Mathematical model demonstrates influence of luminal diameters on venous pressure surveillance.

BACKGROUND: The reliability of dialysis venous pressure (VP) in detecting stenosis is controversial. A mathematical model may help to resolve the controversy by providing insight into the factors that influence static VP. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study used inflow artery and outflow vein luminal diameters from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model, and how they affect the relation among VP, mean arterial pressure (MAP), blood flow, and stenosis was determined. Whether VP/MAP is a valid adjustment for the influence of MAP on VP, and whether the standard VP/MAP referral threshold of 0.50 is valid, were also determined. RESULTS: It was found that there is an approximate one-to-one relation between MAP and VP, so VP/MAP is a valid adjustment. Also, the 0.50 threshold successfully identifies most grafts with stenosis of 65% or more. However, the ratio of artery/vein diameters varied widely between patients, and the ratio independently influences VP/MAP. When the inflow artery is relatively narrow, the VP/MAP increase is delayed followed by a more rapid increase as critical stenosis is reached. CONCLUSIONS: VP/MAP is a valid adjustment for the influence of MAP on VP, and the standard VP/MAP threshold of 0.50 warns of the transition to critical stenosis. However, relatively narrow arteries cause a delay followed by a rapid increase in VP/MAP that may not be detected before thrombosis unless measurements are very frequent. Clinical trials that emphasize trend analysis with frequent measurements are needed to evaluate the efficacy of VP surveillance.

Effect of change in vascular access on patient mortality in hemodialysis patients.

BACKGROUND: Hemodialysis patients using a catheter have a greater mortality risk than those using an arteriovenous (AV) access (fistula or graft). However, catheter-dependent patients also differ from those with an AV access in several clinical features, and these differences may themselves contribute to their excess mortality. METHODS: The current study evaluates whether a change in vascular access affects risk for mortality in patients enrolled in the Hemodialysis Study. Time-dependent Cox regression was used to relate mortality risk to current type of access and change in access type during the preceding 1 year. RESULTS: Compared with patients who dialyzed using an AV access at both the beginning and end of the preceding 1-year interval, relative risks for mortality were 3.43 (95% confidence interval [CI], 2.42 to 4.86) in patients who dialyzed with a catheter at both times; 2.38 (95% CI, 1.76 to 3.23) in patients switching from an AV access to a catheter, and 1.37 (95% CI, 0.81 to 2.32) in patients switching from a catheter to an AV access. Change from AV access to a catheter was associated with an antecedent decrease in serum albumin level (odds ratio, 1.25; 95% CI, 1.09 to 1.45 per 0.5 g/dL; P = 0.002), weight loss (odds ratio, 1.14; 95% CI, 1.06 to 1.22 per 2 kg; P < 0.001), and decreases in equilibrated normalized protein catabolic rate (odds ratio, 2.22; 95% CI, 1.41 to 3.57 per 0.25 g/kg/d; P < 0.001) and non-access-related hospitalization (odds ratio, 1.19; 95% CI, 1.06 to 1.32 per 1 additional hospitalization over 4 months; P = 0.002). Change from a catheter to AV access was predicted by only the antecedent non-access-related hospitalization rate (odds ratio, 0.93; 95% CI, 0.87 to 0.97 per 1 additional hospitalization over 4 months; P < 0.001). CONCLUSION: Change from a catheter to AV access is associated with a substantial decrease in mortality risk.

Cerebrovascular disease in maintenance hemodialysis patients: results of the HEMO Study.

BACKGROUND: Cerebrovascular disease (CBVD) in hemodialysis patients is associated with significant morbidity and mortality. A secondary analysis of CBVD in the Hemodialysis (HEMO) Study was performed. Specific objectives were to: (1) determine risk factors for the presence of CBVD at baseline, (2) assess risk factors for the subsequent occurrence of cerebrovascular deaths, and (3) analyze the effects of dose and flux on cerebrovascular mortality. METHODS: The HEMO Study was a randomized multicenter study evaluating the effects of high-dose versus standard-dose and high-flux versus low-flux hemodialysis. There were 1,846 patients enrolled, with a mean follow-up of 2.84 years. RESULTS: Factors associated with the baseline presence of CBVD included age (P < 0.0001), presence of any cardiac disease (P < 0.0001), and diabetes mellitus (P < 0.0001). There were 65 deaths caused by CBVD (event rate, 1.2/100 patient-years). Multivariate Cox regression using a backward-variables selection procedure showed that diabetes, lower albumin level, greater hematocrit, and lower body mass index at baseline were associated significantly with subsequent CBVD death. There was no effect of flux or dose on overall rate of CBVD deaths. However, an interaction was found between baseline CBVD status and flux intervention on CBVD death (P = 0.016). In the subgroup of patients without the baseline presence of CBVD, high-flux dialysis was associated with a lower risk for death caused by CBVD (P = 0.016). A borderline interaction between years of dialysis therapy and flux on subsequent CBVD death was detected (P = 0.05). The beneficial effect of high flux was evident in those on hemodialysis therapy for longer than 3.7 years (P = 0.012). CONCLUSION: High flux was associated with decreased CBVD mortality in those without known CBVD at baseline and those on hemodialysis therapy for longer than 3.7 years. This secondary analysis strengthens, but does not prove, the hypothesis that high-flux treatment may attenuate the death rate from vascular disease.

Influence of luminal diameters on flow surveillance of hemodialysis grafts: insights from a mathematical model.

Randomized controlled trials have not shown that surveillance of graft blood flow (Q) prolongs graft life. Because luminal diameters affect flow resistance, this study examined whether the influence of diameters on Q can explain the limitations of surveillance. Inflow artery and outflow vein diameters were determined from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model for determination of how they affect the relation between Q and stenosis. Also determined was the correlation between Q (by ultrasound dilution) and diameters, stenosis, and mean arterial pressure in 88 patients. Artery and vein diameters varied widely between patients, but arteries generally were narrower than veins. The model predicts that the relation between Q and stenosis is sigmoid: as stenosis progresses, Q initially remains unchanged but then rapidly decreases. A narrower artery increases flow resistance, causing a longer delay followed by a more rapid reduction in Q. In a multiple regression analysis of data from patients, Q correlated with artery and vein diameters, sum of largest stenoses from each circuit segment, and mean arterial pressure (R = 0.689, P < 0.001). This study helps to explain why Q surveillance predicts thrombosis in some patients but not others. Luminal diameters control the relation between Q and stenosis, and these diameters vary widely. During progressive stenosis, the delay and then rapid reduction in Q may impair recognition of low Q before thrombosis occurs. Surveillance outcomes might be improved by taking frequent measurements so that there is no delay in discovering that Q has decreased.

Design of the Dialysis Access Consortium (DAC) Aggrenox Prevention Of Access Stenosis Trial.

BACKGROUND: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis. RESULTS: This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial.

BACKGROUND: The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. PURPOSE: The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. RESULTS: This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

The spectrum of infection-related morbidity in hospitalized haemodialysis patients.

BACKGROUND: Infection is a common cause of mortality and morbidity in haemodialysis patients. Few prospective studies have examined the clinical consequences of infection-related hospitalizations in haemodialysis patients or the risk factors predictive of clinical outcomes. METHODS: The outcomes of all first infection-related hospitalizations of patients enrolled in the HEMO Study were categorized in terms of mortality, requirement for intensive care unit (ICU) stay and length of hospitalization. In addition, the association of hospitalization outcomes with clinical and laboratory parameters was evaluated. RESULTS: Among the 783 first infection-related hospitalizations, 57.7% had a severe outcome (death, ICU stay or hospitalization >/=7 days). The likelihood of a severe outcome increased with patient age (P<0.0001) and with decreased serum albumin (P<0.001). The frequency of a severe outcome varied greatly by infectious disease category (P<0.001), being highest for cardiac infections (95.6%) and infection of unknown source (68.4%), and lowest for urinary tract infections (35.5%) and access-related infections (43.8%). On multivariate analysis, hospitalization outcome was independently associated with patient age, serum albumin and disease category, but not with the randomized Kt/V or flux, gender, race or diabetic status. CONCLUSION: In summary, infection-related hospitalizations are associated with substantial morbidity. Patient age, serum albumin and infectious disease category are independently correlated with the hospitalization outcome, and can be used to estimate the likelihood of serious outcomes at the time of hospital admission.

Vascular access as a determinant of adequacy of dialysis.

Vascular accesses consist of permanent arteriovenous (AV) accesses (autogenous fistulas and synthetic grafts) and venous accesses (central venous catheters [CVCs]). AV accesses have fewer complications than venous accesses, and are therefore the preferred hemodialysis access. An important additional issue is whether the type of access influences adequacy of dialysis (i.e. Kt/V). Key limiting factors in delivering adequate Kt/V are blood pump speed (Q(B) ), access recirculation, and treatment time. In general, AV accesses support higher Q(B)S with less negative inflow arterial pressures than CVCs. Well-functioning AV accesses are also less likely to exhibit recirculation. Nevertheless, recirculation commonly develops when AV accesses (usually grafts) develop stenosis with decreased access blood flow. Although extension of treatment time can offset the effects of reduced Q(B) and recirculation, this is often impractical and poorly accepted by patients. In conclusion, AV accesses are superior to venous accesses because they are less prone to complications and are more likely to deliver prescribed Kt/V within prescribed treatment time.

Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease.

Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis > or =75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, > or = 90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD.

Impact of dialysis dose and membrane on infection-related hospitalization and death: results of the HEMO Study.

Infection is the second most common cause of death among hemodialysis patients. A predefined secondary aim of the HEMO study was to determine if dialysis dose or flux reduced infection-related deaths or hospitalizations. The effects of dialysis dose, dialysis membrane, and other clinical parameters on infection-related deaths and first infection-related hospitalizations were analyzed using Cox regression analysis. Among the 1846 randomized patients (mean age, 58 yr; 56% female; 63% black; 45% with diabetes), there were 871 deaths, of which 201 (23%) were due to infection. There were 1698 infection-related hospitalizations, yielding a 35% annual rate. The likelihood of infection-related death did not differ between patients randomized to a high or standard dose (relative risk [RR], 0.99 [0.75 to 1.31]) or between patients randomized to high-flux or low-flux membranes (RR, 0.85 [0.64 to 1.13]). The relative risk of infection-related death was associated (P < 0.001 for each variable) with age (RR, 1.47 [1.29 to 1.68] per 10 yr); co-morbidity score (RR, 1.46 [1.21 to 1.76]), and serum albumin (RR, 0.19 [0.09 to 0.41] per g/dl). The first infection-related hospitalization was related to the vascular access in 21% of the cases, and non-access-related in 79%. Catheters were present in 32% of all study patients admitted with access-related infection, even though catheters represented only 7.6% of vascular accesses in the study. In conclusion, infection accounted for almost one fourth of deaths. Infection-related deaths were not reduced by higher dose or by high flux dialyzers. In this prospective study, most infection-related hospitalizations were not attributed to vascular access. However, the frequency of access-related, infection-related hospitalizations was disproportionately higher among patients with catheters compared with grafts or fistulas.

Effect of dialysis dose and membrane flux in maintenance hemodialysis.

BACKGROUND: The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain. METHODS: We undertook a randomized clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. RESULTS: In the standard-dose group, the mean (+/-SD) urea-reduction ratio was 66.3+/-2.5 percent, the single-pool Kt/V was 1.32+/-0.09, and the equilibrated Kt/V was 1.16+/-0.08; in the high-dose group, the values were 75.2+/-2.5 percent, 1.71+/-0.11, and 1.53+/-0.09, respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was 3+/-7 ml per minute in the low-flux group and 34+/-11 ml per minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95 percent confidence interval, 0.84 to 1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95 percent confidence interval, 0.81 to 1.05; P=0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15 percent decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven prespecified subgroups of patients. CONCLUSIONS: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.

Treatment approaches for infected hemodialysis vascular catheters.

PURPOSE OF REVIEW: The focus of the review is to delineate protocols for catheter removal, catheter replacement and duration of therapy when a catheter-related infection occurs, and to demonstrate possible means of preventing such infections. RECENT FINDINGS: The evidence supporting these views will be discussed in the light of our current practice. SUMMARY: Cuffed tunneled hemodialysis catheters have evolved for wide use as both temporary and semi-permanent hemodialysis access. The primary barriers to long-term catheter use are catheter-related infection and catheter dysfunction. Catheter-related infection has emerged as the primary barrier to long-term catheter use. Under both circumstances, however, catheter replacement or some form of intervention is often needed. Because of this, catheters are often removed and replaced, but the duration of therapy and the timing of replacement of these catheters is not completely clear.

Coronary steal from a left internal mammary artery coronary bypass graft by a left upper extremity arteriovenous hemodialysis fistula.

In patients with end-stage renal disease undergoing hemodialysis, the upper extremity arteriovenous (AV) fistula is the dialysis access recommended by the DOQI guidelines for patients with appropriate vasculature. Upper extremity AV fistulae have long periods of usefulness, high flow rates, and low associated complication rates. Placement of AV access may result in increased cardiac output and increased cardiac oxygen demand in these patients. In general, cardiovascular complications from AV access have been limited. We report a novel cardiovascular complication of AV access in an end-stage renal disease patient with a coronary artery bypass graft employing the left internal mammary artery who experienced angina while undergoing hemodialysis. The angina was mediated at least in part by cardiac catheterization laboratory-documented steal of blood flow from the internal mammary artery graft. This phenomenon suggests the need to consider the impact of upper extremity access placement on blood flow to the left internal mammary artery in patients who previously have undergone placement of a coronary artery bypass graft.

Multicenter clinical trial results with the LifeSite hemodialysis access system.

BACKGROUND: The LifeSite Hemodialysis Access System is a subcutaneous access device designed to maximize blood flow while minimizing access-related complications. The purpose of this study was to compare the efficacy and safety of the LifeSite System to a similar but transcutaneous access device, the Tesio-Cath Hemodialysis Catheter. METHODS: The study was conducted in two phases. A multi-center randomized prospective design was utilized for the first phase (Phase 1) where thirty-four patients were enrolled in the Tesio-Cath group and 36 patients into the LifeSite group where 0.2% sodium oxychlorosene was used as an antimicrobial solution for the LifeSite. A nonrandomized, but otherwise identical, second phase of the study followed where a 70% isopropyl alcohol solution was utilized as the antimicrobial solution for 34 additional LifeSite patients (Phase 2). RESULTS: Device function was evaluated in Phase 1 of the trial. Actual blood flow (determined by ultrasound dilution) was greater in the LifeSite versus the Tesio-Cath group (358.7 vs. 331.8 mL/min, P < 0.001 for machine-indicated blood flow of 400 mL/min). Infection comparisons were performed for all three groups encompassing Phase 1 and 2 of the trial; Tesio-Catheter, LifeSite System with oxychlorosene, and LifeSite System with 70% isopropyl alcohol. Device-related infections were defined as systemic bacteremia without another obvious site of origin and exit site infections requiring systemic antibiotics or device removal. This revealed infection rates per 1000 device use days of 1.3 for the LifeSite alcohol group, 3.3 for the Tesio-Cath group, and 3.4 per for the LifeSite oxychlorosene group. There was no statistically significant difference in device related infection rates between the Tesio-Cath and the LifeSite oxychlorosene groups. There were significant differences in infection rate between LifeSite alcohol group and the other two groups (P < 0.05). Device thrombosis was defined by the need for instillation of thrombolytic agents to maintain blood flow>300 mL/min. There was no difference in the need for thrombolytic infusions between the LifeSite oxychlorosene group and the Tesio-Cath group (P = 0.1496); however, the LifeSite alcohol group required significantly fewer thrombolytic infusions than the Tesio-Cath group (P = 0.0295) to maintain adequate blood flow. Device survival at 6 months after stratification by diabetic status and adjusting for age was significantly better in the LifeSite alcohol group (89.9%) than in the LifeSite oxychlorosene group (64.8%, P = 0.0286) and in the Tesio-Cath (69.1%, P = 0.0292) group. CONCLUSIONS: The LifeSite Hemodialysis Access System, when used with 70% isopropyl alcohol as an antimicrobial solution, provides superior performance with a lower infection rate and better device survival than a standard cuffed tunneled hemodialysis catheter.