Bleeding complications and overdosing of anticoagulant therapy
Authors:
Gumulec Jaromír 1,2; Kessler Petr 3; Procházka Václav 1,4; Brejcha Martin 5; Grundmann Milan; Penka Miroslav; Zänger Mathias; Machytka Evžen 9; Klement Petr 1,10
Authors‘ workplace:
Hematoonkologické a transfuzní centrum FN Ostrava
1; Ústav klinické hematologie FN Ostrava
2; Oddělení hematologie a transfuziologie Nemocnice Pelhřimov
3; Ústav radiodiagnostický, Pracoviště intervenční neuroradiologie a angiologie FN Ostrava
4; Oddělení klinické hematologie Onkologického centra J. G. Mendela Nový Jičín
5; Ústav klinické farmakologie FN Ostrava
6; Oddělení klinické hematologie FN Brno
7; BW, Berlin, Spolková republika Německo
8; Interní klinika FN Ostrava
9; McMaster University and Henderson Research Centre, Hamilton, Kanada
10
Published in:
Anest. intenziv. Med., 20, 2009, č. 6, s. 324-331
Category:
The recommendations of professional societies
Overview
Anticoagulant therapy is one of the most common forms of medical intervention. It is the mainstay of prevention and treatment of thrombotic events. Omission of adequate anticoagulant prophylaxis at least for moderate-risk and high-risk patients is a widely recognized medical error.
Bleeding is one of the most feared complications of anticoagulant therapy, and is a risk of all anticoagulants. Whereas unfractionated heparin and warfarin, the oldest and most widely used anticoagulants, have specific antidotes for their anticoagulant effect, many of the newer agents (direct and indirect inhibitors of coagulation factors Xa and/or IIa) do not have specific antidotes to reverse their actions. The use of novel anticoagulants is further complicated by a lack of easily available laboratory tests to measure their levels and thereby optimize their benefit and safety in clinical practice.
In this review, we evaluate the risk of bleeding associated with current anticoagulants, review the data available on current and experimental agents used for the reversal of anticoagulation, and provide recommendations for the management of major bleeding associated with anticoagulant therapy and for the management of asymptomatic overdosing of the anticoagulants.
Keywords:
anticoagulation – bleeding – warfarin – heparin – low molecular weight heparin – fondaparinux – refludan – dabigatran – rivaroxaban
Sources
1. Geerts, W. H., Bergqvist, D., Pineo, G. F. et al. Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 381–453.
2. National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline, 2008, 46, p. 1–160. Available at: http://www.nice.org.uk/CG046.
3. Kearon, C., Kahn, S. R., Agnelli, G. et al. Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 1, p. 454–545.
4. Singer, D. E., Albers, G. W., Dalen, J. E. et al. Antithrombotic Therapy in Atrial Fibrilation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 546–592.
5. Harrington, R. A., Becker, R. C., Cannon, Ch. P. et al. Antithrombotic Therapy for Non-ST Segment Elevation Acute Coronary Syndromes. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 670–707.
6. Goodman, Sh. G., Menon, V., Cannon, Ch. P. et al. Antithrombotic Therapy for Non-ST Segment Elevation Acute Coronary Syndromes. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 708–775.
7. Salem, D. N., O`Gara, P. T., Madias, Ch., Pauker, S. G. Valvular and Structural Heart Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 593–629.
8. Shojania, K. G., Duncan, B. W., McDonald, M. M., Wachter, R. M. Making health care safer: a critical analysis of patient safety practices. Evidence Report/Technology Assessment No. 43 (Prepared by the University of California at San Francisco–Stanford Evidence-based Practice Center under Contract No. 290–97-0013), AHRQ Publication No. 01-E058, Rockville, MD: Agency for Healthcare Research and Quality. July 2001. Dostupné na www: http://www.ahrq. gov/clinic/ptsafety/. Accessed March 15, 2007.
9. Schulman, S., Beyth, R. J., Kearon, C., Levin, M. N. Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 257–298.
10. Ng, H. J., Crowther, M. A. New anti-thrombotic agents: emphasis on hemorrhagic complications and their management. Semin Hematol., 2006, 43, p. 77–83.
11. Weitz, J. I., Hirsh, J., Samama, M. M. New Antithrombotic Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 234–256.
12. Hirsh, J., Bauer, K. A., Donati, M. B. et al. Parenteral Anticoagulans: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 141–159.
13. Crowther, M. A., Warkentin, T. E. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood, 2008, 111, p. 4871–4879.
14. Schulman, S., Kearon, C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J. Thromb. Haemost., 2005, 3, p. 692–694.
15. Černý, V., Cvachovec, K., Kasal, M. et al. Zásady podpory koagulace u život ohrožujícího a neztišitelného krvácení. Dostupné na www: www.thrombosis.cz.
16. Worley, T. P., Heit, J. A., Pruthi, R. K. Bleeding disorders. In: Oliveira, G. H. M., Nesbitt, G. C., Murphy, J. G. Mayo Clinic Medical Manual. Rochester: Mayo Clinic Scientific Press, 2006, p. 41–54.
17. Laposata, M., Green, K., Elizabeth, M. et al. College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch. Pathol. Lab. Med., 1998, 122, p. 799–807.
18. Shanafelt, T. D., Fonseca, R. Thrombocytopenia. In: Oliveira, G. H. M., Nesbitt, G. C., Murphy, J. G. Mayo Clinic Medical Manual. Mayo Clinic Scientific Press. 2006, p. 259–269.
19. Fernandez, F., Nguyen, P., van Ryn, J. et al. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb. Res., 1986, 43, p. 491–495.
20. Blajchman, M. A., Young, E., Ofosu, F. A. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann. NY Acad. Sci., 1989, 556, p. 245–253.
21. Crowther, M. A., Berry, L. R., Monagle, P. T., Chan, A. K. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br. J. Haematol., 2002,116, p. 178–186.
22. American Society of Health-System Pharmacists. Protamine sulfate: antiheparin agents: Bethesda, MD: American Society of Health-System Pharmacists, 1999. Dostupné na www:
http://www.ashp.org/mngrphs/Essentials/a382278e. htm.
23. Weiler, J. M., Gellhaus, M. A., Carter, J. G. et al. A prospective study of the risk of an immediate averse reaction to protamine sulfate during cardiopulmonary bypass surgery. J. Allergy Clin. Immunol., 1990, 85, p. 713–719.
24. Hirsh, J., Levine, M. Low molecular weight heparin. Blood, 1992, 79, p. 1–17.
25. Makris, M., Hough, R.E., Kitchen, S. Poor reversal of low molecular weight heparin by protamine. British Journal of Hematology, 2000, 108, p. 884–885.
26. Kessler, C. M. Current and future challenges of antithrombotic agents and anticoagulants: strategies for reversal of hemorrhagic complications. Semin Hematol., 2004, 41, p. 44–50.
27. Warkentin, T. E., Crowther, M. A. Reversing anticoagulants both old and new. Can. J. Anaesth., 2002, 49, p. S11–S25.
28. Deloughery, T. G. Management of acute hemorrhage. In: Colman, R. W., Marder, V. J., Clowes, A. W., George, J. N., Goldhaber, S. Z. eds. Hemostasis and Thrombosis: Basic Principles and Practice (ed 5). Philadelphia, PA: Lippincott, 2006, p. 1159–1171.
29. Levi, M., Bijsterveld, N. R., Keller, T. T. Recombinant factor VIIa as an antidote for anticoagulant treatment. Semin Hematol., 2004, 41, p. 65–69.
30. Lauritzen, B., Hedner, U., Johansen, P. B. et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J. Thromb. Haemost., 2008, 6, p. 804–811.
31. Crowther, M., Lim, W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr. Opin. Pulm. Med., 2007, 13, p. 409–413.
32. Ng, H., Koh, L., Lee, L. Successful control of postsurgical bleeding by recombinant factor VIIa in a renal failure patient given low molecular weight heparin and aspirin. Ann. Hematom., 2003, 82, p. 257–258.
33. Boneu, B., Necciari, J., Cariou, R. et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thromb. Haemost., 1995, 74, p. 1468–1473.
34. Turpie, A. G., Bauer, K. A., Eriksson, B. I. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a metaanalysis of 4 randomized double-blind studies. Arch. Intern. Med., 2002, 162, p. 1833–1840.
35. Yusuf, S., Mehta, S. R., Chrolavicius, S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N. Engl. J. Med., 2006, 354, p. 1464–1476.
36. Gerotziafas, G. T., Depasse, F., Chakroun, T. et al. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb. Haemost., 2004, 91, p. 531–537.
37. Lisman, T., Bijsterveld, N. R., Adelmeijer, J. et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J. Thromb. Haemost., 2003, 1, p. 2368-2373.
38. Bijsterveld, N., Moons, A., Boekholdt, S. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation, 2002, 106, p. 2550–2554.
39. Gumulec, J., Kessler, P., Penka, M. et al. Krvácivé komplikace při léčbě warfarinem. Vnitř Lék., 2006, 52, 1, p. 79–91.
40. Kessler, P. Farmakogenetika warfarinu. Vnitř Lék., 2006, 52, 1, p. 31–34.
41. Kessler, P. Léčba orálními antikoagulancii. Praha: Orion Pharma, 2002.
42. Matýšková, M., Penka, M. Interakce antikoagulačních léků s potravinami a potravinovými doplňky. Přehledný článek. Interní medicína pro praxi, 2000, 5, p. 29–33.
43. Beyth, R. J., Quinn, L. M., Landefeld, C. S. Prospective evaluation of an index for predicting risk of major bleeding in outpatients treated with warfarin. Am. J. Med., 1998, 105, p. 91–99.
44. Ansell, J., Hirsh, J., Hylek, E. et al. Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 160–198.
45. Gunneman, T., Ruybalid, R. L., Jacobson, A. K. et al. Frequent prothrombin time testing reduces inappropriate warfarin dose changes [abstract]. Thromb. Haemost., 1999, 82, suppl, p. 676.
46. Lousberg, T. R., Witt, D. M., Beall, D. G. et al. Evaluation of excessive anticoagulation in a group model health maintenance organization. Arch. Intern. Med., 1998, 158, p. 528–534.
47. Garcia, D. A., Regan, S., Crowther, M. et al. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J. Am. Coll. Cardiol., 2006, 47, p. 804–808.
48. Hylek, E. M., Regan, S., Go, A. S. et al. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann. Intern. Med., 2001, 135, p. 393–400.
49. Hirsh, J., Fuster, V., Ansell, J. et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation, 2003, 107, p. 1692–1711.
50. Crowther, M. A., Douketis, J. D., Schnurr, T. et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin associated coagulopathy. Ann. Intern. Med., 2002, 137, p. 251–254.
51. Baker, R. I., Coughlin, P. B., Gallus, A. S. et al. Warfarin reversal: consensus guidelines, of behalf of the Australasian Society of Thrombosis and Haemostasis. MJA, 2004, 181, p. 492–497.
52. Hanley, J. P. Warfarin reversal. J. Clin. Pathol., 2004, 57, p. 1132–1139.
53. Nitu, I. C., Perry, D. J., Lee, C. A. Clinical experience with the use of clotting factor concentrates in oral anticoagulation reversal. Clin. Lab. Haematol., 1998, 20, p. 363–367.
54. Aguilar, M. I., Hart, R. G., Kase, C. S. et al. Treatment of warfarin associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin. Proc., 2007, 82, p. 82–92.
55. Lankiewicz, M. W., Hays, J., Friedman, K. D. et al. Urgent reversal of warfarin with prothrombin complex concentrate. J. Thromb. Haemost., 2006, 4, p. 967–970.
56. Pabinger-Fasching, I. Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate. Thromb. Res., 2008, 122, Suppl 2, p. S19–22.
57. Riess, H. B., Meier-Hellmann, A., Motsch, J. et al. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb. Res., 2007, 121, 1, p. 9–16.
58. Cartmill, M., Dolan, G., Byrne, J. L., Byrne, P. O. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br. J. Neurosurg., 2000, 14, p. 458–461.
59. Makris, M., Greaves, M., Phillips, W. S. et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb. Haemost., 1997, 77, p. 477–480.
60. Dentali, F., Ageno, W., Crowther, M. Treatment of coumarin--associated coagulopathy: a systematic review and proposed treatment algorithms. J. Thromb. Haemost., 2006, 4, p. 1853–1863.
61. DeZee, K. J., Shimeall, W. T., Douglas, K. M. et al. Treatment of excessive Anticoagulation With Phytonadione (Vitamin K): A meta-analysis. Arch. Intern. Med., 2006, 166, p. 391–397.
62. Warkentin, T. E., Greinacher, A., Koster, A., Lincoff, A. M. Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence- -Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 340–380.
63. Preston, F. E., Laidlaw, S. T., Sampson, B. et al. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br. J. Haematol., 2002, 116, p. 619–624.
64. Evans, G., Luddington, R., Baglin, T. Beriplex P/N reverses severe warfarin induced overanticoagulation immediately and completely in patiens presenting with major bleeding. Br. J. Haematol., 2001, 115, p. 998–1001.
65. Yasaka, M., Sakata, T., Naritomi, H. et al. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb. Res., 2005, 115, p. 455–459.
66. Deveras, R. A., Kessler, C. M. Reversal of warfarin induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann. Intern. Med., 2002, 137, p. 884–888.
67. Freeman, W. D., Brott, T. G., Barrett, K. M. et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin. Proc., 2004, 79, p. 1495–1500.
68. Sorensen, B., Johansen, P., Nielsen, G. L. et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul. Fibrinolysis, 2003, 14, p. 469–477.
69. Erhardtsen, E., Nony, P., Dechavanne, M. et al. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul. Fibrinolysis, 1998, 9, p. 741–748.
70. Mayer, S. A., Brun, M. C., Begtrup, K. et al. Recombinant activated factor VII for acute intracererbral hemorrhage. N. Engl. J. Med., 2005, 352, p. 277–285.
71. Mayer, S. A. Recombinant activated factor VII for acute intracerebral hemorrhagie. Strok, 2007, 38, p. 63–64.
72. Mayer, S. A., Brun, M. C., Begtrup, K. et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhagie. N. Engl. J. Med., 2008, 15, p. 2127–2137.
73. Ehrlich, H. J., Henzl, M. J., Gomperts, E. D. Safety of factor VIII inhibitor bypass activity (FEIBA): 10 year compilation of thrombotic adverse events. Haemophilia, 2002, 8, p. 83–90.
74. Makris, M., Watson, H. G. Reversal of coumarin-induced over-anticoagulation: reply to Escobar. Br. J. Haematol., 2002, 118, p. 926.
75. Douketis, J. D., Berger, P. B., Dunn, A. S. et al. The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133, p. 299–339.
76. Weitz, J. I., Crowther, M. Direct thrombin inhibitors. Tromb. Res., 2002, 106, p. V275–V284.
77. Bauer, K. A. New Anticoagulants. Hematology Am. Soc. Hematom. Educ. Program. 2006, p. 450–456.
78. Mahdy, A. M., Webster, N. R. Perioperative systemic haemostatic agents. Br. J. Anaesth., 2004, 93, p. 842–858.
79. Mannucci, P. M., Bettega, D., Cattaneo, M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br. J. Haematol., 1992, 82, p. 87–93.
80. Ibbotson, S. H., Grant, P. J., Kerry, R. et al. The influence of infusions of 1-desamino-8-D-arginine vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP39393) in vitro. Thromb. Haemost., 1991, 65, p. 64–66.
81. Bove, C. M., Casey, B., Marder, V. J. DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb. Haemost., 1996, 75, p. 471–475.
82. Fischer, K. G. Hemodialysis in heparin-induced thrombocytopenia. In: Warkentin, T. E., Greinacher, A., eds. Heparin-Induced Thrombocytopenia (ed 4). New York, NY: Informa Healthcare, 2007, p. 463–485.
83. Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin. Pharmacokinet., 2008, 47, p. 285–295.
84. Stangier, J., Stahle, H., Rathgen, K. et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin. Pharmacokinet., 2008, 47, p. 47–59.
85. Kvasnička, J., Slíva, J. Dabigatran. Farmakoterapie, 2008, 4, p. 359–364.
86. Souhrn údajů o přípravku Xarelto. SÚKL Praha, 2008.
87. Ho, K. M., Ismail, H. Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: a meta-analysis. Anaesth. Intensive Care, 2003, 31, p. 529–537.
88. Niskanen, R. O., Korkala, O. L. Tranexamic acid reduces blood loss in cemented hip arthroplasty: a randomized, double-blind study of 39 patients with osteoarthritis. Acta Orthop., 2005, 76, p. 829–832.
89. Barthels, M., Poliwoda, H. Gerinnungsanalysen. Interpretation – Schlellorientierung – Therapiekontrollen. 4. überarbeitete und erweiterte Auflage. Thieme, 1993, p. 150–151, 226–234.
90. Chlumský, J. et al. Antikoagulační léčba. Grada: Praha, 2005.
91. Choudari, C. P., Palmer, K. R. Acute gastrointestinal haemorrhage in patients treated with anticoagulant drugs. Gut, 1995, 36, p. 483–484.
92. Vreeburg, E. M., de Bruijne, H. W., Snel, P. et al. Previous use of non-steroidal anti-inflammatory drugs and anticoagulants: The influence on clinical outcome of bleeding gastroduodenal ulcers. European J. Gastroenterol. Hepatol., 1997, 9, p. 41–44.
93. Kim, K. et al. Acute gastrointestinal bleeding – diagnosis and treatment. Humana Press : New Jersey, 2003.
94. Dítě et al. Akutní nevarikózní krvácení do horní části trávicího ústrojí. In:Akutní stavy v gastroenterologii. Praha: Galen, 2005.
95. Palmer, K. Management of haematemesis and melaena. BMJ, 2005, 1, p. 399–404.
96. Thomopoulos, K. C., Theocharis, G. J., Nikolopoulou, V. N. et al. Acute upper gastrointestinal bleeding in patiens on long-term oral anticoagulation therapy: Endoscopic findings, clinical management and outcome. World J. Gastroenterol., 2005, 11, 9, p. 1365–1368.
97. Keil, R. a kol. Gastroskopie. Maxdorf : Praha, 2006.
98. Kohout, P. Vředová choroba. Maxdorf : Praha, 2005.
99. Machytka, E., Ehrmann, J., Svoboda, P. et al. Dlouhodobé sledování pacientů s klinickými známkami krvácení do horní části trávicího traktu a negativním endoskopickým nálezem. Vnitřní lék., 2007, 53, 9, p. 942–946.
100. Machytka, E., Ehrmann, J., Svoboda, P. et al. Incidence krvácení do horní části zažívacího traktu v regionu Ostrava-Poruba v letech 2002–2005. Čes. a Slov. Gastroent. a Hepatol., 2007, 61, 3, p. 124–128.
Labels
Anaesthesiology, Resuscitation and Inten Intensive Care MedicineArticle was published in
Anaesthesiology and Intensive Care Medicine
2009 Issue 6
Most read in this issue
- Bleeding complications and overdosing of anticoagulant therapy
- Ethical problems experienced during emergency medical care provision
- Continuous infusion versus intermittent administration of vancomycin in critically ill patients with Gram-positive infections resistant to beta-lactam antibiotics
- Prim. MUDr. Jiří Dostál