Norwegian Intensive Care Unit Dalteparin Effect Study

Acute Kidney Injury Clinical Trial

— NORIDES  

Official title:

Norwegian Intensive Care Unit Dalteparin Effect Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01721928
• Other study ID #: 2012/942
• Secondary ID: UiO
• Status: Completed
• Phase: N/A
• First received: October 26, 2012
• Last updated: December 11, 2017
• Start date: December 3, 2012
• Est. completion date: March 1, 2017

Study information

• Verified date: December 2017
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: March 1, 2017
• Est. primary completion date: June 2, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Kidney Injury
• Deep Venous Thrombosis
• Thrombosis
• Venous Thrombosis

Intervention

Device:
• Continuous venovenous hemodialysis
Continuous venovenous hemodialysis

Locations

Country	Name	City	State
Norway	Oslo University Hospital	Oslo

Sponsors (2)

Lead Sponsor	Collaborator
Oslo University Hospital	University of Oslo

Country where clinical trial is conducted

Norway, 

References & Publications (29)

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. Review. — View 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. Review. — View 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. Epub 2004 May 6. — View 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. — View 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. — View 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. Review. — View 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. — View 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. — View 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. Epub 2004 Dec 9. — View 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. Review. — View 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. — View 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. Review. — View 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. Review. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in ICU patients. Chest. 1997 Mar;111(3):661-4. — View 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. Review. — View 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. — View 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. — View 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. Review. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Which of the blood sample analyses anti-Xa activity, TEG or TGA is superior in detecting critically ill patients who will subsequently develop DVT?	The blood sample analyses anti-Xa activity, TEG and TGA will be analysed, and their ability to detect critically ill patients who will subsequently develop DVT. Different patients with and without AKI will be compared. Samples from the same patients one day with and one day without dialysis therapy will also be compared.	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.
Other	Which factors affect heparin effect in critically ill patients?	The following factors will be assessed: Presence of AKI, dialysis therapy, Body mass index (BMI), gender, high severity of illness, use of vasopressors, presence of oedema and serum antithrombin concentrations.	During ICU stay until LOS 30 days or discharge from ICU
Other	What is the incidence of DVT and bleeding in ICU patients with and without CiCa-dialysis therapy, and is it correlated to heparin effect?	Compare the incidence of DVT and bleeding among ICU patients with and without CiCa-dialysis. Investigate if patient with bleeding have different anti-Xa activity levels, TGA and TEG than patients without bleeding, and if patients with DVT have different anti-Xa activity levels, TGA and TEG compared to patients without DVT.	During ICU stay until LOS 30 days or discharge from ICU
Other	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?	Blood flow to the kidneys measured as renal perfusion index during contrast enhanced DUS will be compared in selected ICU patients with and without CRRT.	During ICU stay until LOS 30 days or discharge from ICU
Other	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®?	Blood flow to the kidneys measured as renal perfusion index during contrast enhanced DUS will be compared with global perfusion measured as cardiac index using a pulse contour analysis device (PICCO®).	During ICU stay until LOS 30 days or discharge from ICU
Other	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?	NMR spectroscopy of urine in ICU patients with and without AKI necessitating CRRT will be compared, and levels in the same patients with and without dialysis therapy. Further, NMR spectroscopy of urine in the same patient with and without dialysis therapy will be compared.	During ICU stay until LOS 30 days or discharge from ICU
Other	Which bedside method is superior in predicting dialysis circuit clotting?	Collect data on filter clotting. Evaluate the predictive value of different bedside methods clinically used to forecast filter clotting: Post filter ionised calcium, heparin-active R-time during TEG, access pressure, filter pressure, return pressure and visual inspection of the dialysis circuit air trap.	During ICU stay until LOS 30 days or discharge from ICU
Other	Which factors affects filter lifetime during CiCa-dialysis?	Collect data on filter lifetime during CiCa-dialysis therapy and investigate if there is a correlation between measured filter lifetime and the following factors: Heparin effect, antithrombin levels, post filter ionised calcium, NMR spectroscopy of urine, clinical assessment of clotting as well as anatomical placement of the dialysis catheter.	During ICU stay until LOS 30 days or discharge from ICU
Other	Which risk factors for DVT are present in an ICU population and what is the contribution of each factor in development of DVT?	Prospective collection of data on risk factor for DVT in an ICU population according to international guidelines. Also screening for DVT in an ICU population using DUS. Thereafter we plan to perform an analysis on the contribution of each risk factor and combinations of risk factors on development of DVT, with special attention towards possible avoidable risk factors.	During ICU stay until LOS 30 days or discharge from ICU
Other	Is the presence of DVT in ICU patients influenced by the anatomical placement of catheters such as central venous catheters (CVCs) and dialysis catheters?	Compare the incidence of catheter related DVT if CVC and dialysis catheters are placed in the femoral, subclavian and internal jugular veins.	During ICU stay until LOS 30 days or discharge from ICU
Other	Does the presence of DVT influence the prognosis in ICU patients?	To compare preset prognostic markers for morbidity (ICU and hospital length of stay in addition to time on ventilator and dialysis therapy) and mortality (ICU mortality and 30 days mortality) in patients with and without presence of DVT.	Data will be collected during ICU stay until LOS 30 days or discharge from ICU. Mortality will also be assessed after ICU discharge.
Other	Does metabolic alkalosis due to CiCa-dialysis therapy lead to prolonged ventilator therapy?	To compare arterial blood gases in ICU patients with and without CiCa-dialysis and evaluate if patients treated with dialysis more often have metabolic alkalosis. Further, to study whether there is an association between presence of metabolic alkalosis and time spent on ventilator therapy.	During ICU stay until LOS 30 days or discharge from ICU
Other	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?	To compare occurrence of DVT and its correlation to compliance to clinical practice guidelines for DVT prophylaxis, including pharmacological and non-pharmacological prophylaxis.	During ICU stay until LOS 30 days or discharge from ICU
Other	What is the occurrence of DVT 3 months after ICU discharge?	To find the occurrence of DVT in critically ill patients 3 months after ICU discharge. Survivors who did not develop DVT during ICU stay will be screened for DVT after 3 months using DUS examination.	Patients will be screened for DVT 3 months after ICU discharge.
Other	Future blood and urine analyses of ICU patients with and without AKI and dialysis therapy.	To compare blood and urine samples from critically ill patients with and without AKI and dialysis therapy. The blood and urin samples can be stored for maximum 10 years. The plan is to use new, yet not known analysis methods, and test their utility when assessing ICU patients with and without AKI and dialysis therapy.	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.
Primary	The primary endpoint is development of deep venous thrombosis (DVT)	Screening for DVT using 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.	Twice a week until ICU LOS 30 days or discharge from ICU
Secondary	The secondary endpoint is inadequate 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, TGA and TEG) and other haematological analyses including antithrombin concentrations. Whole blood will be drawn on two separate days 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 CRRT.	Blood samples is drawn 4 times during ICU stay, from minimum day 2 to maximum day 30 dependent on the dialysis therapy