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Published in: Critical Care 2/2008

Open Access 01-04-2008 | Research

Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors

Authors: Deborah Cook, James Douketis, Maureen Meade, Gordon Guyatt, Nicole Zytaruk, John Granton, Yoanna Skrobik, Martin Albert, Robert Fowler, Paul Hebert, Guiseppe Pagliarello, Jan Friedrich, Andreas Freitag, Tim Karachi, Christian Rabbat, Diane Heels-Ansdell, William Geerts, Mark Crowther, the Canadian Critical Care Trials Group

Published in: Critical Care | Issue 2/2008

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Abstract

Background

Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.

Methods

In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.

Results

Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).

Conclusion

In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.

Clinical Trial Registration

Number NCT00138099.
Literature
1.
go back to reference Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, Geerts W, Guyatt G: Deep venous thrombosis in medical–surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005, 33: 1565-1571. 10.1097/01.CCM.0000171207.95319.B2.PubMedCrossRef Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, Geerts W, Guyatt G: Deep venous thrombosis in medical–surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005, 33: 1565-1571. 10.1097/01.CCM.0000171207.95319.B2.PubMedCrossRef
2.
go back to reference Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts WH: Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med. 2001, 161: 1268-1279. 10.1001/archinte.161.10.1268.PubMedCrossRef Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts WH: Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med. 2001, 161: 1268-1279. 10.1001/archinte.161.10.1268.PubMedCrossRef
3.
go back to reference Hirsch DR, Ingenito EP, Goldhaber SZ: Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA. 1995, 274: 335-337. 10.1001/jama.274.4.335.PubMedCrossRef Hirsch DR, Ingenito EP, Goldhaber SZ: Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA. 1995, 274: 335-337. 10.1001/jama.274.4.335.PubMedCrossRef
4.
go back to reference Irish AB, Green FR: Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal disease and dialysis: relationship with dyslipidaemia, inflammation, and factor VII genotype. Nephrol Dial Transplant. 1998, 13: 679-684. 10.1093/ndt/13.3.679.PubMedCrossRef Irish AB, Green FR: Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal disease and dialysis: relationship with dyslipidaemia, inflammation, and factor VII genotype. Nephrol Dial Transplant. 1998, 13: 679-684. 10.1093/ndt/13.3.679.PubMedCrossRef
5.
go back to reference Tveit DP, Hypolite IO, Hshieh P, Cruess D, Agodoa L, Welch PG, Abbot KC: Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis. 2002, 39: 1011-1017. 10.1053/ajkd.2002.32774.PubMedCrossRef Tveit DP, Hypolite IO, Hshieh P, Cruess D, Agodoa L, Welch PG, Abbot KC: Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis. 2002, 39: 1011-1017. 10.1053/ajkd.2002.32774.PubMedCrossRef
6.
go back to reference Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK: Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer. 2003, 98: 1514-1520. 10.1002/cncr.11700.PubMedCrossRef Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK: Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer. 2003, 98: 1514-1520. 10.1002/cncr.11700.PubMedCrossRef
7.
go back to reference Steurer M, Sudmeier I, Stauder R, Gastl G: Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. Br J Haematol. 2003, 121: 101-103. 10.1046/j.1365-2141.2003.04252.x.PubMedCrossRef Steurer M, Sudmeier I, Stauder R, Gastl G: Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. Br J Haematol. 2003, 121: 101-103. 10.1046/j.1365-2141.2003.04252.x.PubMedCrossRef
8.
go back to reference Weitz JI: Low molecular weight heparins. N Engl J Med. 1997, 337: 688-699. 10.1056/NEJM199709043371007.PubMedCrossRef Weitz JI: Low molecular weight heparins. N Engl J Med. 1997, 337: 688-699. 10.1056/NEJM199709043371007.PubMedCrossRef
9.
go back to reference Ravaud P, Durieux P, Fourcade A, the Comite Scientifique Thrombose AP-HP: Prophylaxie des thromboses veineuses post-operatoires: recommendations de L'assistance publique des hopitaux de Paris. Sangue Thromb Vaisseaux. 1995, 7: 119-129. Ravaud P, Durieux P, Fourcade A, the Comite Scientifique Thrombose AP-HP: Prophylaxie des thromboses veineuses post-operatoires: recommendations de L'assistance publique des hopitaux de Paris. Sangue Thromb Vaisseaux. 1995, 7: 119-129.
10.
go back to reference Zytaruk N, Douketis J, Meade M, Crowther M, Guyatt G, Geerts W, Anderson D, Skrobik Y, Albert M, Hebert P, Pagliarello G, Granton J, Fowler R, Freitag A, Karachi T, Rabbat C, Mehta S, Rocker G, Poirier G, Marshall J, Cook D, DIRECT Investigators for the Canadian Critical Care Trials Group: Dalteparin's influence on the renally compromised: anti-ten-a: the DIRECT study. Am Rev Respir Crit Care Med. 2006, 3: A738c- Zytaruk N, Douketis J, Meade M, Crowther M, Guyatt G, Geerts W, Anderson D, Skrobik Y, Albert M, Hebert P, Pagliarello G, Granton J, Fowler R, Freitag A, Karachi T, Rabbat C, Mehta S, Rocker G, Poirier G, Marshall J, Cook D, DIRECT Investigators for the Canadian Critical Care Trials Group: Dalteparin's influence on the renally compromised: anti-ten-a: the DIRECT study. Am Rev Respir Crit Care Med. 2006, 3: A738c-
11.
go back to reference Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron. 1976, 16: 31-41.CrossRef Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron. 1976, 16: 31-41.CrossRef
12.
go back to reference Cook DJ, Medic A, Andrews J, Schiff D, Dobranowski J, Bates S, McDonald E, Landry F, Crowther MA: Doppler compression ultrasound of the lower extremities in ICU patients: an inter-rater reliability study. Crit Care Med. 2003, A346- Cook DJ, Medic A, Andrews J, Schiff D, Dobranowski J, Bates S, McDonald E, Landry F, Crowther MA: Doppler compression ultrasound of the lower extremities in ICU patients: an inter-rater reliability study. Crit Care Med. 2003, A346-
13.
go back to reference Kearon C, Julian JA, Newman TE, Ginsberg JS: Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med. 1998, 128: 663-677.PubMedCrossRef Kearon C, Julian JA, Newman TE, Ginsberg JS: Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med. 1998, 128: 663-677.PubMedCrossRef
14.
go back to reference PIOPED Investigators: Value of ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990, 263: 2753-2759. 10.1001/jama.263.20.2753.CrossRef PIOPED Investigators: Value of ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990, 263: 2753-2759. 10.1001/jama.263.20.2753.CrossRef
15.
go back to reference Remy-Jardin M, Remy J, Deschildre F, Artaud D, Beregi JP, Hossein-Foucher C, Marchandise X, Duhamel A: Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology. 1996, 200: 699-706.PubMedCrossRef Remy-Jardin M, Remy J, Deschildre F, Artaud D, Beregi JP, Hossein-Foucher C, Marchandise X, Duhamel A: Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology. 1996, 200: 699-706.PubMedCrossRef
16.
go back to reference Arnold DM, Donahoe L, Clarke FJ, Tkaczyk AJ, Heels-Ansdell D, Zytaruk N, Cook RJ, Webert KE, McDonald E, Cook DJ: Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med. 2007, 30: E93-E102.PubMed Arnold DM, Donahoe L, Clarke FJ, Tkaczyk AJ, Heels-Ansdell D, Zytaruk N, Cook RJ, Webert KE, McDonald E, Cook DJ: Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med. 2007, 30: E93-E102.PubMed
17.
go back to reference Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC: College of American Pathologists conference XXXI on laboratory monitoring of anticoagulant therapy. Arch Pathol Lab Med. 1998, 122: 799-807.PubMed Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC: College of American Pathologists conference XXXI on laboratory monitoring of anticoagulant therapy. Arch Pathol Lab Med. 1998, 122: 799-807.PubMed
18.
go back to reference Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE: Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001, 119: 64S-94S. 10.1378/chest.119.1_suppl.64S.PubMedCrossRef Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE: Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001, 119: 64S-94S. 10.1378/chest.119.1_suppl.64S.PubMedCrossRef
19.
go back to reference Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med. 1985, 16: 818-819.CrossRef Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med. 1985, 16: 818-819.CrossRef
20.
go back to reference Levine MN, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M: The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost. 1989, 62: 940-944.PubMed Levine MN, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M: The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost. 1989, 62: 940-944.PubMed
21.
go back to reference Mahe I, Aghassarian M, Drouet L, dit-Sollier CB, Lacut K, Heilmann JJ, Mottier D, Bergmann JF: Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007, 97: 581-586.PubMed Mahe I, Aghassarian M, Drouet L, dit-Sollier CB, Lacut K, Heilmann JJ, Mottier D, Bergmann JF: Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007, 97: 581-586.PubMed
22.
go back to reference Rabbat C, Cook DJ, Crowther MA, McDonald E, Clarke F, Meade MO, Lee KA, Cook RJ: Dalteparin thromboprophylaxis for critically ill medical–surgical patients. J Crit Care. 2005, 20: 357-363. 10.1016/j.jcrc.2005.09.009.PubMedCrossRef Rabbat C, Cook DJ, Crowther MA, McDonald E, Clarke F, Meade MO, Lee KA, Cook RJ: Dalteparin thromboprophylaxis for critically ill medical–surgical patients. J Crit Care. 2005, 20: 357-363. 10.1016/j.jcrc.2005.09.009.PubMedCrossRef
23.
go back to reference Lim W, Cook DJ, Crowther MA: Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol. 2004, 15: 3192-3206. 10.1097/01.ASN.0000145014.80714.35.PubMedCrossRef Lim W, Cook DJ, Crowther MA: Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol. 2004, 15: 3192-3206. 10.1097/01.ASN.0000145014.80714.35.PubMedCrossRef
24.
go back to reference Koreth R, Weinert C, Weisdorf DJ, Key NS: Measurement of bleeding severity: a critical review. Transfusion. 2004, 44: 605-617. 10.1111/j.1537-2995.2004.03153.x.PubMedCrossRef Koreth R, Weinert C, Weisdorf DJ, Key NS: Measurement of bleeding severity: a critical review. Transfusion. 2004, 44: 605-617. 10.1111/j.1537-2995.2004.03153.x.PubMedCrossRef
25.
go back to reference Raskob G, Kearon C, Geerts W, Planes A, Eriksson B, Paiement G, Lassen M, Bergqvist D, Turpie G, Agnelli G, Buller H, Hirsh J: Evaluating bleeding complications of thromboprophylaxis after hip replacement: a systematic review. J Thromb Haemost. 2003, 1: 1860-10.1046/j.1538-7836.2003.00355.x.CrossRef Raskob G, Kearon C, Geerts W, Planes A, Eriksson B, Paiement G, Lassen M, Bergqvist D, Turpie G, Agnelli G, Buller H, Hirsh J: Evaluating bleeding complications of thromboprophylaxis after hip replacement: a systematic review. J Thromb Haemost. 2003, 1: 1860-10.1046/j.1538-7836.2003.00355.x.CrossRef
26.
go back to reference Kani C, Markantonis SL, Nicolaou C, Maggina N: Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study. J Crit Care. 2006, 21: 79-84. 10.1016/j.jcrc.2005.09.056.PubMedCrossRef Kani C, Markantonis SL, Nicolaou C, Maggina N: Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study. J Crit Care. 2006, 21: 79-84. 10.1016/j.jcrc.2005.09.056.PubMedCrossRef
27.
go back to reference Tencani E, Mannucci C, Casolari B, Turrini F, Crowther MA, Prisco D, Cenci AM, Bondi M: Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study. Haematologica. 2006, 97: 976-979. Tencani E, Mannucci C, Casolari B, Turrini F, Crowther MA, Prisco D, Cenci AM, Bondi M: Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study. Haematologica. 2006, 97: 976-979.
28.
go back to reference Ibrahim EH, Iregui M, Prentice D, Sherman G, Kollef M, Shannon W: Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med. 2002, 30: 771-774. 10.1097/00003246-200204000-00008.PubMedCrossRef Ibrahim EH, Iregui M, Prentice D, Sherman G, Kollef M, Shannon W: Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med. 2002, 30: 771-774. 10.1097/00003246-200204000-00008.PubMedCrossRef
29.
go back to reference Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, Rigaud JP, Casciani D, Misset B, Bosquet C, Outin H, Brun-Buisson C, Nitenberg G, for the French Catheter Study Group in Intensive Care: Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA. 2001, 286: 700-707. 10.1001/jama.286.6.700.PubMedCrossRef Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, Rigaud JP, Casciani D, Misset B, Bosquet C, Outin H, Brun-Buisson C, Nitenberg G, for the French Catheter Study Group in Intensive Care: Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA. 2001, 286: 700-707. 10.1001/jama.286.6.700.PubMedCrossRef
30.
go back to reference Cook DJ, Rocker G, Meade MO, Guyatt GH, Geerts W, Anderson D, Skrobik Y, Hebert P, Albert M, Cooper J, Bates S, Caco C, Finfer S, Fowler R, Freitag A, Granton J, Jones G, Langevin S, Mehta S, Pagliarello G, Poirier G, Rabbat C, Schiff D, Griffith L, Crowther M, for the PROTECT Investigators and the Canadian Critical Care Trials Group: Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study. J Crit Care. 2005, 20: 364-372. 10.1016/j.jcrc.2005.09.010.PubMedCrossRef Cook DJ, Rocker G, Meade MO, Guyatt GH, Geerts W, Anderson D, Skrobik Y, Hebert P, Albert M, Cooper J, Bates S, Caco C, Finfer S, Fowler R, Freitag A, Granton J, Jones G, Langevin S, Mehta S, Pagliarello G, Poirier G, Rabbat C, Schiff D, Griffith L, Crowther M, for the PROTECT Investigators and the Canadian Critical Care Trials Group: Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study. J Crit Care. 2005, 20: 364-372. 10.1016/j.jcrc.2005.09.010.PubMedCrossRef
Metadata
Title
Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors
Authors
Deborah Cook
James Douketis
Maureen Meade
Gordon Guyatt
Nicole Zytaruk
John Granton
Yoanna Skrobik
Martin Albert
Robert Fowler
Paul Hebert
Guiseppe Pagliarello
Jan Friedrich
Andreas Freitag
Tim Karachi
Christian Rabbat
Diane Heels-Ansdell
William Geerts
Mark Crowther
the Canadian Critical Care Trials Group
Publication date
01-04-2008
Publisher
BioMed Central
Published in
Critical Care / Issue 2/2008
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc6810

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