Überwachung der Heparintherapie bei Akutdialysen

Zusammenfassung

Die Antikoagulation im Rahmen einer Nierenersatztherapie ist notwendig, um die Thrombosierung der Filter zu verhindern und den Blutfluss zu erhalten. Ausnahmen bilden Patienten mit akutem Nierenversagen und Begleiterkrankungen (z. B. Sepsis, Multiorganversagen), bei denen eine drohende Blutung das extrakorporale Verfahren auch ohne Antikoagulation erfordern kann.

Am häufigsten wird unfraktioniertes Heparin als Antikoagulanz eingesetzt. Mit niedermolekularen Heparinen liegen ebenfalls positive Erfahrungen vor. Zur sicheren Therapieführung ist ein Monitoring der Antikoagulation notwendig. Die aktivierte Vollblut-Gerinnungszeit (ACT), die aktivierte partielle Thromboplastinzeit (aPTT) und die Anti-Faktor-Xa-Bestimmung mit chromogenen Substraten stehen als Routine- und Point-of-Care-Tests zur Verfügung. Zum Monitoring der niedermolekularen Heparine (NMH) kann nur die Anti-Faktor-Xa-Messung eingesetzt werden. Die spezifischste und valideste Methode für das Therapiemonitoring der Heparine ist der Anti-Faktor-Xa-Test mit Hilfe chromogener Substrate. Da wenig kontrollierte Studien zur Antikoagulanzientherapie und Monitoring mit dem Anti-Faktor-Xa-Test in der akuten Nierenersatztherapie vorliegen, beruhen die Empfehlungen auf den Erfahrungen mit der chronischen Nierenersatztherapie.

Summary

Anticoagulation during renal replacement therapy is recommended to avoid thrombosis of the filter devices and to maintain the blood flow. However, in the case of multiorgan failure and sepsis, an imminent bleeding complication in patients with acute renal failure may cause the need for an extracorporeal circulation without anticoagulation.

The most common drug used in renal replacement therapy is the unfractionated heparin (UFH). With low molecular weight heparin (LMWH) good experiences are reported, too. Based on the level of evidence from clinical studies plasma measurement of heparin is indispensable for patients with renal insufficiency. The activated whole blood clotting time (ACT), the activated partial thromboplastin time (aPTT), and the determination of the anti-factor Xa activity (anti Xa) with chromogenic substrates are available as routine as well as as point-of-care tests. To monitor plasma levels of LMWH the anti Xa assay serves exclusively as a suitable monitoring. The anti Xa assay using chromogenic substrates is the most specific and valid one for monitoring heparin therapy. In lack of large controlled studies for the anticoagulation therapy and its monitoring with the anti Xa test in acute renal failure, the current experiences are based on the results of chronic renal replacement therapy.

Schlüsselwörter

Akute Niereninsuffizienz - extrakorporales Verfahren - Antikoagulation - Heparin - Monitoring

Keywords

Acute renal failure - extracorporeal circulation - anticoagulation - heparin - monitoring

• Literatur

• 1 Abramson S, Niles JL. Anticoagulation in continous renal replacement therapy. Curr Curr Opin Nephrol Hypertens 1999; 8: 701-7.
• 2 Bara L, Mardiguian J, Samama M. In vitro effect on heptest of low molecular weight heparin fractions and preparations with various anti-IIa and anti-Xa activities. Thromb Res 1990; 5: 585-92.
• 3 Bates SM, Weitz JI, Johnston M. et al. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001; 161: 385-91.
• 4 Beijering RJR, ten Cate H, Nurmohamed MT. et al. Anticoagulants and extracorporeal circuits. Sem Thromb Hemost 1997; 23: 225-33.
• 5 Bounameaux H, De Moerloose O. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost 2004; 2: 551-4.
• 6 Brady HR, Singer GG. Acute renal failure. Lancet 1995; 346: 1533-40.
• 7 Briel RC, Zielke E, Zwirner M. Untersuchungen zur Korrelation der anti-Faktor Xa Aktivität von niedermolekularem Heparin und der aktivierten Vollblutgerinnungszeit im AC-Tester. Ärztl Lab 1987; 33: 237-40.
• 8 Brill-Edwards P, Ginsberg JS, Johnston M. et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993; 119: 104-9.
• 9 Cantini F, Niccoli L, Bellandi F. et al. Effects of short-term, high dose heparin therapy on biochemical markers of bone metabolism. Clin Rheumatol 1995; 14: 663-6.
• 10 Collignon F, Frydman A, Caplain H. et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins – dalteparin, enoxaparin and nadroparin – administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 4: 630-40.
• 11 Davenport A, Mehta S. The acute dialysis quality initiative. Part VI: Access and anticoagulation in CRRT. Adv Ren Repl Therapy 2002; 9: 273-81.
• 12 De Pont AC, Oudemans-van Straaten HM, Roozendaal KJ. et al. Nadroparin versus dalteparin anticoagulation in high-volume, continuous venovenous hemofiltration: a double-blind, randomized, crossover study. Crit Care Med 2000; 28: 421-5.
• 13 De Vriese AS. Prevention and treatment of acute renal failure in sepsis. J Am Soc Nephrol 2003; 14: 792-805.
• 14 Dietrich CP, Shinjo SK, Moraes FA. et al. Structural features and bleeding activity of commercial low molecular weight heparins: neutralization by ATP and protamine. Sem Thromb Hemost 1999; 25 (Suppl. 03) 43-50.
• 15 D’Intini VD, Ronco C, Bonello M. et al. Renal replacement therapie in acute renal failure. Best Pract Res Clin Anesth 2004; 18: 145-57.
• 16 Eiswirth G, Walch S, Bommer J. New bedside test for monitoring anticoagulation during hemodialysis. Artif Organs 1998; 22: 346-52.
• 17 Forni LG, Hilton PJ. Continuous hemofiltration in the treatment of acute renal failure. N Engl J Med 1997; 336: 1303-9.
• 18 Forni LG, Wright DA, Hilton PJ. et al. Prognostic stratification in acute renal failure. Arch Intern Med 1996; 156: 1023-7.
• 19 Frank RD, Brandenburg VM, Lanzmich R. et al. Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis. Nephrol Dial Transplant 2004; 19: 1552-8.
• 20 Greiber S, Weber U, Galle J. et al. Activated clotting time is not a sensitive parameter to monitor anticoagulation with low molecular weight heparin in hemodialysis. Nephron 1997; 76: 15-9.
• 21 Guerin C, Girard R, Selli JM. et al. Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units: results from a multicenter prospective epidemiological survey. Intensive Care Med 2002; 28: 1411-8.
• 22 Hafner G, Klingel R, Wandel E. et al. Laboratory control of minimal heparinization during haemodialysis in patients with a risk of haemorrhage. Blood Coagul Fibrinol 1994; 5: 221-6.
• 23 Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes. J Thromb Haemost 2004; 2: 547-50.
• 24 Hirsh J, Raschke R. Heparin and low-molecularweight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 2004; (Suppl) 126: 188S-203S.
• 25 Hirsh J, Warkentin TE, Raschke R. et al. Heparin and low-molecualr-weight heparin. Mechanisms of Action, pharmacokinetics, dosing considerations, monitoring, efficacay and safety. Chest 1998; 114: 489S-510S.
• 26 Hottelart C, Achard JM, Moriniere P. et al. Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of low molecular weight and unfractionated heparin. Artif Organs 1998; 22: 614-7.
• 27 James LT, Congdon E, Kardinal CG. et al. Monitoring heparin therapy in hemodialysis. JAMA 1973; 226: 1529-33.
• 28 Jeffrey RF, Khan AA, Douglas JT. et al. Anticoagulation with low molecular weight heparin (Fragmin) during continuous hemodialysis in the intensive care unit. Artif Organs 1993; 17: 717-20.
• 29 Jeske WW, Fareed J. In vitro studies on the biochemistry and pharmacology of low molecular weight heparins. Sem Thromb Hemost 1999; 25 (Suppl. 03) 27-33.
• 30 Kaplan AA, Longnecker RE, Folkert VW. Continuous arteriovenous hemofiltration. A report of six months experience. Ann Intern Med. 1984; 100: 358-67.
• 31 Kellum JA, Angus DC, Johnson JP. et al. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med 2002; 28: 29-37.
• 32 Kitchen S, Iampietro R, Woolley AM. et al. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: Inter-assay variability. Thromb Haemost 1999; 82: 1289-93.
• 33 Klingel R, Schaefer M, Schwarting A. et al. Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodiafiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation. Nephrol Dial Transplant 2004; 19: 164-70.
• 34 Klingel R, Altes U, Remke S. et al. Activation of coagulation using single bolus anticoagulation or a combined bolus-continuous mode with low-molecular weight heparin. Kidney Blood Press Res 1999; 22: 234.
• 35 Klingel R, Wandel E, Hafner G. et al. Minimal heparinization in dialysis patients with increased risk of bleeding. Dtsch Med Wochenschr 1993; 118: 1878-83.
• 36 Koerber JM, Smythe MA, Begle RL. et al. Correlation of activated clotting time and activated partial thromboplastin time to plasma heparin concentration. Pharmacotherapy 1999; 19: 922-31.
• 37 Kovacs MJ, Keeney M, Mac Kinnon K. et al. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haem 1999; 32: 55-60.
• 38 Martin PY, Chevrolet JC, Suter O. et al. Anticoagulation in patients treated by continous venovenous hemofiltration: a retrospective study. Am J Kidney Dis 1994; 24: 806-12.
• 39 Mori M, Yoshitake S, Kitano T. et al. Measurement of whole blood factor Xa-activated clotting time during hemodialysis with low-molecular-weight heparin. J Anesth 1998; 12: 130-2.
• 40 Murray DJ, Brosnahan WJ, Pennell B. et al. Heparin detection by the activated coagulation time: a comparison of the sensitivity of coagulation tests and heparin assays. J Cardiothorac Vasc Anesth 1997; 11: 24-8.
• 41 Nishiyama M, Itoh F, Ujiie A. Low-molecularweight heparin (dalteparin) demonstrated weaker effect on rat bone metabolism compared with heparin. Jpn J Pharmacol 1997; 74: 59-68.
• 42 Opatrny K, Polanska K, Krouzecky A. et al. The effect of heparin rinse on the biocompatibility of continuous veno-venous hemodiafiltration. Int J Artif Organs 2002; 25: 520-8.
• 43 Pineo GF, Hull RD. Unfractionated and low-moelcular-weigt heparin – comparisons and current recommendatons. Curr Concepts Thromb 1998; 82: 587-99.
• 44 Raschke R, Hirsh J, Guidry J. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with low molecular weight heparin. Ann Intern Med 2003; 138: 720-4.
• 45 Reeves JH, Cumming AR. Gallagher et al. A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration. Crit Care Med 1999; 27: 2224-8.
• 46 Ronco C, Kellum FJ, Mehta R. The Acute dialysis quality initiative: The new york conference. Adv Renal Repl Therapy 2002; 9: 248-51.
• 47 Ronco C, Bellomo R, Homel P. et al. Effects of different doses in continuous veno-venous haemofiltration on outcome of acute renal failure: a prospective randomised trial. Lancet 2000; 355: 26-30.
• 48 Rosen S, Casoni MC. Heparin therapy and monitoring: A role for the chromogenic antifactor Xa assay. Am Clin Lab 2001; 20: 35-8.
• 49 Sagedal S, Hartmann A. Low molecular weight heparins as thromboprophylaxis in patients undergoing hemodialysis/hemofiltration or continuous renal replacement therapies. Eur J Med Res 2004; 9: 125-30.
• 50 Sagedal S, Hartmann A, Sundstrom K. et al. A single dose of dalteparin effectively prevents clotting during haemodialysis. Nephrol Dial Transplant 1999; 14: 1943-7.
• 51 Schetz M. Anticoagulation for continuous renal replacement therapy. Curr Opin Anaesth 2001; 14: 143-9.
• 52 Schortgen F, Soubrier N, Delclaux C. et al. Hemodynamic tolerance of intermittent hemodialysis in critically ill patients: Usefullness of practice guidelines. Am J Respir Crit Care Med 2000; 162: 197-202.
• 53 Schrader J, Haas S. Unfraktioniertes Standardheparin versus niedermolekulare Heparine. Internist 1993; 34: 1053-8.
• 54 Schulz W, Deuber HJ, Günthner R. et al. Aktueller Stand des Einsatzes von niedermolekularem Heparin in der Hämodialyse-Therapie. Nieren-Hochdruckkrankheiten 1995; 24: 187-97.
• 55 Shanklin N, Ploth DW. Evaluation of an activated clotting time technique for use in hemodialysis. Dial Transplant 1980; 9 /10: 955-8.
• 56 Siguret V, Pautas E, Gouin I. Low molecular weight heparin treatment in elderly subjects with or without renal insufficiency: new insights between June 2002 and march 2004. Curr Opin Pulm Med 2004; 10: 366-70.
• 57 Singer M, McNally T, Screaton G. et al. Heparin clearance during continuous veno-venous haemofiltration. Intensive Care Med 1994; 20: 212-5.
• 58 Smythe AM, Koerber BS, Westley SJ. et al. Use of activated partial thromboplastin time for heparin monitoring. Am J Clin Pathol 2001; 115: 148-55.
• 59 Smythe AM, Koerber BS, Nowak SN. et al. Correlation between activated clotting time and activated partial thromboplastin times. Ann Pharmacol 2002; 36: 7-11.
• 60 Solomon HM, Mullins RE, Lyden P. et al. The diagnostic accuracy of bedside and laboratory coagulation: procedures used to monitor the anticoagulation status of patients treated with heparin. Am J Clin Pathol 1998; 109: 371-8.
• 61 Sperschneider H. Heparine bei extrakorporalen Behandlungsverfahren. Spektrum Nephrol 1999; 12: 3-12.
• 62 Swartz RD, Messana JM, Orzol S. et al. Comparing continuous hemofiltration with hemodialysis in patients with severe acute renal failure. Am J Kidney Dis 1999; 34: 424-32.
• 63 Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996; 334: 1448-60.
• 64 Van de Wetering J, Westendorp RG, van der Hoeven JG. et al. Heparin use in continous renal replacement procedures: the struggle between filter coagulation and patient hemorrhage. J Am Soc Nephrol 1996; 7: 145-50.
• 65 van Bommel EFH, Bouvy ND, So KL. et al. Acute dialytic support for the critically ill: intermittent hemodialysis versus continuous arteriovenous hemodiafiltration. Am J Nephrol 1995; 15: 192-200.
• 66 Vargas Hein O, Kox WJ, Spies C. Anticoagulation in continuous renal replacement therapy. Contrib Nephrol 2004; 144: 308-16.
• 67 von Bonsdorff M, Stiekema J, Harjanne A. et al. A new low molecular weight heparinoid org 10172 as anticoagulant in hemodialysis. Int J Artif Org 1993; 13: 103-8.
• 68 Waele JJ, Cauwenberghe S, Hoste E. et al. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med 2003; 29: 325-8.
• 69 Wandel E, Klingel R, Köhler H. Antikoagulation bei chronischer Hämodialyse. Arzneimitteltherapie 1992; 10: 310-3.
• 70 Ward DM. The approach to anticoagulation in patients treated with extracorporeal therapy in the intensive care unit. Adv Ren Replace Ther 1997; 4: 160-73.
• 71 Weitz JI. Low-molecular weight heparins. New Engl J Med 1997; 337: 688-98.
• 72 White II GC. The partial thromboplastin time: defining an era in coagulation. J Thromb Haemost 2003; 1: 2267-70.
• 73 Wing AJ, Broyer M, Brunner FP. et al. Combined report on regular dialysis and transplantation in Europe, XIII, 1982. Proc Eur Dial Transplant Assoc 1983; 20: 55-6.
• 74 Wynckel A, Bernieh B, Toupance O. et al. Guidelines to the use of enoxaparin in slow continuous hemodialysis. Contrib Nephrol 1991; 93: 221-4.