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

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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.

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Acknowledgments

The authors are very grateful to the research coordinators for their help with this trial. The trial was designed by the PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial) Steering Committee, PROTECT investigators, and the Canadian Critical Care Trials Group. PROTECT was supported by the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. The list of PROTECT collaborators is provided in the Electronic Supplementary Material.

Funding sources

F Lauzier is a recipient of a research career award from the Fonds de la recherche du Québec-Santé. DM Arnold holds a New Investigator Award from the Canadian Institutes of Health Research in partnership with Hoffmann-LaRoche. R Zarychanski receives salary support from CIHR as part of an RCT Mentoring Award. R Fowler is a Clinician Scientist of the Heart and Stroke Foundation of Ontario. M Crowther holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario and the Leo Pharma Chair in Thromboembolism Research at McMaster University and St Joseph’s Healthcare, Hamilton. L McIntyre holds a New Investigator Award from the Canadian Institute of Health Research/Canadian Blood Services. D Cook is a Research Chair of the Canadian Institutes of Health Research. The list of PROTECT collaborators is available in the Supplement Digital Content. This study was funded by the Canadian Institute Health Research (#MCT78568), Heart & Stroke Foundation of Canada (#T6157, #T6950, #NA6186) and the Australian and New Zealand College of Anesthetists Research Foundation (#07/23).

Conflicts of interest

RD Lopes received research grant from Bristol-Myers Squibb and sat on advisory boards for Bristol-Myers Squibb, BI, and Bayer. M Crowther sat on advisory boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, and Artisan Pharma. He prepared educational materials for Pfizer, Octapharm, and CSL Behring, and provided expert testimony for Bayer. M Crowther’s institution has received funding for research projects from Boehringer Ingelheim, Octapharm, Pfizer, and Leo Pharma.

Author information

Authors and Affiliations

  1. Division of Critical Care, Departments of Medicine and of Anesthesiology, Centre de recherche du CHU de Québec, Axe Santé des populations et pratiques optimales en santé, Université Laval, 1401, 18e Rue, Québec, QC, G1J 1Z4, Canada

    François Lauzier

  2. Department of Medicine, McMaster University, Hamilton, Canada

    Donald M. Arnold, Christian Rabbat, Tim Karachi, Mark Crowther & Deborah Cook

  3. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada

    Donald M. Arnold, Diane Heels-Ansdell, Nicole Zytaruk, Mark Crowther & Deborah Cook

  4. Canadian Blood Services, Hamilton, ON, Canada

    Donald M. Arnold

  5. Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada

    Ryan Zarychanski

  6. Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada

    Ryan Zarychanski

  7. Division of Critical Care Medicine, Center for Health Evaluation and Outcome Sciences, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada

    Peter Dodek & Betty Jean Ashley

  8. Departments of Medicine and of Critical Care, Centre de recherche de l’Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Quebec, Canada

    Martin Albert

  9. Departments of Surgery and of Critical Care, McGill University Health Centre, Montréal, QC, Canada

    Kosar Khwaja

  10. Department of Critical Care, King’s College London, Guy’s and St Thomas’ Foundation Hospital, London, UK

    Marlies Ostermann

  11. Lise and Jean Saine Critical Care Chair, Department of Medicine, Université de Montréal; Regroupement de Soins Critiques respiratoires, Réseau de Santé Respiratoire, Québec, Canada

    Yoanna Skrobik

  12. Departments of Critical Care Medicine and of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Robert Fowler

  13. Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada

    Lauralyn McIntyre

  14. Department of Critical Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Joseph L. Nates

  15. Division of Cardiovascular Medicine, Duke Clinical Research Institute, Durham, NC, USA

    Renato D. Lopes

  16. Department of Intensive Care, Royal North Shore Hospital and the George Institute for Global Health, University of Sydney, Sydney, NSW, Australia

    Simon Finfer

Authors
  1. François Lauzier
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  2. Donald M. Arnold
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  3. Christian Rabbat
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  4. Diane Heels-Ansdell
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  5. Ryan Zarychanski
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  6. Peter Dodek
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  7. Betty Jean Ashley
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  8. Martin Albert
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  9. Kosar Khwaja
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  10. Marlies Ostermann
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  11. Yoanna Skrobik
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  12. Robert Fowler
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  13. Lauralyn McIntyre
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  14. Joseph L. Nates
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  15. Tim Karachi
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  16. Renato D. Lopes
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  17. Nicole Zytaruk
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  18. Simon Finfer
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  19. Mark Crowther
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  20. Deborah Cook
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Corresponding author

Correspondence to François Lauzier.

Additional information

For the PROTECT Investigators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group.

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Lauzier, F., Arnold, D.M., Rabbat, C. et al. Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. Intensive Care Med 39, 2135–2143 (2013). https://doi.org/10.1007/s00134-013-3044-3

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  • DOI: https://doi.org/10.1007/s00134-013-3044-3

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