Non-renal indications for continuous renal replacement therapy
1999; Elsevier BV; Volume: 56; Issue: S72 Linguagem: Inglês
10.1046/j.1523-1755.1999.07217.x
ISSN1523-1755
Autores Tópico(s)Dialysis and Renal Disease Management
ResumoNon-renal indications for continuous renal replacement therapy. While there is clear support for the use of continuous renal replacement therapy (CRRT) in critically ill acute renal failure patients, there are other illnesses without renal involvement where CRRT might be of value. These include sepsis and other inflammatory syndromes such as acute respiratory distress syndrome (ARDS) and cardiopulmonary bypass where removal of inflammatory mediators by hemofiltration is hypothesized to improve outcome. Adsorption appears to be the predominant mechanism of mediator elimination. However, the observed hemodynamic improvement can, at least partially, be attributed to a reduction of body temperature or to fluid removal, and the evidence for a clinically important removal of proinflammatory cytokines remains limited. Continuous and therefore smooth fluid removal may improve organ function in ARDS, after surgery with cardiopulmonary bypass, and in patients with refractory congestive heart failure. Continuous removal of endogenous toxins, eventually combined with intermittent hemodialysis, is probably beneficial in inborn errors of metabolism, severe lactic acidosis, or tumor lysis syndrome. Non-renal indications for continuous renal replacement therapy. While there is clear support for the use of continuous renal replacement therapy (CRRT) in critically ill acute renal failure patients, there are other illnesses without renal involvement where CRRT might be of value. These include sepsis and other inflammatory syndromes such as acute respiratory distress syndrome (ARDS) and cardiopulmonary bypass where removal of inflammatory mediators by hemofiltration is hypothesized to improve outcome. Adsorption appears to be the predominant mechanism of mediator elimination. However, the observed hemodynamic improvement can, at least partially, be attributed to a reduction of body temperature or to fluid removal, and the evidence for a clinically important removal of proinflammatory cytokines remains limited. Continuous and therefore smooth fluid removal may improve organ function in ARDS, after surgery with cardiopulmonary bypass, and in patients with refractory congestive heart failure. Continuous removal of endogenous toxins, eventually combined with intermittent hemodialysis, is probably beneficial in inborn errors of metabolism, severe lactic acidosis, or tumor lysis syndrome. Continuous renal replacement therapy (CRRT) is often regarded as one of the more important advances in intensive care medicine in recent years. The use of CRRT in critically ill patients with acute renal failure, combined with cardiovascular instability, severe fluid overload, cerebral edema or hypercatabolism and high fluid requirements, is widely accepted1Schetz M.R.C. Classical and alternative indications for continuous renal replacement therapy.Kidney Int. 1998; 53: S129-S132Google Scholar. CRRT is also used in some non-renal indications, and these are less well established. These non-renal indications are based on the (presumed) elimination of inflammatory mediators [such as systemic inflammatory response syndrome (SIRS) and sepsis, acute respiratory distress syndrome (ARDS), and cardiopulmonary bypass (CPB)], on the removal of fluid (ARDS, CPB, chronic heart failure), or on the elimination of other endogenous toxic solutes (inborn errors of metabolism, lactic acidosis, crush injury, tumor lysis syndrome). Sepsis and other inflammatory syndromes represent the most popular non-renal indications for CRRT. The underlying hypothesis is that hemofiltration removes inflammatory mediators (cytokines, complement activation products, contact activation products, arachidonic acid metabolites, and so forth) from the circulation and thereby dampens the systemic inflammatory response while preserving the local effects that are thought to be beneficial. This is indeed an attractive hypothesis. However, at this moment, the evidence for a clinically important elimination of inflammatory mediators, as well as the evidence for a beneficial effect of hemofiltration on the outcome of septic patients, remains limited2Schetz M. Ferdinande P. Van den Berghe G. Verwaest C. Lauwers P. Removal of pro-inflammatory cytokines with renal replacement therapy: Sense or nonsense?.Intensive Care Med. 1995; 21: 169-176Crossref PubMed Scopus (110) Google Scholar, 3Schetz M. Evidence-based analysis of the use of hemofiltration in sepsis and MODS.Curr Opin Intensive Care. 1997; 3: 434-441Crossref Scopus (15) Google Scholar, 4Van Bommel E.F.H. Should continuous renal replacement therapy be used for “non-renal” indications in critically ill patients with shock?.Resuscitation. 1997; 33: 257-270Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 5Gotloib L. Barzilay E. Shustak A. Wais Z. Jaichenko J. Mev A. Hemofiltration in septic ARDS: The artificial kidney as an artificial endocrine lung.Resuscitation. 1986; 13: 123-132Abstract Full Text PDF PubMed Scopus (75) Google Scholar. With the exception of endotoxin and the biologically active form of tumor necrosis factor (TNF), which is a trimer with molecular weight of 54,000 Da, the molecular weight of most inflammatory mediators is compatible with convective removal through high-flux membranes (cut-off ±30,000 Da). However, the reported sieving coefficients are frequently far beneath 1 Table 15Gotloib L. Barzilay E. Shustak A. Wais Z. Jaichenko J. Mev A. Hemofiltration in septic ARDS: The artificial kidney as an artificial endocrine lung.Resuscitation. 1986; 13: 123-132Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 6Nagaki M. Hughes R.D. Lau J.Y.N. Williams R. Removal of endotoxin and cytokines by adsorbents and the effect of plasma protein binding.Int J Artif Organs. 1991; 14: 43-50PubMed Google Scholar, 7Bellomo R. Tipping P. Boyce N. Tumor necrosis factor clearances during veno-venous hemodiafiltration in the critically ill.Trans Am Soc Artif Intern Organs. 1991; 37: M322-M323Google Scholar, 8Barrera P. Janssen E.M. Demacker P.N.M. Wetzels J.F.M. Van der Meer J.W.M. Removal of interleukin-1beta and tumor necrosis factor from human plasma by in vitro dialysis with polyacrylonitrile membranes.Lymphokine Cytokine Res. 1992; 11: 99-104PubMed Google Scholar, 9Lonnemann G. Schindler R. Dinarello C.A. Koch K.M. Removal of circulating cytokines by hemodialysis membranes in vitro.in: Faist E. Meakins J. Schildberg F.W. Host Defense Dysfunction in Shock and Sepsis. Springer Verlag, Berlin-Heidelberg1992: 613-623Google Scholar, 10Bellomo R. Tipping P. Boyce N. Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.Crit Care Med. 1993; 21: 522-526Crossref PubMed Scopus (327) Google Scholar, 11Tonnesen E. Hansen M.B. Hohndorf K. Diamants M. Bendtzen K. Wanscher M. Toft P. Cytokines in plasma and ultrafiltrate during continuous arteriovenous hemofiltration.Anaesth Intensive Care. 1993; 21: 752-758PubMed Google Scholar, 12Goldfarb S. Golper T.A. Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228-232PubMed Google Scholar, 13Bellomo R. Tipping P. Boyce N. Interleukin-6 and interleukin-8 extraction during hemodiafiltration in septic acute renal failure.Ren Fail. 1995; 17: 457-466Crossref PubMed Scopus (63) Google Scholar, 14Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar, 15Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 16Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Effect of hemofiltration on hemodynamics and systemic concentrations of anaphylatoxins and cytokines in human sepsis.Intensive Care Med. 1996; 22: 1360-1367Crossref PubMed Scopus (98) Google Scholar, 17Heering P. Morgera S. Schmitz F.J. Schmitz G. Willers R. Schultheis H.P. Strauer B.E. Grabensee B. Cytokine removal and cardiovascular hemodynamics in septic patients with continuous hemofiltration.Intensive Care Med. 1997; 23: 288-296Crossref PubMed Scopus (232) Google Scholar, 18Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (48) Google Scholar. One possible explanation is that the membrane cut-off, which has mostly been determined in in vitro conditions, is reduced in clinical conditions because of the presence of a protein layer. Another explanation is binding of the circulating mediators either to each other, as in the TNF trimer, or to other substances such as aspecific binding proteins (α2-macroglobulin) or specific binding substances such as the soluble TNF receptor or the interleukin-1 (IL-1) receptor. Cell-bound mediators and adhesion molecules are also not accessible for removal through the membrane.Table 1Convective removal of mediatorsMediatorMolecular weight daltonsSieving coefficientAA metabolites±6000.5–0.91Bradykinin±1,100Endothelin±2,5000.19C3a/C5a±11,0000.11–0.77Factor D±24,000MDS600–30,000LPS±67,000LPS fragments<1000–20,000TNF-α±17,000 (54,000)0–0.2sTNFr±30,000–50,000<0.1IL-1±17,5000.07–0.42IL-1ra±24,0000.28–0.45IL-6±22,000IL-8±8,0000–0.48IL-10±18,0000INF-γ±20,000Abbreviations are: AA, amino acid; MDS, myocardial depressant substance; LPS, lipopolysaccharide; TNF, tumor necrosis factor; sTNFr, soluble tumor necrosis factor receptor; IL, interleukin; INF-γ, interferon gamma. Open table in a new tab Abbreviations are: AA, amino acid; MDS, myocardial depressant substance; LPS, lipopolysaccharide; TNF, tumor necrosis factor; sTNFr, soluble tumor necrosis factor receptor; IL, interleukin; INF-γ, interferon gamma. Another pathway of mediator elimination is adsorption to the membrane. This adsorption is at least semiselective and depends on both mediator and membrane characteristics (abstract; Silvester et al, Blood Purif 15:127, 1997)8Barrera P. Janssen E.M. Demacker P.N.M. Wetzels J.F.M. Van der Meer J.W.M. Removal of interleukin-1beta and tumor necrosis factor from human plasma by in vitro dialysis with polyacrylonitrile membranes.Lymphokine Cytokine Res. 1992; 11: 99-104PubMed Google Scholar, 9Lonnemann G. Schindler R. Dinarello C.A. Koch K.M. Removal of circulating cytokines by hemodialysis membranes in vitro.in: Faist E. Meakins J. Schildberg F.W. Host Defense Dysfunction in Shock and Sepsis. Springer Verlag, Berlin-Heidelberg1992: 613-623Google Scholar, 12Goldfarb S. Golper T.A. Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228-232PubMed Google Scholar, 14Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar, 18Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (48) Google Scholar, 19Lonneman G. Linnenweber S. Burg M. Koch K. Transfer of endogenous pyrogens across artificial membranes?.Kidney Int. 1998; 53: S43-S46Google Scholar, 20Ronco C. Tetta C. Lupi A. Galloni E. Bettini M.C. Sereni L. Mariano F. De Martino A. 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Generation and removal of anaphylatoxins during hemofiltration with five different membranes.Blood Purif. 1988; 6: 325-335Crossref PubMed Scopus (26) Google Scholar, 25Kandus A. Ponikvar R. Drinovec J. Kladnik S. Ivanovich P. Anaphylatoxins C3a and C5a adsorption on acrylonitrile membrane of hollow-fiber and plate dialyzer: An in vivo study.Int J Artif Organs. 1990; 13: 176-180Google Scholar, 26Cheung A.F. Chenoweth D.E. Otsuka D. Henderson L.W. Compartmental distribution of complement activation products in artificial kidneys.Kidney Int. 1986; 30: 74-80Abstract Full Text PDF PubMed Scopus (61) Google Scholar. In general, the polyacrylonitrile membrane seems to have the highest adsorptive capacity. This adsorption, however, reaches saturation within a few hours. A quantitative important elimination therefore not only requires filters with a large surface area but also frequent changing of the membrane. Kellum et al recently compared hemodialysis and hemofiltration in a cross-over design in septic patients and observed that only hemofiltration is associated with a decrease of the TNF plasma level. There were, however, no important amounts of TNF in the filtrate, suggesting adsorptive elimination and leading to the hypothesis that convective transport increases adsorption caused by exposure of the filtrate to the whole inner structure of the membrane (AN69) representing a tremendous increase of the available surface27Kellum J.A. Johnson J.P. Kramer D. Palevsky P. Brady J.J. Pinsky M.R. Diffusive versus convective therapy: Effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome.Crit Care Med. 1998; 26: 1995-2000Crossref PubMed Scopus (199) Google Scholar. De Vriese et al calculated cytokine mass balances during hemofiltration in septic patients with acute renal failure and demonstrated that adsorption is the predominant clearance mechanism (AN69 membrane), is the most pronounced during the first hour and decreases steadily thereafter. At a higher blood flow rate and filtration rate, the adsorptive as well as the convective elimination was increased, either because the amount delivered per unit of time increases or because the higher transmembrane pressure pushes the molecules deeper into the membrane and thus increases the adsorptive surface area28De Vriese A.S. Colardyn F. Philippé R. Van Holder R. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar. However, despite their filtration and/or adsorption, most controlled clinical trials do not show an effect of hemofiltration on cytokine plasma levels29Sander A. Armbruster W. Sander B. Philipp T. Schafer C. Thurauf N. Lange R. The influence of continuous hemofiltration on cytokine elimination and the cardiovascular stability in early sepsis.Contrib Nephrol. 1995; 116: 99-103Crossref PubMed Google Scholar, 30Braun N. Rosenfeld S. Giolai M. Banzhaf W. Fretscher R. Warth H. Weinstock C. Deppisch R. Erley C.M. Muller G.A. Risler T. Effect of continuous hemodiafiltration on IL-6, TNF-α, C3a, and TCC in patients with SIRS/septic shock using two different membranes.Contrib Nephrol. 1995; 116: 89-98Crossref PubMed Google Scholar, 31Riegel W. Ziegenfuss T. Rose S. Bauer M. Marzi I. Influence of venovenous hemofiltration on posttraumatic inflammation and hemodynamics.Contrib Nephrol. 1995; 116: 56-61Crossref PubMed Google Scholar, 32Sander A. Armbruster W. Sander B. Daul A.E. Lange R. Peters J. Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNFα plasma concentrations.Intensive Care Med. 1997; 23: 878-884Crossref PubMed Scopus (126) Google Scholar, 33Sanchez-Izquierdo J.A. Perez-Vela J.L. Lozano-Quintana M.J. Alted-Lopez E. Ortuno D. E-Solo B. Ambros-Checa A. Cytokines clearance during venovenous hemofiltration in the trauma patient.Am J Kidney Dis. 1997; 30: 483-488Abstract Full Text PDF PubMed Scopus (72) Google Scholar. This is not unexpected in view of their high endogenous clearance compared to which the extracorporeal clearance is probably irrelevant2Schetz M. Ferdinande P. Van den Berghe G. Verwaest C. Lauwers P. Removal of pro-inflammatory cytokines with renal replacement therapy: Sense or nonsense?.Intensive Care Med. 1995; 21: 169-176Crossref PubMed Scopus (110) Google Scholar. Braun et al, on the other hand, found a somewhat more pronounced decrease of TNF in the hemofiltered group30Braun N. Rosenfeld S. Giolai M. Banzhaf W. Fretscher R. Warth H. Weinstock C. Deppisch R. Erley C.M. Muller G.A. Risler T. Effect of continuous hemodiafiltration on IL-6, TNF-α, C3a, and TCC in patients with SIRS/septic shock using two different membranes.Contrib Nephrol. 1995; 116: 89-98Crossref PubMed Google Scholar. Wakabayashi et al showed lower interleukin (IL)-6 and IL-8 levels during hemofiltration compared with a control period in the same patients34Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome or multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (31) Google Scholar, and Kellum et al showed lower TNF levels during hemofiltration compared with hemodialysis27Kellum J.A. Johnson J.P. Kramer D. Palevsky P. Brady J.J. Pinsky M.R. Diffusive versus convective therapy: Effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome.Crit Care Med. 1998; 26: 1995-2000Crossref PubMed Scopus (199) Google Scholar. De Vriese et al found a short-term decrease in the plasma level of proinflammatory cytokines during the first hour of hemofiltration and again after changing the filter. This decrease, however, is followed by an increase that exceeds the baseline level (uncontrolled observation)28De Vriese A.S. Colardyn F. Philippé R. Van Holder R. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar. Most trials on hemofiltration in sepsis have looked at the removal of proinflammatory mediators. The host response not only consists of an inflammatory response, but also of a so-called CARS (compensatory anti-inflammatory response) with release of anti-inflammatory mediators such as IL-4, IL-10, IL-11, IL-13, soluble TNF receptor, IL-1 receptor antagonist, and growth factors35Bone R.C. Sir Isaac Newton, sepsis, SIRS and CARS.Crit Care Med. 1996; 24: 1125-1128Crossref PubMed Scopus (895) Google Scholar. The preponderance of proinflammatory or anti-inflammatory mediators determines whether the result is hyperinflammation or immunosuppression. High levels of both proinflammatory and anti-inflammatory mediators have been associated with mortality, and we still do not know which patient at which time point needs more proinflammatory or more anti-inflammatory substances, nor are there routine parameters that allow us to determine whether the patient is on one or the other side of the balance. If hemofiltration removes both proinflammatory and anti-inflammatory mediators to the same extent, the net result may be zero. If, on the other hand, hemofiltration selectively removes proinflammatory or anti-inflammatory mediators, the resulting imbalance may as well be harmful as beneficial. Lonnemann et al demonstrated an increase of the ratio of the anti-inflammatory soluble TNF receptor to the proinflammatory TNF-α during hemofiltration with a polyamide membrane19Lonneman G. Linnenweber S. Burg M. Koch K. Transfer of endogenous pyrogens across artificial membranes?.Kidney Int. 1998; 53: S43-S46Google Scholar. De Vriese et al, on the other hand, found a stable balance between TNF and its soluble receptors and between IL-1 and its receptor antagonist during hemofiltration with an AN69 membrane28De Vriese A.S. Colardyn F. Philippé R. Van Holder R. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar. A statistically significant effect of zero-balanced hemofiltration on the short-term survival or the survival time of septic animals is found in three of six studies36Staubach K.H. Rau H.G. Kooistra A. Shardey H.M. Hohlbach G. Schildberg F.W. Can hemofiltration increase survival in acute endotoxemia: A porcine shock model.Prog Clin Biol Res. 1989; 308: 821-826PubMed Google Scholar, 37Stein B. Pfenninger E. Grunert A. Schmitz J.E. Hudde M. Influence of continuous haemofiltration on haemodynamics and central blood, in experimental endotoxic shock.Intensive Care Med. 1990; 16: 494-499Crossref PubMed Scopus (111) Google Scholar, 38Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. 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Grootendorst et al and Lee et al, both demonstrating a beneficial effect, used very high filtration rates of more than 100 ml/kg/hr38Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine?.Crit Care Med. 1993; 21: 914-924Crossref PubMed Scopus (97) Google Scholar,40Grootendorst A.F. van Bommel E.F.H. van Leengoed L.A.M.G. Nabuurs M. Bouman C.S.C. Groeneveld A.B.J. High volume hemofiltration improves hemodynamics and survival of pigs exposed to gut ischemia and reperfusion.Shock. 1994; 2: 72-78Crossref PubMed Scopus (79) Google Scholar. In these animal studies, the hemofiltration procedure was started before or shortly after the septic insult, which is mostly not achievable in clinical practice. Moreover, experimental sepsis was induced by infusion of endotoxins or bacteria, resulting in a hypodynamic shock that did not correspond with the hyperdynamic picture seen in clinical sepsis. In this regard, it is interesting to note that Freeman, using a true infection model of chronic intraperitoneal sepsis, did not establish an effect on survival and even a trend toward improved survival in the control group41Freeman B.D. Yatsiv I. Natanson C. Solomon M.A. Quezado Z.M.N. Danner R.L. Banks S.M. Hoffman W. Continuous arteriovenous hemofiltration does not improve survival in a canine model of septic shock.J Am Coll Surg. 1995; 180: 286-292PubMed Google Scholar. In a subsequent study, Lee et al showed that the use of membranes with a very large pores, resulting in a cut-off of approximately 100,000 Da, leads to a further increase in survival42Lee P.A. Weger G.W. Pryor R.W. Matson J.R. Effects of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine.Crit Care Med. 1998; 26: 730-737Crossref PubMed Scopus (73) Google Scholar. 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High volume hemofiltration improves hemodynamics and survival of pigs exposed to gut ischemia and reperfusion.Shock. 1994; 2: 72-78Crossref PubMed Scopus (79) Google Scholar, 45Grootendorst A.F. van Bommel E.F.H. van der Hoven B. van Leengoed L.A.M.G. van Osta A.L.M. High-volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig.Intensive Care Med. 1992; 18: 235-240Crossref PubMed Scopus (224) Google Scholar, 46Gomez A. Wang R. Unruh H. Light R.B. Bose D. Chau T. Correa E. Mink S. Hemofiltration reverses left ventricular dysfunction during sepsis in dogs.Anesthesiology. 1990; 73: 671-685Crossref PubMed Scopus (153) Google Scholar. However, other investigators, including those who use true infection models, did not find an effect of hemofiltration on the hemodynamic parameters of septic animals38Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. 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Continuous arteriovenous hemofiltration attenuates polymorphonuclear leukocyte phagocytosis in porcine intra-abdominal sepsis.Am J Surg. 1997; 173: 174-180Abstract Full Text PDF PubMed Scopus (15) Google Scholar. A few controlled clinical trials compared zero-balanced hemofiltration with no extracorporeal treatment in patients with SIRS or sepsis. Cosentino et al did not find a statistically significant difference in the hemodynamic parameters of ARDS patients43Cosentino F. Paganini E. Lockrem J. Stoler J. Wiedemann H. Continuous arteriovenous hemofiltration in the adult respiratory distress syndrome.Contrib Nephrol. 1991; 93: 94-97Crossref PubMed Google Scholar. Five randomized controlled studies in patients with sepsis or severe polytrauma found an attenuation of the hyperdynamic response [abstract; Armbruster et al, Intensive Care Med 20(Suppl 2):S2, 1994]29Sander A. Armbruster W. Sander B. Philipp T. Schafer C. Thurauf N. Lange R. The influence of continuous hemofiltration on cytokine elimination and the cardiovascular stability in early sepsis.Contrib Nephrol. 1995; 116: 99-103Crossref PubMed Google Scholar, 31Riegel W. Ziegenfuss T. Rose S. Bauer M. Marzi I. Influence of venovenous hemofiltration on posttraumatic inflammation and hemodynamics.Contrib Nephrol. 1995; 116: 56-61Crossref PubMed Google Scholar, 32Sander A. Armbruster W. Sander B. Daul A.E. Lange R. Peters J. Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNFα plasma concentrations.Intensive Care Med. 1997; 23: 878-884Crossref PubMed Scopus (126) Google Scholar, 44Riera J.A.S.I. Alted E. Lozano M.J. Perez J.L. Ambros A. Caballero R. Influence of continuous hemofiltration on the hemodynamics of trauma patients.Surgery. 1997; 122: 902-908Abstract Full Text PDF PubMed Scopus (18) Google Scholar. These studies therefore do not confirm the elimination of a myocardial depressant factor suggested by the animal studies. Wakabayashi et al observed a higher mean arterial pressure during hemofiltration than during the control period between two treatments34Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome or multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (31) Google Scholar. Using a cross-over design in septic patients, Bellomo et al compared high-volume hemofiltration (filtration rate 6 liters/hr) with low-volume hemofiltration (filtration rate 1 liters/hr). Preliminary results on six patients showed a decrease in vasopressor requirement during high-volume treatment49Bellomo R. Baldwin I. Cole L. Ronco C. Preliminary experience with high-volume hemofiltration in human septic shock.Kidney Int. 1998; 53: S182-S185Google Scholar. Whether the observed hemodynamic effects can be attributed to the removal of mediators remains to be proven. A recent study by Van Kuijk showed that the extracorporeal blood temperature plays a critical role in the improved hemodynamic tolerance of hemofiltration versus dialysis50Van Kuijk W.H. Hillion D. Savoiu C. Leunissen K.M. Critical role of the extracorporeal blood temperature in the hemodynamic response during hemofiltration.J Am Soc Nephrol. 1997; 8: 949-955PubMed Google Scholar. Matamis et al showed that mean arterial pressure is higher in patients developing hypothermia during hemofiltration51Matamis D. Tsagourias M. Koletsos K. Riggos D. Mavromatidis K. Sombolos K. Bursztein S. Influence of continuous haemofiltration-related hypothermia on haemodynamic variables and gas exchange in septic patients.Intensive Care Med. 1994; 20: 431-436Crossref PubMed Scopus (69) Google Scholar. He also found an inverse relationship between the decrease of body temperature and the filtration rate, which could explain the hemodynamic effect of high-volume hemofiltration. The effect of zero-balanced hemofiltration on oxygenation in experimental sepsis38Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine?.Crit Care Med. 1993; 21: 914-924Crossref PubMed Scopus (97) Google Scholar, 39Heidemann S.M. Ofenstein J.P. Sarnaik A.P. Efficacy of continuous arteriovenous hemofiltration in endotoxic shock.Circ Shock. 1994; 44: 183-187PubMed Google Scholar, 45Grootendorst A.F. van Bommel E.F.H. van der Hoven B. van Leengoed L.A.M.G. van Osta A.L.M. High-volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig.Intensive Care Med. 1992; 18: 235-240Crossref PubMed Scopus (224) Google Scholar, 46Gomez A. Wang R. Unruh H. Light R.B. Bose D. Chau T. Correa E. Mink S. Hemofiltration reverses left ventricular dysfunction during sepsis in dogs.Anesthesiology. 1990; 73: 671-685Crossref PubMed Scopus (153) Google Scholar, 52Stein B. Pfenninger E. Grunert A. Schmitz J.E. Deller A. Kocher F. The consequences of continuous haemofiltration on lung mechanics and extravascular lung water in a porcine endotoxic shock model.Intensive Care Med. 1991; 17: 293-298Crossref PubMed Scopus (62) Google Scholar, 53Mink S.N. Jha P. Wang R. Yang J. Bose D. Jacobs H. Light R.B. Effect of continuous arteriovenous hemofiltration combined with systemic vasopressor therapy on depressed left ventricular contractility and tissue oxygen delivery in canine Escherichia Coli sepsis.Anesthesiology. 1995; 83: 178-190Crossref PubMed Scopus (27) Google Scholar was evaluated in six studies of which only one, using high volume hemofiltration, established a positive effect45Grootendorst A.F. van Bommel E.F.H. van der Hoven B. van Leengoed L.A.M.G. van Osta A.L.M. High-volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig.Intensive Care Med. 1992; 18: 235-240Crossref PubMed Scopus (224) Google Scholar. Cosentino et al found a better oxygenation in a control group of ARDS patients compared with a group treated with zero-balanced hemofiltration43Cosentino F. Paganini E. Lockrem J. Stoler J. Wiedemann H. Continuous arteriovenous hemofiltration in the adult respiratory distress syndrome.Contrib Nephrol. 1991; 93: 94-97Crossref PubMed Google Scholar. Manasia et al (abstract; Manasia et al, Blood Purif 13:393, 1995), Wakabayashi et al34Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome or multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (31) Google Scholar, and Riera et al44Riera J.A.S.I. Alted E. Lozano M.J. Perez J.L. Ambros A. Caballero R. Influence of continuous hemofiltration on the hemodynamics of trauma patients.Surgery. 1997; 122: 902-908Abstract Full Text PDF PubMed Scopus (18) Google Scholar, on the other hand, found an improved oxygenation in the filtered group, but none of these studies gave information on the fluid balance in the control group. Some authors looked beyond the cardiopulmonary effect and evaluated the influence of hemofiltration on the immune system. Lonnemann showed that endotoxin-induced TNF production by monocytes is decreased in septic patients and increases during hemofiltration, suggesting the elimination of an anti-inflammatory substance (abstract; Lonnemann, Blood Purif 15:6, 1997). Hoffmann et al, on the other hand, reported that in vitro exposure to the ultrafiltrate of septic patients stimulates LPS-induced TNF production by monocytes, suppresses lipopolysaccharide-induced IL-6 production by monocytes, and suppresses IL-2 and IL-6 release from lymphocytes15Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (124) Google Scholar. DiScipio and Burchard demonstrated that CAVH attenuates the up-regulation of phagocytosis in septic animals48Discipio A.W. Burchard K.W. Continuous arteriovenous hemofiltration attenuates polymorphonuclear leukocyte phagocytosis in porcine intra-abdominal sepsis.Am J Surg. 1997; 173: 174-180Abstract Full Text PDF PubMed Scopus (15) Google Scholar. The significance of these findings remains to be proven. Although the evidence for a clinically important elimination of proinflammatory mediators is not very strong, hemofiltration appears to have some effect in patients with sepsis and other inflammatory syndromes. The mechanisms of this effect, however, remain unclear. Studies looking at mediator elimination suggest that adsorption is the most important clearance mechanism. Studies looking at the hemodynamic effect suggest that high filtration rates are important. These findings are now reconciled by two recent studies suggesting that high filtration rates increase adsorption. As long as we do not know the exact mechanism underlying the beneficial effect of hemofiltration, we are not able to define the optimal operational characteristics of the hemofiltration procedure. Should we use membranes with a high adsorptive capacity? Probably yes, but how frequently should they be changed? Should we use large-pore membranes, as suggested by the latest animal studies, or should we use very high filtration rates, and how high should these be? These are all questions that need to be answered before large randomized trials can be designed. The results of these trials should be awaited before the widespread use of hemofiltration in septic patients without renal failure can be recommended.
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