Slide 1. Slide 2 Disclosures. Slide 3 Learning Objectives. Catheter-Related Thrombosis and Infection: Reducing Controllable Risk Factors

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1 Slide 1 Catheter-Related Thrombosis and Infection: Reducing Controllable Risk Factors Thomas P. Nifong, MD Vice President, Clinical Operations Metamark Genetics, Inc Cambridge, Massachusetts USA Slide 2 Disclosures 1. Dr. Nifong has received honoraria and consulting fees from Teleflex 2. Dr. Nifong has received honoraria from AngioDynamics 2 Slide 3 Learning Objectives 1. Understand the basic pathophysiology and clinical significance of upper extremity thrombosis. 2. Recall the controllable risk factors associated with catheterrelated thrombosis. 3. Explain how thrombosis and infection interact in central venous catheters 4. Know how new technologies will play a role in reducing catheter-related complications. 3

2 Slide 4 Venous Thromboembolism Incidence of UE-DVT (1-2% that of LE) Primary UE-DVT due to stress or ideopathic is rare: 2 per 100,000 Secondary UE-DVT was previously considered to be rare, but is now not uncommon in hospitalized patients 4 Slide 5 Hemostasis Coagulation system Activated clotting factors & cofactors Thrombin generation Anticoagulant system Coagulation inhibitors & cofactors Thrombin inhibition Blood clot Fibrinolytic system 5 Slide 6 Pathogenesis of Thrombosis Rudolph Virchow STASIS VTE Risk Factors: PC, PS, AT Deficiency Factor V Leiden Prothrombin G20210A VASCULAR INJURY CAD Risk Factors: Hyperlipidemia HYPERCOAG- ULABILITY Tobacco Diabetes 6 Hypertension Family history

3 Slide 7 Prophylaxis in Cancer Carrier M, et al. Thromboprophylaxis for catheter-related thrombosis in patients with cancer: a systematic review of the randomized, controlled trials. J Thromb Haemost 2007; 5: Clinicians are recommended to NOT use either prophylactic doses of LMWH (Grade 1B) or mini-dose warfarin (Grade 1B) to try to prevent catheter-related thrombosis for cancer patients receiving chemotherapy or hormonal therapy or with indwelling central venous catheters. Hirsh J, Guyatt G,Albers GW, Harrington R, and Schunemann HJ. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 Jun;133:71S- 109S. 7 Slide 8 Catheters and Thrombosis: Controllable Risk Factor Insertion site Femoral vein vs. Subclavian vein vs. Internal Jugular vein vs. PICC Catheter type, size, tip location Endothelial damage Traumatic insertion Tip location Catheter size and rigidity Venous stasis Catheter size relative to vein size Catheter material 8 Slide 9 9 CVC-related Thrombosis Study Type Detection Thrombosis Cimochowski Schillinger Wilkin Trerotola Merrer Timsit Prospective (acute HD) Prospective (acute HD) Asymptomatic Venogram IJ: 0% SC: 50% Asymptomatic Venogram IJ: 10% SC: 42% Prospective Asymptomatic Doppler US IJ: 25.9% (longitudinal HD) Retrospective (tunneled) Prospective Randomized (ICU) Prospective (ICU) Symptomatic Clinical with US or venogram IJ: 3% SC: 13% Asymptomatic Doppler US Femoral: 21.5% SC:1.9% Asymptomatic Doppler US IJ: 41.7% SC: 10.5%

4 Slide 10 PICC-related Thrombosis Study Type Detection Thrombosis Ng Prospective Symptomatic Clinical with US 1.6% confirmation Ultrasound Grove Retrospective Presumed 3.9% Symptomatic Chemaly Retrospective Presumed US or Venogram 2.5% Symptomatic King Retrospective Symptomatic Clinical with US 2.0% confirmation Clinical with Lobo Retrospective Symptomatic US 4.9% confirmation DVT or PE Cowl Prospective Symptomatic Clinical with US 7.8% confirmation (PICC vs. SC) Gonsalves Retrospective Asymptomatic US central veins 7.0% only Abdullah Prospective Asymptomatic Venogram 38.5% Allen Retrospective Asymptomatic Venogram 23.3% 10 Slide 11 PICC-related symptomatic SVT versus DVT Liem TK et al: Peripherally inserted central catheter usage patterns and associated symptomatic upper extremity venous thrombosis. J Vasc Surg; 2012 Retrospective study: All UE venous duplex scans during a 12- month period were reviewed, selecting patients with isolated SVT (219) or DVT (154) and PICCs placed 30 days (2,056) Results: Rates for PICC-SVT (44) were 1.9% for basilic, 7.2% for cephalic, and 0% for brachial vein PICCs Rates for PICC-DVT (54) were 3.1% for basilic, 0% for cephalic, and 2.2% for brachial vein PICCs 11 Slide 12 Laterality of PICC line placement Sperry BW, Roskos M, Oskoui R: The effect of laterality on venous thromboembolism formation after peripherally inserted central catheter placement. J Vasc Access; 2012 Jan-Mar;13(1):91-5 Retrospective study of 798 PICC placements (568 right-sided and 230 left-sided placement Results: VTE rate right-sided: 1.23% vs left-sided: 1.30% Marnejon T, Angelo D, Abu Abdou A, Gemmel D: Risk factors for upper extremity venous thrombosis associated with peripherally inserted central venous catheters. J Vasc Access; 2012 Apr-Jun;13(2):231-8 Retrospective study of 400 consecutive patients with PICC placements Results: Left-sided PICC line sites posed a greater risk (P=.026) 12

5 Slide 13 Is Upper Extremity Thrombosis Clinically Important? 13 Copyright. Gray's Anatomy of the Human Body Slide 14 Study Patients Findings Monreal et al. Thrombosis and Haemostasis Lobo B, et al. Journal of Hospital Medicine 2009 Fletcher, et al. Neurocrit Care 2011 Ong B, et al. Australasian Radiology patients with PICC or SC catheter-related DVT 777 patients with PICC lines (38 patients with VTE) 479 PICC lines placed in neuro ICU (39 patients with DVT) 76 patients with PICCrelated DVT VQ scan showed PE in 15.3% Symptomatic PE in 1% of patients Symptomatic PE in 1.3% of patients (15% of patients with DVT) Post-thrombotic sequelae w/25% mild pain, 2% moderate pain, 15% arm edema Slide 15 Treatment Conservative management along with catheter removal appropriate for basilic, brachial, and cephalic vein thrombosis Recurrence or extension may warrant anticoagulation Catheter removal may lead to PE Axillary vein and above requires anticoagulation (3-6 months). Recommended to NOT remove catheter if it is still functional and needed Initiate with UFH, LMWH, or fondaparinux then maintain with warfarin (INR 2-3) or LMWH Thrombolysis is generally NOT recommended but may be indicated for healthy patients (low risk of bleeding) with primary UEDVT with severe symptoms when appropriate expertise is available Surgical intervention is generally NOT recommended but may be indicated for patients with primary UEDVT who fail above therapy Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th 15 Edition). Chest 2008 Jun;133(6 Suppl):454S-545S.

6 Slide 16 Risk of Anticoagulation for DVT Major bleeding risk with warfarin for deep vein thrombosis Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism. Ann Intern Med 2003; 139: ,422 patients who received warfarin for more than 3 months Approximately 1 in 45 (2.2%) will experience a major bleeding episode Approximately 13% of these patients will die from the bleeding 16 Slide 17 Relationship Between Clot & Infection Stillman et al. Etiology of Catheter-associated sepsis: correlation with thrombogenicity. Arch Surg CVC were evaluated after removal 17 Slide 18 Relationship Between Clot & Infection Timsit et al. CVC-related thrombosis in ICU patients. CHEST IJ or SC catheters were analyzed Event Thrombosis No Thrombosis Significant CVC colonization 32% 19.4% CRS 19% 7% CR-septicemia 11.6% 3.6% Eastman et al. Central Venous Device-Related Infection and Thrombosis in Patients Treated with Moderate Dose Continuous-Infusion Interleukin-2. Cancer IJ or SC tunnelled catheters were analyzed Characteristic No. with CRBSI P value Device-related thrombosis Yes 8 (31%) <0.01 No 13 (10%)

7 Slide 19 Catheters and Thrombosis: Controllable Risk Factor Insertion site Femoral vein vs. Subclavian vein vs. Internal Jugular vein vs. PICC Catheter type, size, tip location Endothelial damage Traumatic insertion Tip location Catheter size and rigidity Venous stasis Catheter size relative to vein size Catheter material 19 Slide 20 Insertion Trauma Thrombosis Previous catheter and number of insertion attempts likely indicate endothelial damage: Odds ratio of 5.5 when 2 insertion Odds ratio of 3.8 with previous central catheter Agnes Y.Y. Lee et al. Incidence, Risk Factors, and Outcomes of Catheter-Related Thrombosis in Adult Patients With Cancer. Journal of Clinical Oncology Slide 21 Tip location Proximal tip may cause endothelial damage Luciani et al. CR UEDVT in Cancer Patients. Radiology patients with oropharyngeal CA with implantable CVC Tip confirmed with CXR then with monthly Doppler US Tip location divided into five segments 21 5% 8% 71% 42% 29%

8 Slide 22 Tip location Study Patients Thrombosis Kearns et al. JPEN patients with PICC; Central tip 16% central tip = in SVC Non-central 61% Grove & Pevec. JVIR 2000 Tesselaar et al. European J of Cancer PICC lines; symptomatic DVT 243 patients with implantable ports; symptomatic DVT Central tip 3.6% Non-central 9.3% 2.7x higher in SVC versus RA Lobo et al. Journal of Hospital Medicine PICC lines; symptomatic DVT/PE Non-central tip: OR 2.43 (95% CI ) 22 Slide 23 Stasis 23 Nifong TP, McDevitt TJ. The effect of catheter to vein ratio on blood flow rates in central venous catheters. CHEST. 2011;140(1):48-53 Slide 24 What does this mean clinically? Eastridge & Lefore J Clin Onc 1995 Trerotola SO, et al. Radiology Hickman catheters placed 279 SC and IJ tunneled catheters (Retrospective) Symptomatic DVT 10 Fr: 7.0% 12.5 Fr: 21% Symptomatic DVT Fr: 5.0% Fr: 12.7% p=0.027 Grove & Pevec. JVIR PICC lines (Retrospective) Symptomatic DVT 3 Fr: 0% 4 Fr: 1.0% p= Fr: 6.6% 6 Fr: 9.8% p= Allen et al. JVIR 2000 Trerotola et al Radiology 2010 Evans et al CHEST PICC lines Asymptomatic Cephalic: 57% (Retrospective) DVT Brachial: 10% Basilic: 14% 50 TLP (167 planned Symptomatic 20% 6 Fr tapered) in Total (A+S) 58%(27% extensive) Brachial or Basilic 2,014 PICCs in 1,879 Symptomatic DVT 4 Fr: 0.8% patients (Prospective) 5 Fr: 2.9% 6 Fr: 8.8%

9 Slide 25 What does this mean clinically? Evans et al. Risk of symptomatic DVT associated with peripherally inserted central catheters. CHEST Slide 26 Catheters and Thrombosis: Controllable Risk Factor Insertion site Femoral >> PICC > Subclavian vein Internal Jugular (lowest for HD) Catheter type, size, tip location Endothelial damage Traumatic insertion ( 2 attempts) Tip location (non-central >> atrial-caval junction) Catheter size and rigidity (large > small) Venous stasis Catheter size relative to vein size Catheter material 26 Slide Prevent Central Venous Catheter Infections (CR-BSI) 5 key components proposed by IHI-100K Hand hygiene Maximal barrier precautions Chlorhexidine skin antisepsis Optimal catheter site selection Daily review of line necessity + 4 interventions recommended by EPIC 2 Education of healthcare workers and patients Selection of catheter: lumens, tunnel, coated Catheter and site care General principles for catheter management + CVC insertion checklists Berenholtz Pronovost

10 Slide 28 Pronovost 2010 Prevent Central Venous Catheter Infections/CRI 5 key components proposed by IHI-100K Hand hygiene Maximal barrier precautions Chlorhexidine skin antisepsis Optimal catheter site selection Daily review of line necessity 28 BMJ 2010;340:c309 doi: /bmj.c309 Slide 29 Guidelines alone will not do the job Pratt, June 2010 WoCoVa Poor standards Wide variation in hospital practice Variable quality of practice Culture: 1. Do you have a champion at your hospital? 2. Do you have external drivers? 3. Do you track and report outcomes to all stakeholders? 4. Are team members empowered to stop a procedure if sterility is breached? 3-4X higher than U.S. 29 Slide 30 Pathogenesis of CRBSI 30

11 Slide 31 Our Goal 31 Slide 32 Infection Protection Technologies Evidence based recommendation by: Intervention Chlorhexidine Maximal Antimicrobial Antimicrobial Skin prep Barrier Dressing Catheter Source of Insertion (Biopatch TM, ) Transmission (e.g. AGB+ TM ) Environmental Yes Yes No No Contamination Skin Flora Yes Yes Yes No Subcutanous No No No Yes Tract (post placement) Hub/Intraluminal No No No Yes Hematogenous No No No Yes Seeding insertion procedure in situ 32 Slide 33 Multiple Strategies to Interrupt Infections Maximal Sterile Barrier Cap, mask, gown, gloves, drape Effective Prepping CHG/IPA Care and maintenance Education, hand hygiene, catheter & site selection, swabbing Dressings and Locks CHG Dressings & Add-on devices, dressing changes, Lock/flush solutions 33

12 % Reduction CRBSI Slide 34 Target zero: Support best practices Level 1 Level 2 Level 3 basic optimization new technology 34 Modified from Pittet D. Slide 35 The Catheter s Role in Interrupting Pathogenesis Additional Technologies Add layer of risk reduction Compliment other bundle layers Last layer of defense: Lapses in technique Compliance-fatigue Not implementing evidence-based practices Antimicrobial Catheters Designed to protect areas other bundle layers can t touch Subcutaneous tract Internal lumen Antimicrobial Catheter 35 Hematogenous Seeding Slide 36 CDC 2011 Category 1A recommendation Recommendation: use chlorhexidine/silver sulfadiazine or minocycline/rifampin impregnated CVC in patients whose catheter is expected to remain in place > 5 days if CLABSI has not been reduced by a comprehensive strategy: Educating persons who insert and care for catheters Use of maximal sterile barriers Use of a >0.5% chlorhexidine prep with alcohol for skin antisepsis during insertion Decision to use chlorhexidine/silver sulfadiazine or minocycline/rifampin impregnated CVC should be based on the need to reduce CLABSI rates, balanced against the concern for the emergence of resistant pathogens and the cost if implementing the strategy 36

13 Ultrasound, magnetics, EKG Slide 37 Catheters and Thrombosis: Controllable Risk Factor Insertion site Femoral >> PICC > Subclavian vein Internal Jugular (lowest for HD) Catheter type, size, tip location Endothelial damage Traumatic insertion ( 2 attempts) Tip location (non-central >> atrial-caval junction) Catheter size and rigidity (large > small) Venous stasis Catheter size relative to vein size Catheter material 37 Slide 38 Platelet Adhesion and Aggregation Vessel Wall Fibrinogen (GPIIbIIIa) Platelet Phospholipid Exterior Interior vwf (GPIb) Subendothelium 38 Slide 39 Central Venous Catheters Catheters provide a thrombogenic surface > Fibrin Sheath Endothelial damage Venous stasis STASIS VASCULAR INJURY 39

14 Slide 40 Fibrin Sheath Hoshal et al. Fibrin sleeve formation on indwelling subclavian CVC. Arch Surg subclavian veins with CVCs dissected at autopsy 100% had a fibrin sheath Materials: polyethylene, Teflon, nylon, siliconized rubber Raad et al JAMA 271(13) Additional radiographic studies show rates of 80-90% Sheath likely forms in first 24 hours Propagation of fibrin sheath originates from intimal injury at point of entry and at catheter tip 40 Slide 41 Catheter Materials Silicone Catheters: Medical grade silicone rubber has traditionally been considered the gold-standard for long-term vascular access in animals and humans. Its properties include: High biocompatibility Relatively non-thrombogenic Flexible Soft Polyurethane: Currently the material of choice. Its properties include: High biocompatibility Relatively non-thrombogenic Easier to insert sufficiently stiff but then softens in body Larger internal diameter compared to same silicone French size Increased flow rate due to increased lumen diameter 41 Slide 42 Platelet Adhesion and Aggregation Vessel Wall Fibrinogen (GPIIbIIIa) Platelet Phospholipid Exterior Interior 42 Thrombogenic surface

15 Slide 43 XI XII (Intrinsic Pathway) Acceleration XIa IX (Extrinsic Pathway) Initiation Tissue Injury Tissue Factor THE COAGULATION CASCADE IXa / VIIIa X Xa / Va X VIIa Crosslinked Fibrin XIIIa II Prothrombin Fibrin IIa Thrombin Fibrinogen 43 Slide 44 Pathogenesis of CR-DVT CR-DVT INSERTION TRAUMA ONGOING STASIS Thrombosis TIP LOCATION UNDERLYING HYPERCOAGULABILITY PLATELET ADHESION (ENDOTHELIUM & CATHETER) 44 Slide 45 Antithrombotic Materials: Current and Future Cook Medical: Heparin coating used to help prevent thrombus formation upon insertion Theoretical risk of HIT R4 Vascular: Biometric coating that resembles glycocalyx of healthy endothelial cells Claim: decrease intraluminal occlusion Teleflex: ArrowEVOLUTION with Chlorag+ard PENDING CLAIM (510K filed): antithrombogenic effect Navilyst: BioFlo products PENDING CLAIM (510K filed): minimizes the accumulation of thrombus in vascular products Semprus Biosciences: Covalent bonding of non-leaching material that simulates endothelial cell membrane; pre-clinical 45

16 Slide 46 Pathogenesis of CRBSI INFECTION INFECTIOUS AGENT SUSCEPTIBLE HOST CHAIN OF INFECTION PORTAL OF ENTRY ATTACHMENT and COLONIZATION 46 Meakins JL, Masterson BJ. Prevention of postoperative infection. ACS Surgery Slide 47 Coated Catheters Carrasco et al. Evaluation of a triple-lumen CV heparin-coated catheter versus a catheter coated with chlorhexidine and silver sulfadiazide in critically ill patients. Int Care Med patients (260 catheters) randomized to receive either CVC Heparin coated (132 catheters): Colonization 23.5/1,000 catheter days CR-BSI 3.2/1,000 catheter days CSS Colonization 11.5/1,000 catheter days CR-BSI 2.6/1,000 catheter day 47 Slide 48 Summary Key Points > CR-BSI and CR-thrombosis are both significant complications of central venous access > Prevention is the Goal > Technology-driven solutions are required to further reduce the risk to patients > Right Care, Right Now (for the) Right Patient > Make a Business case issue for Hospital Administrators > Quality Care with Improved Outcomes 48

17 Slide 49 Thank you for your attention!