Log in | Register

Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis

François Lauzier| Donald M. Arnold| Christian Rabbat| Diane Heels-Ansdell| Ryan Zarychanski| Peter Dodek| Betty Jean Ashley| Martin Albert| Kosar Khwaja| Marlies Ostermann| Yoanna Skrobik| Robert Fowler| Lauralyn McIntyre| Joseph L. Nates| Tim Karachi| Renato D. Lopes| Nicole Zytaruk| Simon Finfer| Mark Crowther| Deborah Cook
Original
Volume 39, Issue 12 / December , 2013

Pages 2135 - 2143

Abstract

Purpose

Bleeding frequently complicates critical illness and may have serious consequences. Our objectives are to describe the predictors of major bleeding and the association between bleeding and mortality in medical–surgical critically ill patients receiving heparin thromboprophylaxis.

Methods

We prospectively studied patients from 67 intensive care units and six countries enrolled in a thromboprophylaxis trial (NCT00182143) comparing dalteparin with unfractionated heparin. Patients with trauma, orthopedic surgery or neurosurgery were excluded. Trained research coordinators used a validated tool to document bleeding, which underwent duplicate independent blinded adjudication. Major bleeding was defined as hypovolemic shock, bleeding into critical sites, requiring an invasive intervention or transfusion of at least two units of red blood cells, or associated with hypotension or tachycardia in the absence of other causes. Adjusted Cox proportional hazard regression analysis was used to identify major bleeding predictors and the association between bleeding and mortality.

Results

Among 3,746 patients, bleeding occurred in 208 [5.6 %, 95 % confidence interval (CI) 4.9–6.3 %]. Time-dependent predictors were prolonged activated partial thromboplastin time [hazard ratio (HR) 1.10, 1.05–1.14 per 10 s increase], lower platelet count (HR 1.16, 1.09–1.24 per 50 × 109/L decrease), therapeutic heparin (HR 3.26, 1.72–6.17), antiplatelet agents (HR 1.38, 1.02–1.88), renal replacement therapy (HR 1.75, 1.20–2.56), and recent surgery (HR 1.64, 1.01–2.65). Type of pharmacologic thromboprophylaxis was not associated with bleeding. Patients with bleeding had a higher risk of in-hospital death (HR 2.09, 1.69–2.57).

Conclusions

As major bleeding has modifiable risk factors and is associated with in-hospital mortality, strategies to mitigate these factors should be evaluated in critically ill patients.

Keywords

References

  1. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KAA, Yusuf S (2006) Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114:774–782
    • View reference on PubMed
    • View reference on publisher's website
  2. van Hattum ES, Algra A, Lawson JA, Eikelboom BC, Moll FL, Tangelder MJ (2009) Bleeding increases the risk of ischemic events in patients with peripheral arterial disease. Circulation 120:1569–1576
    • View reference on PubMed
    • View reference on publisher's website
  3. Nevo S, Swan V, Enger C, Wojno KJ, Bitton R, Shabooti M, Fuller AK, Jones RJ, Braine HG, Vogelsang GB (1998) Acute bleeding after bone marrow transplantation (BMT)- incidence and effect on survival. A quantitative analysis in 1,402 patients. Blood 91:1469–1477
    • View reference on PubMed
  4. Eikelboom JW, Quinlan DJ, O’Donnell M (2009) Major bleeding, mortality, and efficacy of fondaparinux in venous thromboembolism prevention trials. Circulation 120:2006–2011
    • View reference on PubMed
    • View reference on publisher's website
  5. Lauzier F, Arnold D, Rabbat C, Heels-Ansdell D, Dodek P, Ashley B, Albert M, Khwaja K, Ostermann M, Skrobik Y, Fowler R, McIntyre L, Nates J, Karachi T, Lopes R, Zytaruk N, Crowther M, Cook D (2012) In medical–surgical ICU patients, major bleeding is common but independent of heparin prophylaxis. Crit Care 16:P435
    • View reference on publisher's website
  6. Cook D, Meade M, Guyatt G, Walter SD, Heels-Ansdell D, Geerts W, Warkentin TE, Cooper DJ, Zytaruk N, Vallance S, Berwanger O, Rocha M, Qushmaq I, Crowther M (2011) PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan. J Crit Care 26(223):e221–e229
  7. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D D, Meade M, Guyatt G G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE (2011) Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 364:1305–1314
    • View reference on PubMed
    • View reference on publisher's website
  8. Arnold DM, Donahoe L, Clarke FJ, Tkaczyk AJ, Heels-Ansdell D, Zytaruk N, Cook R, Webert KE, McDonald E, Cook DJ (2007) Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med 30:E93–E102
    • View reference on PubMed
  9. Arnold D, Rabbat C, Lauzier F, Zytaruk N, Heels-Ansdell D, Cook D (2009) Adjudicating bleeding outcomes in a large thrombroprophylaxis trial in critical illness. Blood (ASH Annual Meeting Abstracts) 114:A2471
  10. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829
    • View reference on PubMed
    • View reference on publisher's website
  11. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R (2012) Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:e326S–e350S
    • View reference on PubMed
    • View reference on publisher's website
  12. Douketis J, Cook D, Meade M, Guyatt G, Geerts W, Skrobik Y, Albert M, Granton J, Hébert P, Pagliarello G, Marshall J, Fowler R, Freitag A, Rabbat C, Anderson D, Zytaruk N, Heels-Ansdell D, Crowther M, Group CCCT (2008) Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med 168:1805–1812
    • View reference on PubMed
    • View reference on publisher's website
  13. Decousus H, Tapson VF, Bergmann JF, Chong BH, Froehlich JB, Kakkar AK, Merli GJ, Monreal M, Nakamura M, Pavanello R, Pini M, Piovella F, Spencer FA, Spyropoulos AC, Turpie AG, Zotz RB, Fitzgerald G, Anderson FA (2011) Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 139:69–79
    • View reference on PubMed
    • View reference on publisher's website
  14. Di Minno G, Martinez J, McKean ML, De La Rosa J, Burke JF, Murphy S (1985) Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 79:552–559
    • View reference on PubMed
    • View reference on publisher's website
  15. Fiaccadori E, Maggiore U, Clima B, Melfa L, Rotelli C, Borghetti A (2001) Incidence, risk factors, and prognosis of gastrointestinal hemorrhage complicating acute renal failure. Kidney Int 59:1510–1519
    • View reference on PubMed
    • View reference on publisher's website
  16. Cook D, Heyland D, Griffith L, Cook R, Marshall J, Pagliarello J (1999) Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. Crit Care Med 27:2812–2817
    • View reference on PubMed
    • View reference on publisher's website
  17. Luo JC, Leu HB, Huang KW, Huang CC, Hou MC, Lin HC, Lee FY, Lee SD (2011) Incidence of bleeding from gastroduodenal ulcers in patients with end-stage renal disease receiving hemodialysis. CMAJ 183:E1345–E1351
    • View reference on PubMed
    • View reference on publisher's website
  18. Anand SS, Yusuf S, Pogue J, Ginsberg JS, Hirsh J, Investigators OtASfIS (2003) Relationship of activated partial thromboplastin time to coronary events and bleeding in patients with acute coronary syndromes who receive heparin. Circulation 107:2884–2888
    • View reference on PubMed
    • View reference on publisher's website
  19. Anand SS, Bates S, Ginsberg JS, Levine M, Buller H, Prins M, Haley S, Kearon C, Hirsh J, Gent M (1999) Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times. Arch Intern Med 159:2029–2032
    • View reference on PubMed
    • View reference on publisher's website
  20. Anand S, Ginsberg JS, Kearon C, Gent M, Hirsh J (1996) The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin. Arch Intern Med 156:1677–1681
    • View reference on PubMed
    • View reference on publisher's website
  21. Ciavarella D, Reed RL, Counts RB, Baron L, Pavlin E, Heimbach DM, Carrico CJ (1987) Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol 67:365–368
    • View reference on PubMed
    • View reference on publisher's website
  22. Chowdhury P, Saayman AG, Paulus U, Findlay GP, Collins PW (2004) Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 125:69–73
    • View reference on PubMed
    • View reference on publisher's website
  23. Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG (2002) Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 30:1765–1771
    • View reference on PubMed
    • View reference on publisher's website
  24. Shalansky SJ, Verma AK, Levine M, Spinelli JJ, Dodek PM (2002) Risk markers for thrombocytopenia in critically ill patients: a prospective analysis. Pharmacotherapy 22:803–813
    • View reference on PubMed
    • View reference on publisher's website
  25. Cook D, Douketis J, Meade M, Guyatt G, Zytaruk N, Granton J, Skrobik Y, Albert M, Fowler R, Hébert P, Pagliarello G, Friedrich J, Freitag A, Karachi T, Rabbat C, Heels-Ansdell D, Geerts W, Crowther M, Canadian Critical Care Trials Group (2008) Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors. Crit Care 12:R32
    • View reference on PubMed
    • View reference on publisher's website
  26. Lopes RD, Subherwal S, Holmes DN, Thomas L, Wang TY, Rao SV, Magnus Ohman E, Roe MT, Peterson ED, Alexander KP (2012) The association of in-hospital major bleeding with short-, intermediate-, and long-term mortality among older patients with non-ST-segment elevation myocardial infarction. Eur Heart J 33(16):2044–2053
    • View reference on PubMed
    • View reference on publisher's website
  27. Marik PE, Corwin HL (2008) Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med 36:2667–2674
    • View reference on PubMed
    • View reference on publisher's website
  28. Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, O’Byrne MM, Evenson LK, Malinchoc M, DeGoey SR, Afessa B, Hubmayr RD, Moore SB (2007) Transfusion-related acute lung injury in the critically ill: prospective nested case-control study. Am J Respir Crit Care Med 176:886–891
    • View reference on PubMed
    • View reference on publisher's website
  29. Roman-Marchant O, Orellana-Jimenez CE, De Backer D, Melot C, Vincent JL (2004) Septic shock of early or late onset: does it matter? Chest 126:173–178
    • View reference on PubMed
    • View reference on publisher's website
  30. Shintani AK, Girard TD, Eden SK, Arbogast PG, Moons KG, Ely EW (2009) Immortal time bias in critical care research: application of time-varying Cox regression for observational cohort studies. Crit Care Med 37:2939–2945
    • View reference on PubMed
    • View reference on publisher's website
  31. Hui P, Cook DJ, Lim W, Fraser GA, Arnold DM (2011) The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest 139:271–278
    • View reference on PubMed
    • View reference on publisher's website

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement