A New Perspective on A New Perspective on Vascular Access Vascular Access

by Steve Chenby Steve Chen

Director of Nephrology, Shin-Chu Branch of Taipei Veterans General Hospital

Highlights in vascular accessHighlights in vascular access

First hemodialysis: 1924 by George Haas First vascular access: 1943 Quinton-Scribner shunt: 1960 Brescia-Cimino fistula: 1966 Synthetic polytetrafluoroethylene (PTFE) AVG:

1970s Permanent tunneled cuffed indwelling HD

catheter: 1980s Synthetic polyurethane AVG (Vectra): 1990s

Catheter

AVFAVG

Shunt

Access use at initiation of dialysisAccess use at initiation of dialysis

Access at initiation of HD for Access at initiation of HD for early referral early referral

Burdens in vascular access Burdens in vascular access Ivan D. Maya et al: AJKD 2008 (University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008 (University of Alabama at Birmingham)

>20% of dialysis patients hospitalizations: access related

Adjusted mortality: 40 ～ 70% greater for catheter > AV shunt

Fistula prevalence: USA < Europe/Japan75% of US patients initiate dialysis with a

catheter

Choices in vascular accessChoices in vascular accessIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Feature Fistula Graft Catheter

Primary failure rate % 20 ～ 50 10 ～ 20 <5

Time to 1st use (W) 4 ～ 12 2 ～ 3 Immediate

Need to intervene VL Mod H

Qb Excel Excel Mod

Thrombosis rate VL Mod H

Infection rate VL Mod VH

Longevity ～ 5Y ～ 2Y <1Y

Vascular access monitoringVascular access monitoringIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

PE: absent thrill, abnormal bruit, distal edema, pulsating swelling aneurysm (F) or pseudo-aneurysm (G)

Dialysis abnormality: difficult puncture, aspiration of clots, prolonged bleeding from needle site

Unexplained decrease in Kt/V

Vascular access surveillanceVascular access surveillanceIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Static dialysis venous pressure (DVP): Ratio of DVP to systolic BP > 0.5: inaccurate predictor

Access blood flow: < 600mL/min(G) or <400-500 mL/min(F)

A decrease in Qa > 33% from baseline Doppler ultrasound: peak systolic velocity (PSV)

ratio > 2/1 Dynamic DVP and recirculation: less useful Flow and change in flow(Qa and DVP) early in a

dialysis session by monthly flow surveillance: inaccurate predictor Sunanda et al: ALKD 52: 930-938, 2008 (N=176)

WD paulson et al: KI 81: 132-142, 2010

AVF

What is a successful fistula? What is a successful fistula?

Allon et al, KI 62: 1109-24, 2002Allon et al, KI 62: 1109-24, 2002Caliber large enoughBlood flow rate: access Qb > dialysis Qb by at least 100

ml/min to avoid vein collapse and re-circulation

mean dialysis Qb: 400 ml/M (USA) 300 ml/M(Europe) 200 ml/M(Japan)

Vein wall hypertrophy enough Superficial enough

How is a successful fistula? How is a successful fistula?

Allon et al, KI 62: 1109-24, 2002Allon et al, KI 62: 1109-24, 2002 Experience ( >12 procedures) of the surgeon Site of fistula:

primary failure rate: 66% in forearm; 41% upper arm

Pre-operative sonographic vascular mapping: age, DM, race, BMI

Hand exercise ? Anti-platelet agents for 3 ～ 6 W

Kaufman et a, Semin dial 13: 40-46, 2000

Pre-operative vascular mapping Pre-operative vascular mapping

Allon et al, KI 62: 1109-24, 2002Allon et al, KI 62: 1109-24, 2002 Mapping with ultrasonography or venography

Criteria for placement of a shunt: Minimum vein diameter: 0.25cm (AVF) Minimum vein diameter: 0.40cm (AVG) Minimum artery diameter: 0.20cm Draining vein or central vein: lack of stenosis, sclerosis, or

thrombosis A change of planned surgical procedure: 31% Order of preference of vascular access to be

placed: Distal F > Proximal F > Proximal transposed brachio-basilic F > Upper extremity G> Thigh G> Unusual G (Necklace, chest wall)

Assessment of fistula maturationAssessment of fistula maturation

Allon et al, KI 62: 1109-24, 2002Allon et al, KI 62: 1109-24, 2002Post-operative sonographic measurement at

2M: A: minimum vein diameter: >0.4cm

B: Access Qb> 500ml/min A or B: 70% A+B: 95% neither: 33%

Time interval for dialysis use: 2 ～ 4M

AF fistulas: primary failureAF fistulas: primary failureIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

High primary failure rate: 20 ～ 50% Steal syndrome: 1 ～ 4%

Post-operative ultrasound to evaluate maturation: 4 ～ 8 W after surgery

Ultrasound criteria for maturity: Fistula diameter 0.4cm ≧ Access flow 500mL/min ≧ Distance from skin 0.5cm≦

Primary failure rate : early thrombosis or failure to mature adequately (Juxta-anastomotic

stenosis/Large accessory veins/Excessively deep fistula)Primary survival ( intervention-free): time from

access placement to initial intervention Cumulative survival ( assisted ) : time from

access placement to permanent failurePrimary or cumulative survival at 1 year:

Oliver et al, KI 60: 1532-39, 2001 F > G: if primary failure excluded F = G: if primary failure included

Primary failure

Effect of clopidogrel on early Effect of clopidogrel on early failure of AVFs for HDfailure of AVFs for HD

Multicenter randomized controlled trial: N= 877 Clopidogrel: 300mg loading dose/75mg/D for 6 weeks

Inclusion criteria: upper extremity AVF/start HD within 6 M Primary outcome: unassisted AVF patency at 6W Secondary outcome: AVF dialysis suitability ( Use of AVF with 2

needles at Q-b >300 ml/min for 8 sessions this began 120 days after ≧ ≧AVF creation)

Clopidogrel group: 37% lower risk of thrombosis(RR 0.46 p=0.018); Forearm(RR 0.53); upper arm(RR 0.89)

A surprising high primary failure in both groups(61%/59%) →more than reducing early fistula thrombosis in required Dember LM et al: JAMA 299: 2164-71, 2008

Anti-platelet agents for fistula Anti-platelet agents for fistula

Study N Intervention/Duration Thrombosis (%) Intervention Control

Andrassy et al 92 Aspirin 500mg/D x 4W 4 23 1974

Grontoft et al 36 Ticlopidine 250mg/D x 4W 11 47 1985

Grontoft et al 260 Ticlopidine 250mg/D x 4W 12 19 1998

Dember et al 877 Clopidegrel 300mg/D(L) 12 19 2008 75mg/D x 6W

DOPPS: N= 2815: aspirin to reduce significantly lower risk of final AVF failure

AV fistulas: late failureAV fistulas: late failureIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Late fistula failure by stenosis 60% at venous outlet 25% at arterial anastomosis 5% at central vessels A large aneurysm, rarely

Thrombosed fistula requires thrombectomy with 48 Hr

Primary patency rate after: 27 ～ 81% at 6M; 18 ～ 70% at 12M

AVG: go faster!

AV grafts: graft failureAV grafts: graft failureIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Graft failure: ～ 80% thrombosis ～ 20% infection A large pseudo-aneurysm, rarely

Underlying stenosis in most thrombosed grafts: ～ 60% Venous anastomosis 15% venous outlet 10% central veins 10% intragraft 5% arterial anastomosis

AV grafts: graft failureAV grafts: graft failureIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Intervention-free patency after elective angioplasty: 70 ～ 85% at 3M; 20 ～ 40% at 12M

Intervention-free patency after thrombectomy: 33 ～ 63% at 3M; 10 ～ 39% at 6M

Stents may prolong patency in selected grafts: elastic lesion

No clear advantage of bovine or cadaveric human vein grafts over PTFE grafts

Polyurethane grafts (Vectra): can be cannulated within 24 Hr

Vascular access stenosis: VNHVascular access stenosis: VNHIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

VNH: venous neo-intimal hyperplasia (SMC + micro-F + microvessels)

Hemo-dynamic turbulence: an shear forces Dialysis needle injury Surgical vascular damage PTFE Uremia Vascular damage from angioplasty Expression of genes for cytokines Local anti-proliferative drug delivery system:

Human study in progress

Preventive strategy for VNHPreventive strategy for VNHStrategy Mechanism of action Used in AVF model

Mechanical design Tapered graft and pre-cuffed graft geometry at anastomosis Y Deculluarized xenograft elastic mismatch between graft/vessel Y

Biological reagents Antisense ODNs inhibit DNA transcription N Decoy(E2F) inhibit cell cycle progression Y Gene transfer VEGF promote endothelialization N C-type natriuretic peptide inhibit proliferation via cGMP Y Cell based therapy Endothelial progenitor cells promote endothelialization of graft surface Y Endothelial cell implant promote endothelial function Y

Small molecule drugs Rapamycin inhibit protein translation Y Paclitaxel inhibit mitosis by stabilizing microtubules Y Dypiridamole inhibit phosphodiesterase activity Y Imatinib inhibit PDGF receptor activity N

Irradiation induce DNA damage Y

ODN: antisense oligonucleotide Li Li Christi et al: KI 74 1247-61, 2008(University of Utah, USA)

Catheter: fastest!

26

So think twice…

Catheter-related bacteremia Catheter-related bacteremia (CRB) (CRB)

N Per 1000 catheter-days

GPC

Kairaitis

Bethard

Saad

Cuevas

105

387

101

189

6.5

3.4

5.5

1.54

100%

84.5%

67.4%

84%

Definition of CRBDefinition of CRB Public Health Agency of CanadaDefinite CRB diagnosis:

1> blood cultures from both catheter lumen and a peripheral vein grow the same organism 2>Colony count in catheter (C) ≧ 5～ 10X colony count in vein (V) or C V, ≧ 2 Hours earlier

False positive diagnosis: colonization if from only one lumen

Diagnosis of CRBDiagnosis of CRB

Probable CRB diagnosis: 2 positive blood ≧culture ( blood culture/catheter tip:+/- or -/+ ) + no evidence of a source of infection other than catheter

Possible CRB diagnosis: negative or single blood culture + no evidence of a source of infection other than catheter , but fever ↓after catheter removal

Catheter culture( positive ): CRB 63%

Catheter-related bacteremia (CRB)Catheter-related bacteremia (CRB)

Similar rates but different average timetunneled: 1/1000 catheter-days

non-tunneled: 1.54/1000 catheter-days (p=0.98) Cuevas et al, JASN 1999

tunneled: 66.2 days non-tunneled: 20.6 days

35% of patients within 3 months48% of patients within 6 months

Risk factors for CRBRisk factors for CRB

Femoral route Duration of catheter use ( FVC: 5D; JVC: 3 ～ 4W) Nasal/skin colonization with S.A. Poor personal hygiene:

Povidone-iodine/Mupirocin over exit site of catheter

Use of occlusive transparent dressing DM Immuno-suppression Low albumin; high ferritin

Complications of bacteremiaComplications of bacteremia

Mortality: 8 ～ 25% Recurrence: 14.5 ～ 44% Endocarditis: mortality 30% Epidural abscess Purulent pericarditis Septic arthritis or osteomyelitis Septic pulmonary emboli Liver abscess Endopthalmitis

Use rate of HD permanent catheter < 10% NKF-K/DOQI guidelines

CQI process to reduce catheter rates in CQI process to reduce catheter rates in incident patients: a call to action incident patients: a call to action

1. Discuss with referral sources about criteria for referral: GFR≦ 30 ml/min2. Refer patients and family to educational classes about treatment options that should include PD, transplantation, etc: GFR ≦ 20 ml/min3.Explicitly discuss with patients and family the need for a permanent access at a GFR ≦ 20 ml/min4.Track success of surgical outcomes by surgeon Refer back to surgeon in 6-8 weeks if fistula is not maturing 5.Provide full disclosure of catheter related risks to patients and family who refuse surgery for permanent access6.Weaning of a medi-alert bracelet to protect one arm from veni-puncture 7.Classify requests to hospitals for access placement as urgent

RM Hakim et al: K 76: 1040-1048, 2009

Prophylaxis of CRBProphylaxis of CRB

Nasal mupirocin or 5-D course of oral RIF/3M: S.A. carrier (50% in HD )who have a previous catheter-related bacteremia caused by S.A. and continue to need HD catheter ongoing by IDSA: Infectious Diseases Society of America

Prophylaxis of exit site colonization by mupirocin or polysporin( Bacitracin+gramicidin+polymyxin B) ointment at exit site

Lock therapy: GM/Citrate; Taurolidine/Citrate

Vancomycin plus Gentamicin in febrile HDVancomycin plus Gentamicin in febrile HD Life-threatening infection by β-lactam resistant

GPC or MRSA GPC infection+ serious allergy to β-lactam

antibiotics Antibiotic-associated colitis unresponsive to

Metronidazole or that is life-threatening Prophylaxis of endocarditis in high-risk Patients:

Presence of central venous dialysis catheter Alternative: Vancomycin plus 3rd cephalosporin Rationale: mixed bacteremia 9.8 ～ 12.2%

Clinical approach to (tunneled) CRBClinical approach to (tunneled) CRBIvan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)Ivan D. Maya et al: AJKD 2008(University of Alabama at Birmingham)

Vancomycin/Ceftazidime or GM/Antibiotic lock

Negative cultureX 5D

Positive cultureFever resolve in 2-3D

Positive cultureFever persists

Stop

CNS GNB CPS CandidaCatheter(-)

ECHOMetastatic

Workup: bone Anti Duration

6-8W

Catheter(+)Keep lockAnti: 3W

Guidewire exchange

Catheter(-)Anti: 3WConsider

ECHO/bone scan

Catheter(-)Fluconazole

2W

Catheter removal ?Catheter removal ?

Non-cuffed Cuffed

Exit site infection Yes No

Tunnel infection Yes Yes

Catheter-related bacteremia(CRB)

Yes S.A.: Yes

CNS: No ?

Enterococcus: Yes

Antibiotic dosing in HD patients Antibiotic dosing in HD patients

Systemic antibiotics

Vancomycin 20mg/Kg loading during last one hour ; 500 mg TIW Gentamicin 1mg/Kg (maximum <100mg) TIWCeftazidime 1G TIWCefazolin 20mg/Kg TIWDaptomycin 6mg/Kg TIW

Antibiotic lock: volume of solution(ml)

Vancomycin/Ceftazidime /Heparin: 1.0 /0.5/0.5 Vancomycin/Heparin: 1.0/1.0Ceftazidime/Heparin: 1.0/1.0Cefazolin/Heparin: 1.0/1.0

Tunnel infection Tunnel infection CDC guideline:

Erythema, tenderness, and induration in tissues overlying the catheter + > 2cm from the exit site

Public Health Agency of Canada: Definite: 1> Purulent discharge from tunnel 2> Erythema, tenderness, induration(2/3) at tunnel with a positive culture from serous discharge Probable: Erythema, tenderness, induration(2/3) at tunnel with serous discharge, but negative culture /no discharge, but lack of alternative Possible: Erythema, tenderness, induration(2/3) at tunnel , but alternative cause cannot be ruled out

Careful observation needed for tunnel infection !

Exit site infectionExit site infection CDC guideline:

Erythema, tenderness, and induration or purulence in tissues overlying the catheter within 2cm from the exit site

Public Health Agency of Canada: Definite: 1> Purulent discharge at exit site 2> Erythema, tenderness, induration(2/3) at exit site with a positive culture from serous discharge Probable: Erythema, tenderness, induration(2/3) at exit site with serous discharge, but negative culture /no discharge, but lack of alternative Possible: Erythema, tenderness, induration(2/3) at exit site , but alternative cause cannot be ruled out

Watch out the signs of AVG infection!

AVG infectionAVG infection

30-day infection rate: 6% Risk factors:

femoral route poor hygiene repetitive cannulations perigraft hematoma formation prolonged postdialysis bleeding from graft repeat surgical revisions HIV status(30%), DM, low albumin, high ferritin transient bacteremia from distal site or CRB

AVG infection: S/SAVG infection: S/S

Local pain, irritation, tendernessRedness, warmthDiffuse or local swelling Skin breakdownSerous or purulent discharge Leukocytosis, fever

Sub-clavian vein obstructionSub-clavian vein obstruction

CVC placed for > 2 ～ 3 weeks:

40 ～ 50% If infected:

75% PTA+/- stentVeno-venous bypass surgeryAccess ligantion

Antibiotic-heparin lock therapyAntibiotic-heparin lock therapy

If Vancomycin: 2.0 mg/ml; Ceftazidime: 2.0 mg/ml plus heparin 5000IU/ml, each concentration > 100µg/ml will persist > 21 days.

Cefazolin, Vancomycin: 10mg/ml; Ceftazidime, Ciprofloxacin: 10mg/ml; Gentamycin: 5mg/ml

No benefit to UK instillation as an adjunct to antibiotic lock

Antibiotic lock: indications Antibiotic lock: indications

Catheter retained during an episode of catheter-related bacteremia O’Grady et al, MMWR Morb Mortal Wkly Rep 51: 1-29, 2002

History of multiple catheter-related bacterremias despite optimal aseptic technique Mernet et al, Clinical Infect Dis 32: 1249-72, 2001

Antibiotic lock: pathogenAntibiotic lock: pathogenAllon et al, NDT 2004Allon et al, NDT 2004

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

GNB CNS SA

Positive surv cx

Persistent fever

Success

Ideal lock solution for prophylaxis Ideal lock solution for prophylaxis

Prophylaxis of bio-film formation → CRB↓1> Cidal activity against a broad spectrum of

GPC/GNB/Fungi 2> Low likelihood of promoting antibiotic resistant bacteria 3> Compatible with catheter material and anticoagulant agent 4> Safe if inadvertently instilled systemically

Potential antimicrobial lock solutionsPotential antimicrobial lock solutionsMichael Allon: AJKD 44: 2004Michael Allon: AJKD 44: 2004

1st 2nd 3rd 4th

殺菌 低阻 質合 安全GM 40mg/dl /Citrate OK No OK OK

30% Citrate OK OK OK OK

70% Isopropyl alcohol OK OK OK No

Taurolidine OK OK OK No

CRB prevalence: per 1000 daysCRB prevalence: per 1000 days

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Dogra Mcintyre Kim Nori Saxena

Heparin lock

Antimicrobial lock

CRB prevalence: per 1000 daysCRB prevalence: per 1000 days

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Betjes Weijmer

Taurolidine

30% Citrate

Antibiotic lock: barriersAntibiotic lock: barriers

All randomized trials: F-U for < 6M Selection of antibiotic resistant infection if longer use

Systemic toxicity from leaks into circulation 10-fold lower concentration of GM: 4 ～ 5 mg/mL

Economic FDA not approved