Clinical trial NCT01721928: Norwegian Intensive Care Unit Dalteparin Effect Study
Official title: Norwegian Intensive Care Unit Dalteparin Effect Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Acute Kidney Injury
Deep Venous Thrombosis
Keywords: Acute kidney injury
Deep venous thrombosis
Dialysis
Prophylaxis
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: University of Oslo
First posted: 2012-11-06
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The main objective is to compare the prophylactic effect of dalteparin in intensive care unit patients with acute kidney injury and continuous renal replacement therapy with a control group of intensive care unit patients with normal kidney function.

Brief summary: The main purpose of the NORIDES study is to investigate the effect of pharmacological thromboprophylaxis with low molecular weight heparins (LMWHs) in critically ill patients, and how it is affected by presence of acute kidney injury (AKI) and treatment with hemodialysis. The main objective is to compare the prophylactic effect of dalteparin in intensive care unit (ICU) patients with AKI and Citrate-Calcium dialysis (CiCa-dialysis) with a control group of ICU patients with normal kidney function. Our main hypothesis is that CiCa-dialysis reduces dalteparin effect, and that patients undergoing CiCa-dialysis do not achieve adequate prophylaxis against venous thromboembolism (VTE). The primary endpoint is development of DVT during ICU stay, the secondary endpoint inadequate heparin effect measured in blood samples.

Detailed description: Description of deep venous thrombosis (DVT) diagnosis: Screening for DVT using Doppler Ultrasound (DUS) of both upper- and lower extremities will be performed within 48 hours after ICU admission and thereafter twice a week until discharge from ICU or ICU stay equal to 30 days. An additional DUS will be performed 3 months after ICU discharge.

Description of heparin effect measured in blood samples: Blood samples will be drawn from intravasal catheters (preferably arterial, alternatively central venous) to examine heparin effect (anti-Xa activity, thrombin generation assay (TGA) and thrombelastography (TEG) and other haematological analyses including antithrombin concentrations. Whole blood will be drawn on two separate days (from minimum day 2 to maximum day 30 dependent on the dialysis therapy) of ICU stay immediately before and 4 hours after dalteparin administration in order to measure tough and peak effect of heparin. Dalteparin effect in ICU patients undergoing dialysis therapy will be measured one day with and one day without ongoing dialysis therapy in order to distinguish the effect of AKI from the effect of continuous renal replacement therapy (CRRT).

Eligibility criteria: Inclusion Criteria:

* ICU patients receiving prophylactic dalteparin

Exclusion Criteria:

* Age \< 18 years
* Intraocular bleeding
* Intracranial bleeding
* Acute spinal cord lesion
* Inherited coagulopathy
* Ongoing, uncontrolled bleeding
* Therapeutic anticoagulation
* Uncorrected coagulopathy
* Pregnancy or postpartum \< 6 weeks
* Participation in an interventional study
* RIFLE class E
* Consent not received
* ICU length of stay less than 48 hours
* DVT detected at first DUS examination

Primary outcomes:
measure: The primary endpoint is development of deep venous thrombosis (DVT)
timeFrame: Twice a week until ICU LOS 30 days or discharge from ICU
Secondary outcomes:
measure: The secondary endpoint is inadequate heparin effect measured in blood samples
timeFrame: Blood samples is drawn 4 times during ICU stay, from minimum day 2 to maximum day 30 dependent on the dialysis therapy
Other outcomes:
measure: Which of the blood sample analyses anti-Xa activity, TEG or TGA is superior in detecting critically ill patients who will subsequently develop DVT?
timeFrame: Whole blood will be drawn on two separate days from minimum day 2 to maximum day 30 dependent on the dialysis therapy, immediately before and 4 hours after dalteparin administration in order to measure tough and peak effect of heparin.
measure: Which factors affect heparin effect in critically ill patients?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: What is the incidence of DVT and bleeding in ICU patients with and without CiCa-dialysis therapy, and is it correlated to heparin effect?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Do ICU patients with AKI treated with CRRT have lower blood flow to the kidneys measured as renal perfusion index during contrast enhanced DUS compared to similar ICU patients without AKI?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Is the renal blood flow measured as renal perfusion index during contrast enhanced DUS correlated to a global blood flow measured as cardiac index using PICCO®?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Is examination of patient urine using Nuclear Magnetic Resonance (NMR) spectroscopy different in ICU patient with and without AKI and what is the effect of CiCa-dialysis on NMR spectroscopy?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Which bedside method is superior in predicting dialysis circuit clotting?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Which factors affects filter lifetime during CiCa-dialysis?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Which risk factors for DVT are present in an ICU population and what is the contribution of each factor in development of DVT?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Is the presence of DVT in ICU patients influenced by the anatomical placement of catheters such as central venous catheters (CVCs) and dialysis catheters?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: Does the presence of DVT influence the prognosis in ICU patients?
timeFrame: Data will be collected during ICU stay until LOS 30 days or discharge from ICU. Mortality will also be assessed after ICU discharge.
measure: Does metabolic alkalosis due to CiCa-dialysis therapy lead to prolonged ventilator therapy?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: What is the compliance to our clinical practice guidelines for thromboprophylaxis in the ICU, and does low compliance to guidelines lead to more frequent DVT?
timeFrame: During ICU stay until LOS 30 days or discharge from ICU
measure: What is the occurrence of DVT 3 months after ICU discharge?
timeFrame: Patients will be screened for DVT 3 months after ICU discharge.
measure: Future blood and urine analyses of ICU patients with and without AKI and dialysis therapy.
timeFrame: Blood and urine samples will be collected during ICU stay until LOS 30 days or discharge from ICU. The samples will be stored for future analysis with a maximum of 10 years storage.
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: Oslo University Hospital
name: Kjetil Sunde, Professor
role: STUDY_CHAIR
affiliation: Oslo University Hospital
name: Sigrid Beitland, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital
name: Per M Sandset, Professor
role: STUDY_DIRECTOR
References:
citation: McCunn M, Reynolds HN, Reuter J, McQuillan K, McCourt T, Stein D. Continuous renal replacement therapy in patients following traumatic injury. Int J Artif Organs. 2006 Feb;29(2):166-86. doi: 10.1177/039139880602900204.
citation: Cook DJ, Douketis J, Arnold D, Crowther MA. Bleeding and venous thromboembolism in the critically ill with emphasis on patients with renal insufficiency. Curr Opin Pulm Med. 2009 Sep;15(5):455-62. doi: 10.1097/MCP.0b013e32832ea4dd.
citation: Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):338S-400S. doi: 10.1378/chest.126.3_suppl.338S.
citation: Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S. doi: 10.1378/chest.08-0656.
citation: Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, Wheeler HB. Prevention of venous thromboembolism. Chest. 2001 Jan;119(1 Suppl):132S-175S. doi: 10.1378/chest.119.1_suppl.132s. No abstract available.
citation: Leclerc JR, Gent M, Hirsh J, Geerts WH, Ginsberg JS. The incidence of symptomatic venous thromboembolism after enoxaparin prophylaxis in lower extremity arthroplasty: a cohort study of 1,984 patients. Canadian Collaborative Group. Chest. 1998 Aug;114(2 Suppl Evidence):115S-118S. doi: 10.1378/chest.114.2_supplement.115s. No abstract available.
citation: Ribic C, Lim W, Cook D, Crowther M. Low-molecular-weight heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review. J Crit Care. 2009 Jun;24(2):197-205. doi: 10.1016/j.jcrc.2008.11.002. Epub 2009 Feb 7.
citation: Spyropoulos AC, Anderson FA Jr, FitzGerald G, Decousus H, Pini M, Chong BH, Zotz RB, Bergmann JF, Tapson V, Froehlich JB, Monreal M, Merli GJ, Pavanello R, Turpie AGG, Nakamura M, Piovella F, Kakkar AK, Spencer FA; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011 Sep;140(3):706-714. doi: 10.1378/chest.10-1944. Epub 2011 Mar 24.
citation: Khouli H, Shapiro J, Pham VP, Arfaei A, Esan O, Jean R, Homel P. Efficacy of deep venous thrombosis prophylaxis in the medical intensive care unit. J Intensive Care Med. 2006 Nov-Dec;21(6):352-8. doi: 10.1177/0885066606292880.
citation: Rabbat CG, Cook DJ, Crowther MA, McDonald E, Clarke F, Meade MO, Lee KA, Cook RJ. Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency. J Crit Care. 2005 Dec;20(4):357-63. doi: 10.1016/j.jcrc.2005.09.009.
citation: Crowther MA, Cook DJ, Griffith LE, Devereaux PJ, Rabbat CC, Clarke FJ, Hoad N, McDonald E, Meade MO, Guyatt GH, Geerts WH, Wells PS. Deep venous thrombosis: clinically silent in the intensive care unit. J Crit Care. 2005 Dec;20(4):334-40. doi: 10.1016/j.jcrc.2005.09.011.
citation: Douketis JD, Rabbat C, Crowther MA; VTE in the ICU Workshop Participants. Anticoagulant prophylaxis in special populations with an indwelling epidural catheter or renal insufficiency. J Crit Care. 2005 Dec;20(4):324-9. doi: 10.1016/j.jcrc.2005.09.001.
citation: Cook D, Crowther MA, Douketis J; VTE in the ICU Workshop Participants. Thromboprophylaxis in medical-surgical intensive care unit patients. J Crit Care. 2005 Dec;20(4):320-3. doi: 10.1016/j.jcrc.2005.09.007. No abstract available.
citation: Cook D, Douketis J, Crowther MA, Anderson DR; VTE in the ICU Workshop Participants. The diagnosis of deep venous thrombosis and pulmonary embolism in medical-surgical intensive care unit patients. J Crit Care. 2005 Dec;20(4):314-9. doi: 10.1016/j.jcrc.2005.09.003. No abstract available.
citation: Cook DJ, Crowther MA, Meade MO, Douketis J; VTE in the ICU Workshop Participants. Prevalence, incidence, and risk factors for venous thromboembolism in medical-surgical intensive care unit patients. J Crit Care. 2005 Dec;20(4):309-13. doi: 10.1016/j.jcrc.2005.09.005. No abstract available.
citation: Cook DJ, Crowther MA, Geerts WH. On the need for a workshop on venous thromboembolism in critical care. J Crit Care. 2005 Dec;20(4):306-8. doi: 10.1016/j.jcrc.2005.09.004. No abstract available.
citation: Swarczinski C, Dijkers M. The value of serial leg measurements for monitoring deep vein thrombosis in spinal cord injury. J Neurosci Nurs. 1991 Oct;23(5):306-14. doi: 10.1097/01376517-199110000-00007.
citation: Makris PE, Pithara E. Clinical evaluation of new global clotting assay for monitoring of LMWH treatment: pilot study. Int Angiol. 1998 Jun;17(2):69-79.
citation: Haas FJ, Kluft C, Biesma DH, Schutgens RE. Patients with deep venous thrombosis and thrombophilia risk factors have a specific prolongation of the lag time in a chromogenic thrombin generation assay. Blood Coagul Fibrinolysis. 2011 Sep;22(6):506-11. doi: 10.1097/MBC.0b013e328347404d.
citation: Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in ICU patients. Chest. 1997 Mar;111(3):661-4. doi: 10.1378/chest.111.3.661.
citation: Cook DJ, Rocker G, Meade M, Guyatt G, 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; PROTECT Investigators; Canadian Critical Care Trials Group. Prophylaxis of Thromboembolism in Critical Care (PROTECT) Trial: a pilot study. J Crit Care. 2005 Dec;20(4):364-72. doi: 10.1016/j.jcrc.2005.09.010.
citation: Patel R, Cook DJ, Meade MO, Griffith LE, Mehta G, Rocker GM, Marshall JC, Hodder R, Martin CM, Heyland DK, Peters S, Muscedere J, Soth M, Campbell N, Guyatt GH; Burden of Illness in venous ThromboEmbolism in Critical care (BITEC) Study Investigators; Canadian Critical Care Trials Group. Burden of illness in venous thromboembolism in critical care: a multicenter observational study. J Crit Care. 2005 Dec;20(4):341-7. doi: 10.1016/j.jcrc.2005.09.014.
citation: Crowther MA, Cook DJ, Griffith LE, Meade M, Hanna S, Rabbat C, Bates SM, Geerts W, Johnston M, Guyatt G. Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients. Intensive Care Med. 2005 Jan;31(1):48-55. doi: 10.1007/s00134-004-2467-2. Epub 2004 Dec 9.
citation: Cook D, Meade M, Guyatt G, Griffith L, Granton J, Geerts W, Crowther M; Canadian Critical Care Trials Group. Clinically important deep vein thrombosis in the intensive care unit: a survey of intensivists. Crit Care. 2004 Jun;8(3):R145-52. doi: 10.1186/cc2859. Epub 2004 May 6.
citation: Malinoski D, Jafari F, Ewing T, Ardary C, Conniff H, Baje M, Kong A, Lekawa ME, Dolich MO, Cinat ME, Barrios C, Hoyt DB. Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma. 2010 Apr;68(4):874-80. doi: 10.1097/TA.0b013e3181d32271.
citation: Malinoski D, Ewing T, Patel MS, Jafari F, Sloane B, Nguyen B, Barrios C, Kong A, Cinat M, Dolich M, Lekawa M, Hoyt DB. Risk factors for venous thromboembolism in critically ill trauma patients who cannot receive chemical prophylaxis. Injury. 2013 Jan;44(1):80-5. doi: 10.1016/j.injury.2011.10.006. Epub 2011 Nov 1.
citation: Van PY, Cho SD, Underwood SJ, Morris MS, Watters JM, Schreiber MA. Thrombelastography versus AntiFactor Xa levels in the assessment of prophylactic-dose enoxaparin in critically ill patients. J Trauma. 2009 Jun;66(6):1509-15; discussion 1515-7. doi: 10.1097/TA.0b013e3181a51e33.
citation: Klein SM, Slaughter TF, Vail PT, Ginsberg B, El-Moalem HE, Alexander R, D'Ercole F, Greengrass RA, Perumal TT, Welsby I, Gan TJ. Thromboelastography as a perioperative measure of anticoagulation resulting from low molecular weight heparin: a comparison with anti-Xa concentrations. Anesth Analg. 2000 Nov;91(5):1091-5. doi: 10.1097/00000539-200011000-00009.
citation: Schleyer AM, Schreuder AB, Jarman KM, Logerfo JP, Goss JR. Adherence to guideline-directed venous thromboembolism prophylaxis among medical and surgical inpatients at 33 academic medical centers in the United States. Am J Med Qual. 2011 May-Jun;26(3):174-80. doi: 10.1177/1062860610382289. Epub 2011 Apr 13.