate-buffered solution, within group A bicarbonate was significantly higher on days 5-8 (p = 0.043), while within group B bicarbonate was significantly @ = 0.018) higher on days 14, indicating a higher bicarbonate concentration during the treatment with lactate-buffer in both groups. Hyperlactatemia has been reported during lactate-buffered substitution in critically ill patients with ARF administered in intermittent hemofiltration with a lactate load of 1902 10 mmol/h [ lo], whereas patients in CRRT receive a maximum lactate load of 90 mmol/h, even when fluid exchange in filtration- or dialysate techniques increases to 2 L/h. The slower ultrafiltration in CRRT compared
2.49ic 1.04 1.59* 1.17** 1.25f 0.83**
p c 0.05 vs days 1-4 within group B. syndrome: CVVH: continuous veno-venous
to intermittent hemoliltration may be the reason for the better lactate tolerance in critically ill patients, despite the same total quantity of substituted lactate (1 ,OOO- 1,200 mmol/d). In contrast to Davenport’s study, where a tendency to metabolic acidosis in the ARF group was described, renal acidosis was sufficiently controlled in our patients. with no differences between bicarbonate- or lactate buffered solutions. Lactate could be shown to be an effective bicarbonate generating base in patients with acute or chronic renal failure [lo, 201. Under stable clinical conditions lactate is metabolized to bicarbonate on an equimolar basis. Critically ill patients with ARF, especially with concomitant sepsis or circulatory shock, have been reported to present a reduced lactate tolerance [ 111. In our study, which excluded patients with liver disease, the only sign of a possible lactate intolerance was the significantly higher lactate levels during lactate-buffering. The bicarbonate levels were also significantly higher during lactate-buffering. This is probably due to a lower quantity of buffer substances in the bicarbonatebuffered solution (34.5 mmol/L bi-
carbonate and 3 mmol/L lactate) compared to the lactate-buffered solution (44.5 mmol/L lactate) but may also be explained by the physiological metabolism of lactate to bicarbonate, as lactate was also elevated in these patients. In a recently published study, a bicarbonate buffered substitution solution with a higher amount of bicarbonate (40 mmol/L) showed a better control of acidosis than a lactatebuffered solution [2 11.There was also a clear trend to higher serum bicarbonate concentrations in the group with the bicarbonate-buffered solution [21]. In our study, no differences between the two groups in phosphate, potassium, chloride or sodium concentration occurred. Differences in chloride, calcium and magnesium were released by the composition of the bicarbonate buffer determined by the chemical properties of the compound. The solution must be stable for a 24-hour period without precipitation of calcium carbonate or magnesium carbonate ] 141. The magnesium and calcium concentration is reduced compared to the lactate-buffered solution To adjust ionic strength the chloride concentration must be increased. Possible precipitation does not allow a higher phosphate concentration in one of the solutions, so phosphate must separately be substituted to avoid phosphate depletion, as MODS patients with ARF tend to develop hypophosphatemia leading to decreased respiratory and cardiac function. The readily mixed bicarbonate-buffered solution was prepared in bags of special plastic sheeting to prevent evaporation of carbon dioxide [ 141. Acetate-buffered substitution fluids should be avoided, as a significantly reduced control of acidosis compared to a lactate-buffered solution has been recently reported during CVVH [22],
Rban Urg 1998 ; 7 : 215-9
HP Kierdorfet al . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
Cuprophane membranes have been shown to have a negative influence on the survival of critically ill ARF patients [4, 51. This is mainly due to bioincompatibility of these membranes. A variety of filters using different membrane materials are available for CCRT. As compared to cuprophane used in IHD, only synthetic
membrane materials (polysulfone, polyacrylnitrile, polyamide) are used. The activation of the complement system and the release of proteases and other mediators, which are said to be responsible for bioincompatibility, seems to be absent using these synthetic membranes [25,26]. The use of cuprophane membranes in patients treated with IHD as opposed to synthetic membranes used in CRRT may explain differences or advantages in favour of CRRT during the last decade. There are no data comparing biocompatible IHD, ie with polymethyhnetacrylate mebranes with CRRT, so it has not been defined whether bioincompatibility will be a further disadvantage of IHD as compared to CRRT. Renal recovery may also be influenced by the type of membrane used in extracorporeal therapy. Cuprophane membranes used in IHD have proved to prolong the duration of ARF and anuria [4]. Little is known about the influence of CRRT or IHD on the duration of ARF. In retrospective studies clear trends towards a shorter duration of anuria and significant differences in the duration of ARF were found in patients treated by CRRT compared to those treated by IHD [27, 281. Notably, when biocompatible membranes (cellulosic-triacet) were also used in the II-ID group, the length of dialytic support was significantly higher in the IHD group [27].
The filters used in CRRT have different sieving coefficients, depending on the membrane material used [29]. Different advantages are claimed for each of these by their manufacturers. Until now no data have identified any material as superior over others, especially in terms of filter-running time, renal recovery or biocompatibility. Different membrane pore sizes or adhesive properties may perhaps become more interesting in the coming years, especially in the attempt to eliminate mediator substances, such as tumour necrosis factor or cytokines, with molecular weights between 15,000 and 50,000 Da [7]. There is some evidence that synthetic membranes differ in adsorption and sieving capacities [30]. The clinical relevance of these and other data [3 11 has to be proven, as the small amounts of cytokines eliminated by CRRT seem to be of no or minor interest compared to a high turnover and a high total body clearance [32]. In conclusion, modem CRRT use the most biocompatibie membranes known according to today’s standards. Really no clinical data identify any material as superior over others, especially in terms of filterrunning time and renal recovery. The clinical evidence of the elimination of cytokines due to adsorption or convective transport has not yet been defined. n
1 Kramer P, Wigger W, Rieger J, Matthai 0, Scheler F. Arteriovenous haemofiltration: a new and simple method for treatment of overhydrated patients resistant todiuretics. K/in Wochenschr 1977 ; 55 : 1121-2 2 Geronemus R, Schneider N. Continuous arteriovenous hemodialysis: a new modality for treatment of acute renal failure. Trans Am Sot Artif Intern Organs 1984 ; 30 : 61 o-3 3 Kierdorf H. Continuous versus intermittent treatment: clinical results in acute
renal failure. Confrib Nephfoll991 ; 93 : 1-12 4 Hakim RM, Wingard RL, Parker RA. Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994 ; 331 : 1338-42 5 Schiffl H, Lang SM, Konig A, Strasser T, Haider MC, Held E. Biocompatible membranes in acute renal failure: prospective casecontrolled study. Lancer 1994 ; 344 : 570-2 6 Ronco C, Burckardi H. Management of acute renal failure in the critically ill patient,
In: Pinsky MR, Dhainant JFA. eds. Pathophysiologic Foundations of Critical Care. Baltimore: Wiliams & Wiliams; 1993. p 630-77 7 Kierdorf H, Sieberth HG. Continuous treatment modalities in acute renal failure. Nephrol Dial Transplant 1995 ; 10 : 2001-8 8 Van Geelen JA, Vincent HH, Schalekamp MADH. Continuous arteriovenous haemofiltration and haemodiafiltration in acute renal failure. NephrolDial Transplant 1988 ; 2 : 181-6
and lower hemodynamic stability is described in dialysis procedures [ 19, 231. Solutions used in peritoneal dialysis have also been recommended as an alternative [2, 131, but their high glucose concentration can lead to incomplete metabolism, requiring additional insulin intake, and may lead to carbohydrate overload. In conclusion, in patients with reduced lactate metabolism, eg concomittant hepatic failure, severe septic shock or after liver transplantation, bicarbonate-buffered solutions should be used as the replacement fluid. In nearly all other cases the physiological capacity of lactate metabolism of up to 2,000 mmol of lactate per day [24] allows the use of lactate-buffered substitute solutions. Acetate-buffered solutions and solutions containing high amounts of glucose should be avoided.
Importance of membranes, biocompatibility
R&an Urg 1998 ; 7 : 215-9
CCRlJ membranes and solutionsfor fluid replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
9Veech L. The untoward effects of the anions of dialysis fluid. Kidney Int 1988 ; 934 : 587-97 10 Davenport A, Will E, Davison AM. The effect of lactate-buffered solutions on the acid-base status of patients with renal failure. Nephrol Dial Transplant 1989 ; 4 : 800-4 11 Giblert GM, Haupt MT, Calson RW. Lactate predicts the relationship between oxygen transport and oxygen consumption in patients with circulatory shock. Crit CareMedl984;12:299 12 Reynolds HN, Belzberg H, Connelly J. Hyperlactemia in patients undergoing continuous arteriovenous hemofiltration with dialysis. Crif Care Med 1990 ; 18 : 582 13 Golper TA. Continuous arteriovenous hemofiltration in acute renal failure. Am J Kidney Dis 1985 ; 6 : 373-86 140lbricht CJ, Huxmann-Nageli D, Bischoff H. Bikarbonat- statt laktatgepufferter Substitutionsliisung zur kontinuierlithen Hamofiltration im Intensivbereich. Anasfhesiol lntensivther Noffallmed 1990;25:164-7 15 Kierdorf H, Leue C, Heintz B, Riehi J, Melzer H, Sieberth HG. Continuous venovenous hemofiltration in acute renal failure: is a bicarbonate-or lactate-buffered substitution better? Contrib Nephrol 1995 ; 116 : 38-47 16 Canaud G, Carred LJ, Christol JP, Aubas S, Beraud JJ, Mion C. Pump-assisted continuous venovenous haemofiltration for treating acute uremia. Kidney Int 1988 ; 33 SuppI : 154-6
17 Wendon J, Smithies M, Sheppard M, Bullen K, Tinker J, Bihari D. Continuous high volume veno-venous haemofiltration in acute renal failure. lntens Care Med 1989 ; 15 : 358-63 18 Saman S, Opie LH. Mechanism of reduction of action potential duration of ventricular myocarduum by exogenous lactate. J MO/ Cell Cardioll984 ; 10 : 659-62 19Mansell MA, Morgan SH, Moore L, Kong CH, Laker MF, Wing AJ. Cardiovascular and acid-base effects of acetate and bicarbonate haemodialysis. Nephrol Dial Transplant 1987 ; 1 : 229-32 20 Hayashi JA, Dauirdas JT. Use of lactate as a base in hemodialysis. AmJNephroll987 ; 7 :434-g 21 McLean A, Goddard J, Haber M, Naidoo R, Davenport A, Sweny P. Lactate-free dialysate for continuous hemodiafiltration. Effects on acidosis, blood pressure, and inotropic requirement [abstract]. J Am Sot Nephroll996 ; 9 : 1413 22 Morgera S,Heering P,Szentandrasi T, Manassa E,Heintzen M.Willers R, PasslickDeetjen J, Grabensee B. Renal Failure 1997 ; 19 : 155-64 23 Leunissen KML, Hoorntje SJ, Fiers HA, Dekkers WT, Mulder AW. Acetate versus bicarbonate haemodialysis in critically ill patients. Nephron 1986 ; 42 : 145-51 24 Berry MN. The liver and lactic acidosis. froc R Sot Med 1967 ; 60 : 52-4 25 Bohler J, Kramer P, Gotze 0, Schwartz P, Scheler F. Leucocyte counts and complement activation during pump-driven and
arteriovenous haemofiltration. Contrib Nephrol1983 ; 36 : 15-25 26 Horl WH, Schaefer RM, Heidland A. Effect of different dialyzers on proteinases and proteinase inhibitors during hemodialysis. Am J Nephrol 1985 ; 5 : 320-6 27 Van Bommel EFH. Are continuous therapies superior to intermittent haemodialys/s in the acute renal failure on the internsive care unit? Nephrol Dial Transplant 1995 ; 10 : 311-4 28 Stevens PE, Rainford DJ. lsovolemic hemodialysis combined with hemofiltration in acute renal failure. Renal Failure1990 ; 12 : 205-11 29 Sieberth HG. Continuous renal replacement therapy in acute renal failure. In: Cameron S, Davison AM, Grijnfeld JP, Kerr D, Ritz E, eds. Oxford Textbook of Cinical Nephrology Oxford: Oxford University Press; 1992. p 1026-34 30Van Bommel EFH, Hesse CJ, Jutte NHPM, Zietse R, Bruining HA! Weimar W. Cytokine Kinetics (TNF-a, IL-16, IL-6) during continuous hemofiltration: Alaboratory and clinical study. Confrib Nephroll995 ; 113 : 62-75 31 Bellomo R, Tipping P, Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 1993 ; 21 : 522-6 32 Schetz M. Removal of cytokines in septic patients using continuous veno-venous hemodiafiltration. Crit Care Med 1994; 22 :715-6
Wan
Urg 1998 ; 7 : 215-9
Continuousextracorporeal renal replacementtherapies: membranesandsolutions for fluid replacement HP Kierdorf,
C Leue, S Arns
M
any efforts have been made to reduce the high mortality of patients with acute renal failure (ARF); one of these is continuous renal replacement therapies (CCRT). These treatments, first published in 1977 as “continuous arteriovenous hemofiltration (CAVH)” by Kramer et al for patients with ARF, quickly gained ground owing to its simplicity [ 11. However, bloodpressure-dependent filtration could not adequately control azotemia in hemodynamically unstable patients. A number of treatment methods aimed at combining the advantages of continuous therapy with a higher effectiveness have been developed since the beginning of the eighties [2, 31. The common feature of these new methods, for instance continuous arteriovenous hemodialysis (CAVD), and pump-assisted venovenous methods, such as continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVD), is that their greater efficacy enables them to satisfactorily maintain even hemodynamically unstable
Department of Internal Medicine II, University Clinic of the Technical University, Aachen, Germany.
hypercatabolic patients with ARF and multiple organ dysfunction syndrome (MODS) [3]. In contrast to CAVH in these forms of treatment, daily fluid exchange reaches 25 to 40 L so that the composition of the substitution fluid becomes more relevant than in early low volume CAVH. In recent years, bioincompatibility of membrane materials (eg cuprophane) has been shown to have negative influence on the survival of critically ill ARF patients [4, 51. As CRRT are used 24 hours a day, biocompatibility of the employed membranes seems to be of major importance.
Solutions for fluid replacement: importance of buffer Renal replacement therapy in ARF has three major aims [6]: detoxification, fluid elimination and compensation of acidosis. In CRRT, the physical properties of hemofiltration, hemodialysis or hemodiafiltration techniques are therefore used. In continuous treatment forms exclusively utilizing hemofiltration, the ultrafiltrate is completely replaced by a sterile substitute solution. For suffi-215
cient control of azotemia (also in hypercatabolic patients) CVVH treatment minimally requires a total of 20-30 L hemofiltrate per day [7]. In techniques utilizing hemodialysis, a defined quantity of dialysate passes on the outer side of the dialyzator, using the counterflow principle. A certain quantity of ultrafiltrate is still produced, so that the therapy represents a combination of dialysis and filtration, ie of diffusive and convective transport [8]. The dialysate flow rate is l-2 L/h (24-48 L/d). Substitution fluids and dialysate used in CRRT have been primarily developed for intermittent hemofiltration or peritoneal dialysis. In CRRT techniques, including dialysis, any ready-to-use commercial dialysis solution may be employed. In such commercially available fluids lactate (30-45 mmol/L), which is converted to bicarbonate on an equimolar basis under physiological conditions, is used as the buffer to correct acidosis. The lactate buffer has the advantage of greater stability over a physiologic bicarbonate buffer. However, lactate is thought to have negative effects on metabolic parameters, eg enhanced protein catabolism and decreased regeneration rate of ATP 191, and on hemodynamic parameters [ lo]. The theoretical disadvantages of lactatebuffered substitution fluids are listed in table I. Lactate-buffered substitution solutions or dialysate may lead to a daily lactate load of 8001,300 mmol. ARF patients, especially those with concomitant hepatic insufficiency or hemodynamic instability, present an increased plasma lactate level. Reports of a reduced lactate tolerance and a tendency to develop hyperlactataemia during treatment with lactate-buffered solutions are also extent [l 11. In patients with lactacidosis and hepatic failure. conversion of lactate into bicarbonate
R&an Urg 1998 ; 7 : 215-9 ~72Elsevier,
Pars
. . . HP . . . .Kierdorf’et . . . . . . . . . .al . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
TABLE I. Theoreticat disadvantages of lactate-buffered replacement fluids in CRRT. -_..____ ., I. ..-.- _--_ _._ .“..l_^ __--- 111_-.,-_.....”. l
l
l
l
l
Reducedhemodynamic stability Conversion from lactateto bicarbonate needsenergy Hypercatabolism - Reduced ATP-regeneration - Protein catabolism Negahve Influence on lymphocyte function Reduced control of acidosis in patients with hepatic insufficiency or strong hypoxemia ^_.
is also diminished, and hyperlactatemia due to the lactate-buffer in the substitution solution can be a negative side effect in continuous treatment of critically ill patients Il2J. As early as 19X.5 the possibility of bicarbonarebuffered substituion fluids for CAVH have been indicated out as an alternative [ I3 I. There is some evidence that metabolic and hemodynamic disadvantages of lactate buffering can be avoided by the use of hicarbonatebuffered solutions 13, IO. 14). The disadvantage of solutions with a bicarbonate-buffer is that the limited stability of the bicarbonate requires addition directly prior to application of- the substitution solution 1141. We Investigated the influence of a lactate-buffered and a bicarbonatebuffered substitution solution on acidbase status. electrolytes and metabolic changes in critically ill patients with ARF and MODS undergoing CVVII 1IS]. Patients received a bicarbonate-solution on days l-4 and a lactate-solution on days 5-8, or in the reverse order. The composition of the solutions manufactured by Schiwa, Germany is given m r&k II. All critically ill patients with ARF were effectively treated by CVVH using tither bicarbonate-buffered or lactate-buffered solutions. Within 48 hours uremia was well controlled in both groups and hyperhydration was well balanced with a daily hemofiltrate of about 29 L, in accordance with the data of other group< using
R&n
Urg 1698
; 7 :215-g
,“_
_
__ ._
-._
L-”
,,.-.,.
_.*..“.“~._-.
__
lactate-buffered substitution solutions [ 16. 171. There was no difference in mean arterial blood pressure (7.5.5 f 24.0 mm Hg for all patients) or in the need for positive inotropic substances neither between the two groups nor within each group. Primarily acetate, but also lactate buffer. have been shown to exert li lIf?giltiVe influence on mean arterial blood pressure and cardiac function 110, IX, 191. During hyperlactataemia (lactate = 354 mmol/L) a reduced myocardial performance ( IS aus B) due to an increased intra-
cellular lactate concentration, leading to reduced cellular ATP production, has been reported. A correlation of mean arterial blood pressure to the degree of lactate intolerance has also been described. As mentioned above, in our study there was no negative influence of lactate buffer, the hemodynamic status of the patients was comparable using either the bicarbonate or lactate-buffered solutions. This blood pressurestability is probably due to the fact that in our patients, despite a significantly higher lactate level during the substitution with lactate-buffer. lactate levels never left the normal limits. On days 1-4 the lactate level was increased in the group receiving the lactate-buffer (JI = 0.002). on day S-8 in group A, receiving rhe lactate-buffer in this phase (p = 0.00 18). Within both groups there was a significant difference between the phase with bicarbonate and the phase with lactate substitution (/7 = 0.0018; table II/). Comparing
TABLE II. Composition of lactate-buffered (Ski05@) and bicarbonatebuffered (SH35Hep@) replacement solutions for CRRT. Other commonly used compositions are given in parenthesis.
Sodium (mmol/L)
142 (135-l 50)
140 (138-142)
Chloride (mmoliL)
103 (100-112)
110 (108-110)
Lactate (mmol/L)
44.5 (33-45)
3.0 (O-3.0)
Bicarbonate
34.5 (33-43.5)
(lTlMO\/L)
Calcium (mmol/L)
2.0 (1.5-2.0)
1 75 (1.5-l .75)
Magnesium (mmol/L)
0.75
Potassium (mmol/L)
0.5 -
(o-4)
(O-2)
Glucose (mmoliL)
^.
216
5.6 (O-l 1.2) -. .~ “.. _^ I.- ” “l_-. .., .I.
_
(D-5.6) ..; _^--“_^ ,.“,-...-. .“. _.,_- _-__.
CCRl? membranes and solutions for fluid replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
TABLE III. Comparison of acid-base status (mean and SD) of patients with ARF and MODS during CVVH with bicarbonate-buffered or lactate-buffered replacement solutions in a cross-over study (adapted from 15).
BeforeCWH Daysl-4 Days5-8
7.38 f 0.06 7.43f 0.03 7.43f: 0.05
7.43f: 0.07 7.43f 0.07 7.42zt 0.07
Bicarbonate BeforeCWH (mmol/L) Daysl-4 Days5-8
19.9f 4.4 22.5+ 2.5 23.2f 3.0*
23.5+ 3.9 23.8 f 2.5** 22.5i: 2.3’**
PH
Lactate (mmol/L)
BeforeCWH Daysl-4 Days5-8
2.54f 2.49 0.76+ 0.86 2.05f 1.21* p < 0.05 vsgroup A; *”
* p < 0.05 vs days 1-4 within group A; ‘* ARF: acute renal failure: MODS: multibe orclan hemofiltration; SD: standard deviation: -
dvsfunction .
lactate values before CVVH treatment in both groups, there was a slight decrease in lactate, the decrease being most marked during bicarbonate substitution. Renal acidosis was sufficiently controlled with no difference in pH or base excess between the groups or within the groups (table Ill). On days 14 bicarbonate concentration was significantly higher 0, = 0.035) in the group receiving lactate-buffered solution, within group A bicarbonate was significantly higher on days 5-8 (p = 0.043), while within group B bicarbonate was significantly @ = 0.018) higher on days 14, indicating a higher bicarbonate concentration during the treatment with lactate-buffer in both groups. Hyperlactatemia has been reported during lactate-buffered substitution in critically ill patients with ARF administered in intermittent hemofiltration with a lactate load of 1902 10 mmol/h [ lo], whereas patients in CRRT receive a maximum lactate load of 90 mmol/h, even when fluid exchange in filtration- or dialysate techniques increases to 2 L/h. The slower ultrafiltration in CRRT compared
2.49ic 1.04 1.59* 1.17** 1.25f 0.83**
p c 0.05 vs days 1-4 within group B. syndrome: CVVH: continuous veno-venous
to intermittent hemoliltration may be the reason for the better lactate tolerance in critically ill patients, despite the same total quantity of substituted lactate (1 ,OOO- 1,200 mmol/d). In contrast to Davenport’s study, where a tendency to metabolic acidosis in the ARF group was described, renal acidosis was sufficiently controlled in our patients. with no differences between bicarbonate- or lactate buffered solutions. Lactate could be shown to be an effective bicarbonate generating base in patients with acute or chronic renal failure [lo, 201. Under stable clinical conditions lactate is metabolized to bicarbonate on an equimolar basis. Critically ill patients with ARF, especially with concomitant sepsis or circulatory shock, have been reported to present a reduced lactate tolerance [ 111. In our study, which excluded patients with liver disease, the only sign of a possible lactate intolerance was the significantly higher lactate levels during lactate-buffering. The bicarbonate levels were also significantly higher during lactate-buffering. This is probably due to a lower quantity of buffer substances in the bicarbonatebuffered solution (34.5 mmol/L bi-
carbonate and 3 mmol/L lactate) compared to the lactate-buffered solution (44.5 mmol/L lactate) but may also be explained by the physiological metabolism of lactate to bicarbonate, as lactate was also elevated in these patients. In a recently published study, a bicarbonate buffered substitution solution with a higher amount of bicarbonate (40 mmol/L) showed a better control of acidosis than a lactatebuffered solution [2 11.There was also a clear trend to higher serum bicarbonate concentrations in the group with the bicarbonate-buffered solution [21]. In our study, no differences between the two groups in phosphate, potassium, chloride or sodium concentration occurred. Differences in chloride, calcium and magnesium were released by the composition of the bicarbonate buffer determined by the chemical properties of the compound. The solution must be stable for a 24-hour period without precipitation of calcium carbonate or magnesium carbonate ] 141. The magnesium and calcium concentration is reduced compared to the lactate-buffered solution To adjust ionic strength the chloride concentration must be increased. Possible precipitation does not allow a higher phosphate concentration in one of the solutions, so phosphate must separately be substituted to avoid phosphate depletion, as MODS patients with ARF tend to develop hypophosphatemia leading to decreased respiratory and cardiac function. The readily mixed bicarbonate-buffered solution was prepared in bags of special plastic sheeting to prevent evaporation of carbon dioxide [ 141. Acetate-buffered substitution fluids should be avoided, as a significantly reduced control of acidosis compared to a lactate-buffered solution has been recently reported during CVVH [22],
Rban Urg 1998 ; 7 : 215-9
HP Kierdorfet al . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
Cuprophane membranes have been shown to have a negative influence on the survival of critically ill ARF patients [4, 51. This is mainly due to bioincompatibility of these membranes. A variety of filters using different membrane materials are available for CCRT. As compared to cuprophane used in IHD, only synthetic
membrane materials (polysulfone, polyacrylnitrile, polyamide) are used. The activation of the complement system and the release of proteases and other mediators, which are said to be responsible for bioincompatibility, seems to be absent using these synthetic membranes [25,26]. The use of cuprophane membranes in patients treated with IHD as opposed to synthetic membranes used in CRRT may explain differences or advantages in favour of CRRT during the last decade. There are no data comparing biocompatible IHD, ie with polymethyhnetacrylate mebranes with CRRT, so it has not been defined whether bioincompatibility will be a further disadvantage of IHD as compared to CRRT. Renal recovery may also be influenced by the type of membrane used in extracorporeal therapy. Cuprophane membranes used in IHD have proved to prolong the duration of ARF and anuria [4]. Little is known about the influence of CRRT or IHD on the duration of ARF. In retrospective studies clear trends towards a shorter duration of anuria and significant differences in the duration of ARF were found in patients treated by CRRT compared to those treated by IHD [27, 281. Notably, when biocompatible membranes (cellulosic-triacet) were also used in the II-ID group, the length of dialytic support was significantly higher in the IHD group [27].
The filters used in CRRT have different sieving coefficients, depending on the membrane material used [29]. Different advantages are claimed for each of these by their manufacturers. Until now no data have identified any material as superior over others, especially in terms of filter-running time, renal recovery or biocompatibility. Different membrane pore sizes or adhesive properties may perhaps become more interesting in the coming years, especially in the attempt to eliminate mediator substances, such as tumour necrosis factor or cytokines, with molecular weights between 15,000 and 50,000 Da [7]. There is some evidence that synthetic membranes differ in adsorption and sieving capacities [30]. The clinical relevance of these and other data [3 11 has to be proven, as the small amounts of cytokines eliminated by CRRT seem to be of no or minor interest compared to a high turnover and a high total body clearance [32]. In conclusion, modem CRRT use the most biocompatibie membranes known according to today’s standards. Really no clinical data identify any material as superior over others, especially in terms of filterrunning time and renal recovery. The clinical evidence of the elimination of cytokines due to adsorption or convective transport has not yet been defined. n
1 Kramer P, Wigger W, Rieger J, Matthai 0, Scheler F. Arteriovenous haemofiltration: a new and simple method for treatment of overhydrated patients resistant todiuretics. K/in Wochenschr 1977 ; 55 : 1121-2 2 Geronemus R, Schneider N. Continuous arteriovenous hemodialysis: a new modality for treatment of acute renal failure. Trans Am Sot Artif Intern Organs 1984 ; 30 : 61 o-3 3 Kierdorf H. Continuous versus intermittent treatment: clinical results in acute
renal failure. Confrib Nephfoll991 ; 93 : 1-12 4 Hakim RM, Wingard RL, Parker RA. Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994 ; 331 : 1338-42 5 Schiffl H, Lang SM, Konig A, Strasser T, Haider MC, Held E. Biocompatible membranes in acute renal failure: prospective casecontrolled study. Lancer 1994 ; 344 : 570-2 6 Ronco C, Burckardi H. Management of acute renal failure in the critically ill patient,
In: Pinsky MR, Dhainant JFA. eds. Pathophysiologic Foundations of Critical Care. Baltimore: Wiliams & Wiliams; 1993. p 630-77 7 Kierdorf H, Sieberth HG. Continuous treatment modalities in acute renal failure. Nephrol Dial Transplant 1995 ; 10 : 2001-8 8 Van Geelen JA, Vincent HH, Schalekamp MADH. Continuous arteriovenous haemofiltration and haemodiafiltration in acute renal failure. NephrolDial Transplant 1988 ; 2 : 181-6
and lower hemodynamic stability is described in dialysis procedures [ 19, 231. Solutions used in peritoneal dialysis have also been recommended as an alternative [2, 131, but their high glucose concentration can lead to incomplete metabolism, requiring additional insulin intake, and may lead to carbohydrate overload. In conclusion, in patients with reduced lactate metabolism, eg concomittant hepatic failure, severe septic shock or after liver transplantation, bicarbonate-buffered solutions should be used as the replacement fluid. In nearly all other cases the physiological capacity of lactate metabolism of up to 2,000 mmol of lactate per day [24] allows the use of lactate-buffered substitute solutions. Acetate-buffered solutions and solutions containing high amounts of glucose should be avoided.
Importance of membranes, biocompatibility
R&an Urg 1998 ; 7 : 215-9
CCRlJ membranes and solutionsfor fluid replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......
9Veech L. The untoward effects of the anions of dialysis fluid. Kidney Int 1988 ; 934 : 587-97 10 Davenport A, Will E, Davison AM. The effect of lactate-buffered solutions on the acid-base status of patients with renal failure. Nephrol Dial Transplant 1989 ; 4 : 800-4 11 Giblert GM, Haupt MT, Calson RW. Lactate predicts the relationship between oxygen transport and oxygen consumption in patients with circulatory shock. Crit CareMedl984;12:299 12 Reynolds HN, Belzberg H, Connelly J. Hyperlactemia in patients undergoing continuous arteriovenous hemofiltration with dialysis. Crif Care Med 1990 ; 18 : 582 13 Golper TA. Continuous arteriovenous hemofiltration in acute renal failure. Am J Kidney Dis 1985 ; 6 : 373-86 140lbricht CJ, Huxmann-Nageli D, Bischoff H. Bikarbonat- statt laktatgepufferter Substitutionsliisung zur kontinuierlithen Hamofiltration im Intensivbereich. Anasfhesiol lntensivther Noffallmed 1990;25:164-7 15 Kierdorf H, Leue C, Heintz B, Riehi J, Melzer H, Sieberth HG. Continuous venovenous hemofiltration in acute renal failure: is a bicarbonate-or lactate-buffered substitution better? Contrib Nephrol 1995 ; 116 : 38-47 16 Canaud G, Carred LJ, Christol JP, Aubas S, Beraud JJ, Mion C. Pump-assisted continuous venovenous haemofiltration for treating acute uremia. Kidney Int 1988 ; 33 SuppI : 154-6
17 Wendon J, Smithies M, Sheppard M, Bullen K, Tinker J, Bihari D. Continuous high volume veno-venous haemofiltration in acute renal failure. lntens Care Med 1989 ; 15 : 358-63 18 Saman S, Opie LH. Mechanism of reduction of action potential duration of ventricular myocarduum by exogenous lactate. J MO/ Cell Cardioll984 ; 10 : 659-62 19Mansell MA, Morgan SH, Moore L, Kong CH, Laker MF, Wing AJ. Cardiovascular and acid-base effects of acetate and bicarbonate haemodialysis. Nephrol Dial Transplant 1987 ; 1 : 229-32 20 Hayashi JA, Dauirdas JT. Use of lactate as a base in hemodialysis. AmJNephroll987 ; 7 :434-g 21 McLean A, Goddard J, Haber M, Naidoo R, Davenport A, Sweny P. Lactate-free dialysate for continuous hemodiafiltration. Effects on acidosis, blood pressure, and inotropic requirement [abstract]. J Am Sot Nephroll996 ; 9 : 1413 22 Morgera S,Heering P,Szentandrasi T, Manassa E,Heintzen M.Willers R, PasslickDeetjen J, Grabensee B. Renal Failure 1997 ; 19 : 155-64 23 Leunissen KML, Hoorntje SJ, Fiers HA, Dekkers WT, Mulder AW. Acetate versus bicarbonate haemodialysis in critically ill patients. Nephron 1986 ; 42 : 145-51 24 Berry MN. The liver and lactic acidosis. froc R Sot Med 1967 ; 60 : 52-4 25 Bohler J, Kramer P, Gotze 0, Schwartz P, Scheler F. Leucocyte counts and complement activation during pump-driven and
arteriovenous haemofiltration. Contrib Nephrol1983 ; 36 : 15-25 26 Horl WH, Schaefer RM, Heidland A. Effect of different dialyzers on proteinases and proteinase inhibitors during hemodialysis. Am J Nephrol 1985 ; 5 : 320-6 27 Van Bommel EFH. Are continuous therapies superior to intermittent haemodialys/s in the acute renal failure on the internsive care unit? Nephrol Dial Transplant 1995 ; 10 : 311-4 28 Stevens PE, Rainford DJ. lsovolemic hemodialysis combined with hemofiltration in acute renal failure. Renal Failure1990 ; 12 : 205-11 29 Sieberth HG. Continuous renal replacement therapy in acute renal failure. In: Cameron S, Davison AM, Grijnfeld JP, Kerr D, Ritz E, eds. Oxford Textbook of Cinical Nephrology Oxford: Oxford University Press; 1992. p 1026-34 30Van Bommel EFH, Hesse CJ, Jutte NHPM, Zietse R, Bruining HA! Weimar W. Cytokine Kinetics (TNF-a, IL-16, IL-6) during continuous hemofiltration: Alaboratory and clinical study. Confrib Nephroll995 ; 113 : 62-75 31 Bellomo R, Tipping P, Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 1993 ; 21 : 522-6 32 Schetz M. Removal of cytokines in septic patients using continuous veno-venous hemodiafiltration. Crit Care Med 1994; 22 :715-6
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Urg 1998 ; 7 : 215-9